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Li J, Feng X, Wang M, Liu H, Yang M, Pang J, Zou M, Xiao Y, Zhang X, Hu H, Zhou Y, Alqusseireen YM, Yan W, Zhou X, Li W. Demographic characteristics and disease severity associated with IgA/IgG deposition patterns in autoimmune bullous diseases: a cohort study based on a registry database. Front Immunol 2025; 16:1565073. [PMID: 40491920 PMCID: PMC12146370 DOI: 10.3389/fimmu.2025.1565073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/28/2025] [Indexed: 06/11/2025] Open
Abstract
Background Direct immunofluorescence (DIF) microscopy is the gold standard for diagnosing autoimmune bullous diseases (AIBDs), but the clinical significance of IgA and IgG co-deposition was unclear. Objective Investigate the demographic differences and disease severity among different IgG/IgA deposition patterns in DIF. Methods We conducted a retrospective cohort study based on a registry database that analyzed demographic data, involvement sites, and immunofluorescence patterns of patients with DIF biopsy. Patients were categorized into intercellular (group A) and basement membrane zone (group B) deposition patterns. Logistic regression models assessed associations between deposition status and demographic characteristics. Disease severity and prognosis were analyzed retrospectively through subgroup analyses. Results In group A, female gender (OR = 1.665, P = 0.011) and stronger IgG deposition (OR = 3.881, P < 0.001) were associated with IgA and IgG co-deposition. In group B, female gender (OR = 1.382, P = 0.002), stronger IgG deposition (OR = 2.673, P < 0.001), and mucosa tissue (OR = 3.052, P < 0.001) were associated with IgA and IgG co-deposition. IgA and IgG co-deposition in group A was associated with higher Pemphigus Disease Area Index scores (P = 0.036), while in group B, it correlated with mucosal involvement (P = 0.007). No differences in the proportion of disease severity scores improvement after 6 months of standard treatment were found in both groups. Conclusions Female gender, stronger IgG deposition, and mucosa tissue are key factors affecting IgA and IgG co-deposition in AIBD patients. For clinical correlation, patients with IgA and IgG co-deposition in pemphigus exhibit more severe disease severity compared with those with IgG deposition only, while patients with co-deposition in pemphigoid are more prone to mucosal involvement.
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Affiliation(s)
- Jishu Li
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Xun Feng
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Mi Wang
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hongjie Liu
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mei Yang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Jiyun Pang
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Min Zou
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yue Xiao
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiwen Zhang
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hongxiang Hu
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuxi Zhou
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yazan Moufaq Alqusseireen
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Yan
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xingli Zhou
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Li
- Department of Dermatology and Venereology and Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
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Alimohammadi M, Kahkesh S, Abbasi A, Hashemi M, Khoshnazar SM, Taheriazam A, Hushmandi K. LncRNAs and IgA nephropathy: underlying molecular pathways and clinical applications. Clin Exp Med 2025; 25:140. [PMID: 40328979 PMCID: PMC12055897 DOI: 10.1007/s10238-025-01660-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Accepted: 04/01/2025] [Indexed: 05/08/2025]
Abstract
IgA nephropathy (IgAN), also known as Berger's disease, is a prevalent kidney disorder caused by the accumulation of IgA antibodies in the glomerular tissue. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs longer than 200 nucleotides, play crucial roles in regulating various cellular and molecular processes, including translation, chromatin remodeling, and transcriptional efficiency. Research has highlighted the significant impact of lncRNA imbalances on the development and progression of kidney diseases, including IgAN. These molecules influence several key signaling pathways, such as PI3K/AKT/mTOR, PTEN, Notch, JNK, and immune-related pathways, with their dysregulation contributing to IgAN pathogenesis. This review aims to provide a comprehensive analysis of the molecular signaling pathways involving lncRNAs in IgAN, underscoring their potential as biomarkers for screening, diagnosis, and prevention. Furthermore, it explores the therapeutic potential of lncRNAs as precise targets for personalized treatment strategies.
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Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amirhosein Abbasi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Seyedeh Mahdieh Khoshnazar
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Pereira IM, Pereira M, Lopes JA, Gameiro J. The gut microbiome as a potential therapeutic target in IgA nephropathy. Nephrol Dial Transplant 2025; 40:641-650. [PMID: 39663206 DOI: 10.1093/ndt/gfae274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Indexed: 12/13/2024] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and a leading cause of kidney failure, with limited treatment options available. The pathophysiology of IgAN remains unclear; however, recent studies suggest that genetic, epigenetic and environmental factors play significant roles. There is also strong evidence linking the gut microbiome to the development of IgAN. In this review, we will examine the relationship between the microbiome and the pathogenesis of IgAN, as well as its potential as a target for future therapeutic interventions.
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Affiliation(s)
- Inês Miguel Pereira
- Clínica Universitária de Nefrologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
| | - Marta Pereira
- Serviço de Nefrologia e Transplantação Renal, ULS Santa Maria, Lisboa, Portugal
| | - José António Lopes
- Clínica Universitária de Nefrologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Serviço de Nefrologia e Transplantação Renal, ULS Santa Maria, Lisboa, Portugal
| | - Joana Gameiro
- Clínica Universitária de Nefrologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Serviço de Nefrologia e Transplantação Renal, ULS Santa Maria, Lisboa, Portugal
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Jash R, Maji HS, Chowdhury A, Maparu K, Seksaria S, Gupta P, Paria A, Nandi A, Das A, Chattaraj B, Prasanth DNK. Oxymatrine ameliorates epithelial mesenchymal transition in IgA nephropathy induced rats. Tissue Cell 2025; 93:102671. [PMID: 39705868 DOI: 10.1016/j.tice.2024.102671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 12/04/2024] [Accepted: 12/06/2024] [Indexed: 12/23/2024]
Abstract
In this study, we investigated the efficacy of oxymatrine, a phytochemical alkaloid, in reducing inflammation and fibrosis in a rat model of IgA nephropathy (IgAN) through modulation of the TGF-β/SMAD signaling pathway. Thirty Sprague Dawley rats were randomized into control, IgAN, and treatment groups, the latter receiving oxymatrine postinduction of IgAN. Induced by bovine serum albumin, carbon tetrachloride, and lipopolysaccharides, the disease model was validated by immunofluorescence and histopathological analyses, confirming significant renal deposition of IgA and increased fibrosis markers (IL-6, TGF-β, SMAD 3, and α-SMA). Oxymatrine treatment led to a notable decrease in urine protein levels and red blood cells at 10 weeks, suggesting reduced kidney damage. There was no significant impact on the SGOT or SGPT levels, while it reduced the BUN, serum ALB and creatinine levels, indicating minimal hepatotoxicity and renoprotective effects. Histopathology demonstrated preservation of the glomerular diameter in the treatment group. Immunofluorescence and ELISA revealed a reduction in the levels of proinflammatory (IL-6,TNF-α) and profibrotic (TGF-β, SMAD 3, and α-SMA) markers in treated rats, suggesting that oxymatrine has renoprotective effects on the inhibition of pathological EMT processes and fibrosis in IgAN. Our results suggest that oxymatrine is a potential therapeutic agent for IgAN that attenuates disease progression by targeting the TGF-β/SMAD pathways involved in EMT and fibrosis. Further research is warranted to establish long-term efficacy and safety profiles.
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Affiliation(s)
- Rajiv Jash
- Department of Pharmaceutical Sciences, JIS University, Kolkata 700109, India; Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India.
| | | | - Arnab Chowdhury
- Department of Pathology, Shri Ramkrishna Institute of Medical Sciences and Sanaka Hospital, Malandighi, Durgapur, West Bengal 713212, India
| | - Kousik Maparu
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Sanket Seksaria
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Priyanka Gupta
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Arghya Paria
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Arijit Nandi
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Anwesha Das
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Bornika Chattaraj
- Department of Pharmacy, Sanaka Educational Trust's Group of Institutions, Malandighi, Durgapur, West Bengal 713212, India
| | - Ds Nb K Prasanth
- School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS), Polepally SEZ, TSIIC, Jadcherla, Mahbubnagar, Hyderabad 509301, India
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Tian C, Yan M, Guo J, Zhou Y, Du B, Cheng G. Yeast Cell Wall-Mediated Ileal Targeted Delivery System for IgA Nepharopathy Therapy. ACS Biomater Sci Eng 2025; 11:1498-1509. [PMID: 39957538 DOI: 10.1021/acsbiomaterials.4c01941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2025]
Abstract
IgA nephropathy (IgAN) is a primary glomerulonephritis mediated by autoimmunity, characterized by an abnormal increase and the deposition of IgA in the glomeruli. In recent years, most studies have emphasized the crucial role of the gut-kidney axis in the pathogenesis of IgA nephropathy, and the ileal Peyer patches in the intestinal mucosal immune system are the main site for IgA production. Therefore, in this study, hydroxychloroquine (HCQ) and dexamethasone (DXM) were used as model drugs, and yeast cell wall (YCW)-coated oleic acid-grafted chitosan (CSO) was used as a carrier to construct a yeast cell wall oral drug delivery system HCQ/DXM@CSO@YCW. This delivery system achieves ileal targeted delivery through the yeast cell wall (YCW), reduces IgA production, and synergistically regulates the inflammatory pathological environment. The delivery system had good gastrointestinal stability and biocompatibility. In vitro cell experiments had shown the targeted uptake ability of dendritic cells and macrophages, and in vitro intestinal experiments showed that the YCW has ileal targeting properties. In vivo pharmacodynamic experiments showed that the HCQ/DXM@CSO@YCW delivery system could significantly reduce the serum IgA levels and IgA deposition in the renal tissue of IgAN mice, as well as the levels of IL-6, TNF-α, and TGF-β in the renal tissue, improving the pathological morphology of the renal tissue. Therefore, the DXM/HCQ@CSO@YCW oral administration system provided a new intestinal targeted delivery platform for intestinal mucosal immunotherapy in IgA nephropathy.
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Affiliation(s)
- Chaoying Tian
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, Henan 450001, China
| | - Mei Yan
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, Henan 450001, China
| | - Jialing Guo
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, Henan 450001, China
| | - Yingying Zhou
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, Henan 450001, China
| | - Bin Du
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou, Henan 450001, China
- Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou, Henan 450001, China
| | - Genyang Cheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
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Fan D, Jiao S, Fu Y, Zhang J, Zhuang Y, Huang J, Bi Y, Zhang J, Zhang N. Bacillus pumilus 315 improves intestinal microbiota and barrier function to alleviate diarrhea of neonatal goats. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2025; 20:366-375. [PMID: 40034463 PMCID: PMC11872662 DOI: 10.1016/j.aninu.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/06/2024] [Accepted: 10/29/2024] [Indexed: 03/05/2025]
Abstract
Diarrhea is the leading cause of mortality in postnatal goat kids, seriously impacting breeding efficiency. This study aimed to explore the effects of Bacillus pumilus 315 (B. pumilus) on goat kids' diarrhea and its regulatory mechanism. Thirty-six 1-day-old goat kids were assigned into four treatments, the control (CON) group and low-, medium- and high-dose groups supplemented with B. pumilus at 1 × 108 (BP1), 5 × 108 (BP5), and 1 × 109 CFU/d (BP10). Each group consisted of 9 replicates with 1 goat kid per replicate. The results showed that the incidence of diarrhea and fecal scores decreased significantly (P < 0.05). A dose of 5 × 108 CFU/d B. pumilus reduced pro-inflammatory factors (including tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], interleukin-6 [IL-6], P < 0.05), increased the expression levels of anti-inflammatory factors (including transforming growth factor-β [TGF-β], peroxisome proliferate-activated receptor-gamma [PPAR-γ], interleukin-10 [IL-10], P < 0.05), immune indicators (including immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M [IgM], secretory immunoglobulin A [sIgA], P < 0.05) and antioxidant indicators (including total antoxidative capacity [T-AOC], superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT], P < 0.05) in both jejunum and colon, and ultimately improved the barrier function of the jejunum and colon mucosa. The enhanced gut immunity and barrier function were associated with increased abundance of Enterococcus and Lactobacillus (P < 0.05) and decreased abundance of Campylobacter and Escherichia-Shigella (P < 0.05). In conclusion, dietary addition of B. pumilus may improve gut health by modulating the composition and function of the flora, ultimately alleviating diarrhea in goat kids.
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Affiliation(s)
- Dingkun Fan
- Key Laboratory of Feed Biotechnology, The Ministry of Agriculture and Rural Affairs, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Shuai Jiao
- Key Laboratory of Feed Biotechnology, The Ministry of Agriculture and Rural Affairs, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing 100081, China
- College of Animal Science, Shanxi Agricultural University, Taigu 030801, China
| | - Yuze Fu
- Key Laboratory of Feed Biotechnology, The Ministry of Agriculture and Rural Affairs, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Jixian Zhang
- Key Laboratory of Feed Biotechnology, The Ministry of Agriculture and Rural Affairs, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Yimin Zhuang
- Key Laboratory of Feed Biotechnology, The Ministry of Agriculture and Rural Affairs, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Juan Huang
- Key Laboratory of Feed Biotechnology, The Ministry of Agriculture and Rural Affairs, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Yanliang Bi
- Key Laboratory of Feed Biotechnology, The Ministry of Agriculture and Rural Affairs, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Jianxin Zhang
- College of Animal Science, Shanxi Agricultural University, Taigu 030801, China
| | - Naifeng Zhang
- Key Laboratory of Feed Biotechnology, The Ministry of Agriculture and Rural Affairs, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing 100081, China
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Przybyciński J, Czerewaty M, Kwiatkowska E, Dziedziejko V, Safranow K, Domański L, Pawlik A. MicroRNAs miR-148a-3p, miR-425-3p, and miR-20a-5p in Patients with IgA Nephropathy. Genes (Basel) 2025; 16:125. [PMID: 40004454 PMCID: PMC11854660 DOI: 10.3390/genes16020125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/15/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES IgA nephropathy (IgAN) is one of the most common forms of glomerulonephritis leading to renal failure. MicroRNAs have been shown to play an important role in the pathogenesis and clinical course of IgA nephropathy; therefore, they offer the possibility of noninvasive diagnosis of this disease and have some value in predicting disease prognosis. This study aimed to evaluate the plasma levels of miR-148a-3p, miR-425-3p, and miR-20a-5p in patients with IgA nephropathy and their correlation with selected clinical parameters. METHODS This study included 44 patients with IgA nephropathy and 46 control subjects. RESULTS The results of our study indicated that in patients with IgA nephropathy, the increased plasma levels of miR-148a-3p and miR-425-3p correlated negatively with eGFR values. According to the Haas classification, plasma levels of miR-20a-5p were statistically significantly increased in patients with histopathological changes classified as Stages 3, 4, and 5 compared with patients with histopathological changes classified as Stages 1 and 2. CONCLUSIONS The results of our study suggest the possible involvement of miR-148a-3p, miR-425-3p, and miR-20a-5p in the pathogenesis of IgA nephropathy.
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Affiliation(s)
- Jarosław Przybyciński
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.P.); (E.K.); (L.D.)
| | - Michał Czerewaty
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Ewa Kwiatkowska
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.P.); (E.K.); (L.D.)
| | - Violetta Dziedziejko
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (V.D.); (K.S.)
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (V.D.); (K.S.)
| | - Leszek Domański
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.P.); (E.K.); (L.D.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland;
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Li R, Wang M, Li J, Zhu L, Xie X, Wang H, Zhang X, Tian W, Zhang Y, Dong Y, Zan J, Li H, Zhang Y, Zhou X, Shi S, Shu C, Liu L, Jin J, Lv J, Zhang H. Lactobacillus casei Cell Wall Extract and Production of Galactose-Deficient IgA1 in a Humanized IGHA1 Mouse Model. J Am Soc Nephrol 2025; 36:60-72. [PMID: 39172518 PMCID: PMC11706567 DOI: 10.1681/asn.0000000000000465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 08/16/2024] [Indexed: 08/24/2024] Open
Abstract
Key Points We generated a transgenic mouse model expressing the human IgA1 heavy chain, which has a hinge region with rich O -linked glycosylation. After inflammatory stimulation, the mouse model showed elevated galactose-deficient IgA1 levels in the serum. Coupled with complement H factor mutant, the mice model exhibited glomerular lesions, associated with hematuria and albuminuria like IgA nephropathy. Background IgA nephropathy is the most common primary glomerulonephritis worldwide, and there is emerging evidence linking galactose-deficient IgA1 (Gd-IgA1) to the pathogenesis of the disease. However, mouse models that can be used to study Gd-IgA1's origin of production, biochemical characteristics, and immune reactivity are lacking. Methods We generated a humanized IgA1 mouse model with transgenic expression of the human IGHA1 gene from the mouse chromosomal locus of IgA heavy chain. The IGHA1 +/+ mice were crossed with complement factor H heterozygous mutant (FHW/R) to generate IGHA1 +/+FHW/R mice. IGHA1 +/+ mice were exposed to different levels of environmental pathogens in the first 4 months, as housed in germ-free, specific pathogen–free, or conventional environments. In addition, wild-type C57BL/6J mice, IGHA1 +/+ mice, and IGHA1 +/+FHW/R mice were inoculated with Lactobacillus casei cell wall extract (LCWE) mixed with complete Freund's adjuvant (CFA) at 2 months of age to develop a mouse model of IgA nephropathy. Results Elevated levels of human IgA1 in blood circulation and mucosal sites were observed in IGHA1 +/+ mice from exposure to pathogens. Compared with buffer-treated control mice, LCWE plus CFA-treated mice had moderately elevated levels of circulating human IgA1 (by one-fold) and human IgA1 immune complexes (by two-fold). Serum Gd-IgA1 levels increased four-fold after LCWE treatments. Analyses of the O -glycopeptides of the IgA1 hinge region confirmed hypogalactosylation of IgA1, with the variety of the glycoforms matching those seen in clinical samples. Furthermore, LCWE induced persistent IgA1 and C3 deposition in the glomerular mesangial areas in association with mesangial expansion and hypercellularity, which are frequently observed in IgA nephropathy biopsies. The IGHA1+/+FHW/R mice stimulated with LCWE and CFA developed albuminuria and hematuria. Conclusions We observed elevated plasma Gd-IgA1 levels with kidney deposition of IgA1 in the IGHA1 +/+ mice after LCWE and CFA. In conjunction with factor H mutation, the mice exhibited severe glomerular alterations, associated with hematuria and albuminuria in resemblance of clinical IgA nephropathy.
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Affiliation(s)
- Run Li
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Manliu Wang
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Jingyi Li
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Li Zhu
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediate Kidney Disease, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Xinfang Xie
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hui Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
| | - Xu Zhang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
| | - Wenmin Tian
- Department of Biochemistry and Biophysics, Center for Precision Medicine Multi-Omics Research, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yong Zhang
- Department of Nephrology, Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu, China
| | - Yaping Dong
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Jincan Zan
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Hongyu Li
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Yuemiao Zhang
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediate Kidney Disease, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Xujie Zhou
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediate Kidney Disease, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Sufang Shi
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediate Kidney Disease, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Chutian Shu
- Shanghai Alezyme Pharmaceuticals Ltd., Shanghai, China
| | - Lijun Liu
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediate Kidney Disease, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Jing Jin
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Jicheng Lv
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediate Kidney Disease, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Hong Zhang
- Renal Division, Key Laboratory of Renal Disease, Ministry of Health of China, Peking University Institute of Nephrology, Peking University First Hospital, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediate Kidney Disease, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
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9
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Wang X, Zhou XJ, Qiao X, Falchi M, Liu J, Zhang H. The evolving understanding of systemic mechanisms in organ-specific IgA nephropathy: a focus on gut-kidney crosstalk. Theranostics 2025; 15:656-681. [PMID: 39744688 PMCID: PMC11671385 DOI: 10.7150/thno.104631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 11/18/2024] [Indexed: 01/11/2025] Open
Abstract
The interplay between multiple organs, known as inter-organ crosstalk, represents a complex and essential research domain in understanding the mechanisms and therapies for kidney diseases. The kidneys not only interact pathologically with many other organs but also communicate with other systems through various signaling pathways. It is of paramount importance to comprehend these mechanisms for the development of more efficient therapeutic strategies. Despite extensive research in IgA nephropathy (IgAN), the most common kidney disease, the elaboration mechanism of IgAN remains challenging. Numerous studies suggest that alterations in the intestinal microbiome and its metabolites are pivotal in the progression of IgAN, opening new avenues for understanding its mechanisms. Interestingly, certain presumed probiotics, such as Akkermansia muciniphila, have been implicated in the onset of IgAN, making the exploration of gut microbiota in the context of IgAN pathogenesis even more intriguing. In this review, we summarize the status of gut microbiology studies of IgAN and explore the possible mechanisms and intervention prospects. Future research and treatment directions may increasingly emphasize systemic, multi-organ combined interventions to decelerate the advancement of kidney disease and enhance the overall prognosis of patients.
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Affiliation(s)
- Xin Wang
- Renal Division, Peking University First Hospital, Beijing, China
- Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Xu-Jie Zhou
- Renal Division, Peking University First Hospital, Beijing, China
- Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Xue Qiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Mario Falchi
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Jing Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, University of Chinese Academy of Science, Beijing, 100190, China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Beijing, China
- Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
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10
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Cheung CK, Alexander S, Reich HN, Selvaskandan H, Zhang H, Barratt J. The pathogenesis of IgA nephropathy and implications for treatment. Nat Rev Nephrol 2025; 21:9-23. [PMID: 39232245 PMCID: PMC7616674 DOI: 10.1038/s41581-024-00885-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2024] [Indexed: 09/06/2024]
Abstract
IgA nephropathy (IgAN) is a common form of primary glomerulonephritis and represents an important cause of chronic kidney disease globally, with observational studies indicating that most patients are at risk of developing kidney failure within their lifetime. Several research advances have provided insights into the underlying disease pathogenesis, framed by a multi-hit model whereby an increase in circulating IgA1 that lacks galactose from its hinge region - probably derived from the mucosal immune system - is followed by binding of specific IgG and IgA antibodies, generating immune complexes that deposit within the glomeruli, which triggers inflammation, complement activation and kidney damage. Although treatment options are currently limited, new therapies are rapidly emerging that target different pathways, cells and mediators involved in the disease pathogenesis, including B cell priming in the gut mucosa, the cytokines APRIL and BAFF, plasma cells, complement activation and endothelin pathway activation. As more treatments become available, there is a realistic possibility of transforming the long-term outlook for many individuals with IgAN.
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Affiliation(s)
- Chee Kay Cheung
- Mayer IgA Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK.
| | | | - Heather N Reich
- Department of Medicine, Division of Nephrology, University of Toronto, University Health Network, Toronto, ON, Canada
| | - Haresh Selvaskandan
- Mayer IgA Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, P. R. China
| | - Jonathan Barratt
- Mayer IgA Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK.
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11
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Li X, Li C, Wu P, Zhang L, Zhou P, Ma X. Recent status and trends of innate immunity and the gut-kidney aixs in IgAN: A systematic review and bibliometric analysis. Int Immunopharmacol 2024; 143:113335. [PMID: 39423662 DOI: 10.1016/j.intimp.2024.113335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 09/24/2024] [Accepted: 10/04/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND There is a significant global demand for precise diagnosis and effective treatment of IgA nephropathy (IgAN), with innate immunity, particularly the complement system, exerting a profound influence on its pathogenesis. Additionally, the gut-kidney axis pathway is vital in the emergence and development of IgAN. METHODS We conducted a comprehensive search in the Web of Science database, spanning from January 1, 2000 to December 18, 2023. The gathered literature underwent a visual examination through CiteSpace, VOSviewer, and Scimago Graphica to delve into authors, nations, organizations, key terms, and other pertinent elements. RESULT Between 2000 and 2023, a total of 720 publications were identified, out of which 436 publications underwent screening for highly relevant literature analysis. The average annual number of articles focusing on IgAN, innate immunity, and the gut-kidney axis is approximately 31, with an upward trend observed. In terms of research impact encompassing publication count and authorship, the United States emerged as the leading contributor. Prominent keywords included "complement", "activation", "microbe", "gut-kidney axis", "C4d deposition", "alternative pathway" and "B cells" along with other prospective hot topics. CONCLUSION The correlation between IgAN and innate immunity is a focal point in current scientific research. Recent literature underscores the significance of the gut-kidney axis, where intestinal microorganisms and metabolites may influence IgAN. The complement system, a key component of innate immunity, also has a crucial function.Advancements in prevention, diagnosis, and treatment hinge on unraveling this intricate relationship.
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Affiliation(s)
- Xun Li
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, China; Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Chengni Li
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, China; Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Peiwen Wu
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, China; Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Lifang Zhang
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, China; Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Ping Zhou
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, China; Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
| | - Xin Ma
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, China; Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
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12
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Zhang H, Li S, Deng Z, Wang Y. Molecular Differences in Glomerular Compartment to Distinguish Immunoglobulin A Nephropathy and Lupus Nephritis. J Inflamm Res 2024; 17:11357-11373. [PMID: 39722731 PMCID: PMC11669337 DOI: 10.2147/jir.s496138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 12/14/2024] [Indexed: 12/28/2024] Open
Abstract
Background Immunoglobulin A nephropathy (IgAN) and lupus nephritis (LN) are the most prevalent primary and secondary glomerular diseases, respectively, with several similarities in clinical presentations. Common pathogenic mechanisms in IgAN and LN have been well investigated by previous studies. However, the manifestation mechanism of these two independent diseases carrying distinct immunofluorescent pathological features is still unknown considering the similarities between them. Therefore, differences in pathogenic mechanisms between IgAN and LN were compared in this study. Methods R packages were used for processing the glomerular gene expression datasets acquired from the Gene Expression Omnibus (GEO) database. Least Absolute Selection and Shrinkage Operator (LASSO) and multivariate logistic regression analysis were used to construct models predicting IgAN and LN. Cibersort was used to process the immune cell infiltration analysis. Immunochemistry was used to validate the findings by bioinformatics analysis. Results In the predicting models based on differentially expressed genes (DEG) and weighted correlation network analysis (WGCNA), retinoic acid receptor γ (RARG) and prolactin releasing hormone (PRLH) were independent risk factors for IgAN, and HECT domain and RCC1-like domain-containing protein 5 (HERC5) and interferon stimulated exonuclease gene 20 (ISG20) were independent risk factors for LN. Gene Ontology (GO) analysis revealed that DEGs mostly correlated to IgAN were enriched in ligand-receptor activity-induced cellular growth and development, while DEGs mostly correlated to LN were enriched in nucleic acid/nucleotide binding-induced type I interferon-related activity and response to virus infection. Immune infiltration analysis showed CD4+ T-cells and M2 macrophage abundance in the glomerular compartment in IgAN and LN, respectively. Immunochemistry validated the predicting models for IgAN and LN and revealed different expression patterns of RARG, PRLH, HERC5, and ISG20. Conclusion We investigated key differences in the pathogenesis between IgAN and LN and provided validated predicting models to distinguish IgAN and LN. RARG and PRLH, HERC5 and ISG20 might play an essential role in the formation of IgAN and LN, respectively.
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Affiliation(s)
- Haidong Zhang
- Department of Nephrology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China
| | - Sicong Li
- School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China
| | - Zhenling Deng
- Department of Nephrology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China
| | - Yue Wang
- Department of Nephrology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China
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13
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Yu S, Zhang R, Lin Y, Lei K, Zhang J, Chang H. Blood soluble CD89-IgA complex may be a potential biomarker for predicting multi-organ involvement, especially renal involvement in children with immunoglobulin A vasculitis. Int Immunopharmacol 2024; 142:113063. [PMID: 39241523 DOI: 10.1016/j.intimp.2024.113063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 06/29/2024] [Accepted: 08/30/2024] [Indexed: 09/09/2024]
Abstract
BACKGROUND Immunoglobulin A vasculitis (IgAV) is a kind of systemic vasculitis mediated by IgA immune complexes (IgA-ICs). Soluble CD89-IgA complex (sCD89-IgA) as a type of IgA-IC associated with renal involvement in IgAV, the ability of blood sCD89-IgA as a biomarker to predict renal or multi-organ involvement in children with IgAV is not evident, and this study mainly focused on this. METHODS The clinical characteristics and blood samples of 57 pediatric patients with IgAV were collected. ELISA was used to detect plasma IgA-ICs and sCD89-IgA levels. Serum IgA levels were detected by Nephelometry method. Statistical analysis was conducted to analyze the relationship between sex, age, serum IgA levels, plasma IgA-ICs levels, plasma sCD89-IgA levels and the involvement of multiple organs (except skin) including kidneys in these patients. RESULTS Compared to patients with simple skin involvement, patients with multi-organ involvement, especially kidneys, had higher levels of plasma IgA-ICs and sCD89-IgA, and the statistical difference was significant. In addition, a high level of plasma sCD89-IgA was a high-risk factor for patients to develop multi-organ or renal involvement in addition to the skin. ROC curve analysis showed that the AUC was 0.861 (Sensitivity: 83 %, Specificity: 88 %, p < 0.0001) when plasma sCD89-IgA predicted multi-organ involvement, and AUC 0.926 (Sensitivity: 94 %, Specificity: 88 %, p < 0.0001) for predicting renal involvement. CONCLUSIONS The results suggested that plasma sCD89-IgA may be a potential biomarker for predicting multi-organ involvement (in addition to skin), especially renal involvement in IgAV pediatric patients.
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Affiliation(s)
- Shufeng Yu
- Pediatrics Department, the Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China
| | - Ranran Zhang
- Pediatrics Department, the Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China
| | - Yi Lin
- Pediatrics Department, the Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China
| | - Ke Lei
- Qingdao University, Qingdao, Shandong 266000, China
| | - Juan Zhang
- Pediatrics Department, the Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China
| | - Hong Chang
- Pediatrics Department, the Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China.
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14
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Xu L, Dong H, Xue D, Zhang Y, Li X. Delayed diagnosis of angioimmunoblast T-cell lymphoma presenting with immunoglobulin a vasculitis. Ren Fail 2024; 46:2416935. [PMID: 39465652 PMCID: PMC11520118 DOI: 10.1080/0886022x.2024.2416935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 09/26/2024] [Accepted: 10/10/2024] [Indexed: 10/29/2024] Open
Abstract
Although vasculitis and renal involvement might be associated with malignancy, they are rarely associated with lymphoproliferative diseases. We observed a case of immunoglobulin A vasculitis associated with segmental and focal glomerulonephritis in a patient with Angioimmunoblastic T-cell lymphoma. The most interesting aspect of this case is that this patient's main initial manifestations were skin rash and fever. No significant lymph node enlargement was found at the time. Routine urine examination found positive urine protein, and renal puncture biopsy indicated purpura nephritis. More than one year later, the patient was admitted to the Department of Hematology of our hospital again after finding a mass in the neck. After that, the patient was diagnosed with Angioimmunoblastic T-cell lymphoma by lymph node biopsy. To our great surprise, successful treatment of the underlying malignancy was associated with the remission of glomerulonephritis and cutaneous vasculitis.
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Affiliation(s)
- Lu Xu
- Department of Hemopurification, Affiliated Hospital of Jining Medical College, Jining, China
| | - Huihui Dong
- Department of Nephrology, Yanzhou District People’s Hospital, Jining City, China
| | - Dandan Xue
- Department of Nephrology, Affiliated Hospital of Jining Medical College, Jining, China
| | - Yiming Zhang
- Department of Nephrology, Affiliated Hospital of Jining Medical College, Jining, China
| | - Xinjian Li
- Department of Nephrology, Affiliated Hospital of Jining Medical College, Jining, China
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15
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Zhai Y, Sun S, Zhang W, Tian H. The prognostic value of the systemic immune inflammation index in patients with IgA nephropathy. Ren Fail 2024; 46:2381613. [PMID: 39039867 PMCID: PMC11268256 DOI: 10.1080/0886022x.2024.2381613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/13/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND Immune and inflammatory factors are considered the basic underlying mechanisms of IgA nephropathy (IgAN). The systemic immune inflammation index (SII) is a new inflammatory biomarker and has been identified as a prognostic indicator for various diseases. However, limited studies have been conducted on the prognostic value of the SII in patients with IgAN, and we aimed to address this gap. METHODS A total of 374 patients with IgAN confirmed by renal biopsy performed from 1 January 2015 to 1 April 2019, were retrospectively included. The follow-up period of all patients was at least 12 months after diagnosis, and the endpoint was defined as end-stage kidney disease (ESKD). Patients were further divided into a high-risk group (SII ≥ 456.21) and a low-risk group (SII < 456.21) based on the optimal cutoff value of the SII determined by receiver operating characteristic (ROC) curve analysis. Baseline clinicopathological parameters were compared between the groups, and Cox proportional hazards analyses and Kaplan-Meier analysis were performed to assess renal survival in IgAN patients. RESULTS After a median follow-up period of 32.5 months, a total of 53 patients eventually reached ESKD. Patients in the high-SII group tended to have a lower hemoglobin level (p = 0.032) and eGFR (p < 0.001), a higher serum creatinine level (p = 0.023) and 24-hour total protein level (p = 0.004), more severe tubular atrophy and interstitial fibrosis (p = 0.002) and more crescents (p = 0.030) than did those in the low-SII group. Univariate and multivariate Cox regression analyses demonstrated that an SII ≥456.21 was an independent risk factor for poor renal survival in IgAN patients (HR 3.028; 95% CI 1.486-6.170; p = 0.002). Kaplan-Meier analysis revealed that a high SII was significantly associated with poor renal prognosis (p < 0.001) and consistently exhibited remarkable discriminatory ability across different subgroups in terms of renal survival. CONCLUSION A high SII was associated with more severe baseline clinical and pathological features, and an SII ≥456.21 was an independent risk factor for progression to ESKD in IgAN patients.
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Affiliation(s)
- Yaling Zhai
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- The Renal Research Institution of Zhengzhou University, Zhengzhou, China
| | - Shuaigang Sun
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- The Renal Research Institution of Zhengzhou University, Zhengzhou, China
| | - Wenhui Zhang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- The Renal Research Institution of Zhengzhou University, Zhengzhou, China
| | - Huijuan Tian
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- The Renal Research Institution of Zhengzhou University, Zhengzhou, China
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16
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Chen Y, Huang M, You Z, Sa R, Zhao L, Ku C, Wang W, Duan X. Unveiling the genetic link and pathogenesis between psoriasis and IgA nephropathy based on Mendelian randomization and transcriptome data analyses. Arch Dermatol Res 2024; 316:717. [PMID: 39460798 DOI: 10.1007/s00403-024-03465-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 10/07/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024]
Abstract
It has been reported that many people with psoriasis have been diagnosed with secondary IgA nephropathy (IgAN). However, the mechanisms behind the association between psoriasis and IgAN have not been well clarified. The connection between psoriasis and IgAN deserves deeper exploration. Mendelian randomization (MR) analysis would be employed to explore the link of causality between IgAN and psoriasis, psoriasis vulgaris, other and unspecified psoriasis, guttate psoriasis, and arthropathic psoriasis. Transcriptomic analyses were carried out against the Gene Expression Omnibus databases. We identified crosstalk genes through the analysis of Differentially expressed genes and weight gene co-expression network analysis. Functional annotations were enriched for these crosstalk genes. Subsequently, we established a protein-protein interaction network, and candidate genes would be discovered through the utilization of the MCODE and CytoHubba plug-in applications. Lastly, the predictive efficacy of these genes was examined via creating receiver operating characteristic curves. The MR analysis suggested that psoriasis vulgaris patients were at a higher risk for IgAN. [OR = 1.040, 95%CI (1.005,1.076), p = 0.026 < 0.05]. Additionally, arthropathic psoriasis may augment the incidence of IgAN [OR = 1.081, 95%CI (1.040-1.124), p < 0.01] in the European population. Through the analysis of DEGs and WGCNA, we identified 12 significant genes (NETO2, RRM2, SLAMF7, GBP1, KIF20A, CCL4, MMP1, IL1β, NDC80, CXCL9, C15orf48, GSTA3), which may be potential crosstalk genes between the two diseases. Then, the functional annotation results indicated that the crosstalk genes seemed primarily involved in immune and inflammatory responses. By establishing the PPI network, we further discovered that CXCL9, IL1β, CCL4, and MMP1 play a vital part in psoriasis and IgAN, and all have good diagnostic values. Our MR analysis provided evidence that genetic vulnerability to IgAN may be associated with an elevated risk of psoriasis vulgaris and arthropathic psoriasis respectively among Europeans. Doctors should be aware of these associations when patients with psoriasis present with renal dysfunction, especially those with psoriasis vulgaris and arthropathic psoriasis. Chronic inflammation, drug effects, and immunity may contribute to the generation and development of both diseases. IL1β, CXCL9, CCL4, and MMP1 may be core biomarkers for psoriasis and IgAN.
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Affiliation(s)
- Yingwen Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Min Huang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ziqing You
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Rule Sa
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Lu Zhao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Congwen Ku
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Wenying Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Xingwu Duan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
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17
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Suzuki Y. B cell targeting in IgA nephropathy. Nephrology (Carlton) 2024; 29 Suppl 2:39-43. [PMID: 39327767 DOI: 10.1111/nep.14367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/28/2024] [Accepted: 07/02/2024] [Indexed: 09/28/2024]
Abstract
The "multi-hit theory/4-hit theory" pathogenesis hypothesis is widely accepted and IgA nephropathy (IgAN) is understood to be a disease originating from Hit 1, galactose deficient IgA1 (GdIgA1). The chronic repetitive activation of the complement pathway (alternative and lectin pathways) and the subsequent inflammation results in progressive glomerular damage that spills over into increased intraglomerular pressure and other hemodynamic changes, increased urinary protein, glomerulosclerosis, and tubulointerstitial fibrosis. The basic pathophysiology of this disease is the progression of a mixture of such acute and chronic pathologies. Currently, a number of new drugs has emerged as promising agents, such as complement regulators, endothelin receptor antagonists, and SGLT2 inhibitors, which are associated with each pathological step after glomerular deposition of GdIgA1/immune complexes. On the other hand, the molecular mechanisms of GdIgA1 production are gradually being elucidated, and the development of several novel therapeutic agents targeting the responsible B cells and their international clinical trials are progressing. These agents that inhibit or control the production of the Hit1, GdIgA1, are highly expected as essential therapies for this disease. The large body of clinical and basic research findings to date strongly suggest that nephritogenic GdIgA1 is a polymeric IgA1 of mucosal origin. In addition, the B cells involved in its nephritogenic GdIgA1 production are mainly differentiated mature B cells such as plasma cells, which may migrate to the bone marrow as well as the mucosa. The innate immune system in the mucosa, especially Toll-like receptors (TLRs), is thought to be involved in their production. Among TLRs, TLT9 and TLR7, which recognize bacterial and viral unmethylated DNA and RNA, have been reported to be involved. The mucosal activation of these TLRs is associated with the production of APRIL (A Proliferation Inducing Ligand) and BAFF (B cell activating factor), which are TNF superfamily cytokines involved in B cell maturation, survival, and IgA class switching, and may also be involved in the production of nephritogenic GdIgA1. It is still inconclusive whether APRIL or BAFF is more closely involved in the production of nephritogenic GdIgA1. Phenotypes in transgenic animal models suggest BAFF involvement, however, a genome wide association study (GWAS) analysis of human IgAN has identified APRIL, not BAFF, as a candidate gene. Based on the above background, several international clinical trials are underway for drugs such as TLR regulators (hydroxychloroquine), anti-APRIL drugs, anti-BAFF drugs, APRIL/BAFF receptor (TACI) binding inhibitors, and cytoreductive drugs (proteasome inhibitors, anti-CD38 antibodies) to inhibit nephritogenic GdIgA1 production in responsible B cells. This session will provide an overview of the responsible B cells, their GdIgA1 production mechanism, and ongoing drugs.
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Affiliation(s)
- Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
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18
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Roberts LE, Williams CEC, Oni L, Barratt J, Selvaskandan H. IgA Nephropathy: Emerging Mechanisms of Disease. Indian J Nephrol 2024; 34:297-309. [PMID: 39156850 PMCID: PMC11326799 DOI: 10.25259/ijn_425_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 08/20/2024] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis reported across the world and is characterized by immunoglobulin A (IgA) dominant mesangial deposits, which are poorly O-glycosylated. This deposition leads to a cascade of glomerular and tubulointerstitial inflammation and fibrosis, which can progress to chronic kidney disease. The variability in rate of progression reflects the many genetic and environmental factors that drive IgAN. Here, we summarize the contemporary understanding of the disease mechanisms that drive IgAN and provide an overview of new and emerging therapies, which target these mechanisms.
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Affiliation(s)
- Lydia E Roberts
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, United Kingdom
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
| | - Chloe E C Williams
- Royal Liverpool and Broadgreen University Hospital Trusts, Liverpool, United Kingdom
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Louise Oni
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
- Department of Paediatric Nephrology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, United Kingdom
| | - Jonathan Barratt
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, United Kingdom
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
| | - Haresh Selvaskandan
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, United Kingdom
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
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19
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Chen Y, Lu M, Lin M, Gao Q. Network pharmacology and molecular docking to elucidate the common mechanism of hydroxychloroquine treatment in lupus nephritis and IgA nephropathy. Lupus 2024; 33:347-356. [PMID: 38285068 DOI: 10.1177/09612033241230377] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2024]
Abstract
OBJECTIVE Hydroxychloroquine (HCQ), characterized by a broad effect on immune regulation, has been widely used in the treatment of autoimmune glomerulonephritis such as lupus nephritis (LN) and immunoglobulin A nephropathy (IgAN). The current research investigates whether HCQ plays a role in the treatment of LN and IgAN through common mechanisms since the pathogenesis of both LN and IgAN is closely related to immune complex deposition, complement activation, and ultimately inflammation. METHODS Seventy-two common targets were obtained related to the common mechanism of HCQ treatment of LN and IgAN. Targets associated with LN and IgAN were collected based on DisGeNET, GeneCards, and OMIM databases. Possible HCQ targets were obtained from the PubChem database and PharmMapper databases. The overlapping targets of HCQ ingredients, IgAN, and LN were discovered via the Venn 2.1.0 online platform. Through the DAVID database, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted. Cytoscape (v3.9.1) was used to build a protein-protein interaction (PPI) network. Molecular docking was performed by using AutoDockTools 1.5.6 software and PyMol software to match the binding activity between HCQ and the 10 core targets. RESULTS The results showed that core targets (including MMP 2, PPARG, IL-2, MAPK14, MMP 9, and SRC), three signaling pathways (including the PI3K-Akt, AGE-RAGE, and MAPK), and cell differentiation (including Th1, Th2, and Th17) might be related to the body's immunity and inflammation. These results suggested that HCQ might act on targets and pathways involved in inflammation and immune regulation to exert a common effect on the treatment of LN and IgAN. CONCLUSIONS The current study provided new evidence for the protective mechanism and clinical utility of HCQ against LN and IgAN.
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Affiliation(s)
- Yixuan Chen
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Meiqi Lu
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Mengshu Lin
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Qing Gao
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
- Department of Nephrology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
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20
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González-Pereira P, Trinh R, Vasuthasawat A, Bartsch-Jiménez A, Nuñez-Soto C, Altamirano C. Enhancing Antibody-Specific Productivity: Unraveling the Impact of XBP1s Overexpression and Glutamine Availability in SP2/0 Cells. Bioengineering (Basel) 2024; 11:201. [PMID: 38534475 DOI: 10.3390/bioengineering11030201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/10/2024] [Accepted: 02/17/2024] [Indexed: 03/28/2024] Open
Abstract
Augmentation of glycoprotein synthesis requirements induces endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR) and triggering unconventional XBP1 splicing. As a result, XBP1s orchestrates the expression of essential genes to reduce stress and restore homeostasis. When this mechanism fails, chronic stress may lead to apoptosis, which is thought to be associated with exceeding a threshold in XBP1s levels. Glycoprotein assembly is also affected by glutamine (Gln) availability, limiting nucleotide sugars (NS), and preventing compliance with the increased demands. In contrast, increased Gln intake synthesizes ammonia as a by-product, potentially reaching toxic levels. IgA2m(1)-producer mouse myeloma cells (SP2/0) were used as the cellular mammalian model. We explored how IgA2m(1)-specific productivity (qIgA2m(1)) is affected by (i) overexpression of human XBP1s (h-XBP1s) levels and (ii) Gln availability, evaluating the kinetic behavior in batch cultures. The study revealed a two and a five-fold increase in qIgA2m(1) when lower and higher levels of XBP1s were expressed, respectively. High h-XBP1s overexpression mitigated not only ammonia but also lactate accumulation. Moreover, XBP1s overexpressor showed resilience to hydrodynamic stress in serum-free environments. These findings suggest a potential application of h-XBP1s overexpression as a feasible and cost-effective strategy for bioprocess scalability.
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Affiliation(s)
- Priscilla González-Pereira
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Avenida Brasil 2085, Valparaíso 2340000, Chile
| | - Ryan Trinh
- Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Alex Vasuthasawat
- Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Angelo Bartsch-Jiménez
- Escuela Kinesiología, Facultad de Medicina, Universidad de Valparaíso, Valparaíso 2362735, Chile
| | - Constanza Nuñez-Soto
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Avenida Brasil 2085, Valparaíso 2340000, Chile
| | - Claudia Altamirano
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Avenida Brasil 2085, Valparaíso 2340000, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Av. Monseñor Álvaro del Portillo 12455, Las Condes, Santiago 7550000, Chile
- Centro Regional de Estudios en Alimentos Saludables, Av. Universidad 330, Curauma-Placilla, Valparaíso 2340000, Chile
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21
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Jash R, Maparu K, Seksaria S, Das S. Decrypting the Pathological Pathways in IgA Nephropathy. RECENT ADVANCES IN INFLAMMATION & ALLERGY DRUG DISCOVERY 2024; 18:43-56. [PMID: 37870060 DOI: 10.2174/0127722708275167231011102924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/17/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023]
Abstract
IgAN is the most common form of glomerulonephritis affecting 2000000 people annually. The disease ultimately progresses to chronic renal failure and ESRD. In this article, we focused on a comprehensive understanding of the pathogenesis of the disease and thus identifying different target proteins that could be essential in therapeutic approaches in the management of the disease. Aberrantly glycosylated IgA1 produced by the suppression of the enzyme β-1, 3 galactosyltransferase ultimately triggered the formation of IgG autoantibodies which form complexes with Gd-IgA1. The complex gets circulated through the blood vessels through monocytes and ultimately gets deposited in the glomerular mesangial cells via CD71 receptors present locally. This complex triggers the inflammatory pathways activating the alternate complement system, various types of T Cells, toll-like receptors, cytokines, and chemokines ultimately recruiting the phagocytic cells to eliminate the Gd-IgA complex. The inflammatory proteins cause severe mesangial and podocyte damage in the kidney which ultimately initiates the repair process following chronic inflammation by an important protein named TGFβ1. TGF β1 is an important protein produced during chronic inflammation mediating the repair process via various downstream transduction proteins and ultimately producing fibrotic proteins which help in the repair process but permanently damage the glomerular cells.
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Affiliation(s)
- Rajiv Jash
- Department of Pharmacology, Sanaka Educational Trust's Group Of Institutions, Malandighi, Durgapur, 713212, West Bengal, India
- Department of Pharmacy, JIS University, Kolkata, 700109, West Bengal, India
| | - Kousik Maparu
- Department of Pharmacology, Sanaka Educational Trust's Group Of Institutions, Malandighi, Durgapur, 713212, West Bengal, India
| | - Sanket Seksaria
- Department of Pharmacology, Sanaka Educational Trust's Group Of Institutions, Malandighi, Durgapur, 713212, West Bengal, India
| | - Saptarshi Das
- Department of Pharmacy, JIS University, Kolkata, 700109, West Bengal, India
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22
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Huang Y, Sun X, Nie G, Xu H, Zou M. Follicular Helper T Cells in Peyer's Patches and Galactose- Deficient Iga1 Contribute to Iga Nephropathy. Curr Mol Med 2024; 24:1033-1044. [PMID: 37475555 DOI: 10.2174/1566524023666230720112215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 06/05/2023] [Accepted: 06/05/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND Common primary glomerulonephritis with aberrant mucosal immunity is IgA nephropathy (IgAN). T follicular helper (TFH) cells are essential in regulating B cell differentiation. Peyer's patches (PPs) are the main site where IgA+ plasmablasts differentiate. OBJECTIVE Our study aimed to investigate the TFH cell's potential contribution to the etiology of IgA nephropathy. METHODS In PPs from IgAN mouse models, the ratio of the TFH cell, B220+IgA+, B220+IgM+, and B220-IgA+ lymphocytes were assessed. Then, we used Western blot to assess the expression of Bcl-6, Blimp- 1, and IL-21 proteins in PPs and used RTPCR to assess the expression of IL-21 and TGF-β1 mRNA. TFH cells coculture with spleen cells to measure the degree of IL-21 and the ratio of activation marker CD69 on the TFH cells. Naive B cells (CD27-IgD+) from children suffering from IgAN were cultured with TFH cell-related cytokines. The supernatant was detected to assess the excretion of galactose-deficient IgA1 (Gd-IgA1). RESULTS IgAN mice developed noticeably increased degrees of IL-21 and CD69 on TFH cells than controls did, as well as higher percentages of B220+IgA+, B220+IgM+, B220+IgA+, TGF- β1, and IL-21 mRNA and Bcl-6, IL-21 proteins in PPs. The Gd-IgA1 level in the supernatant and IgAN- positive children's serum were noticeably higher than those of the healthy controls (P < 0.05). PPs provide the microenvironment to induce the production of IgA-secreting plasmablasts. CONCLUSION TFH cells may be a key moderator to induce B cell differentiation into IgAsecreting plasmablasts and produce Gd-IgA1, which plays a significant part in IgAN's pathogenesis. It could be a new therapeutic target in the future.
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Affiliation(s)
- Yuye Huang
- Department of Pediatrics, General Hospital of Central Theater Command, No. 627, Wuluo Road, Wuhan 430030, Hubei Province, P.R. China
| | - Xunling Sun
- Department of Pediatrics, General Hospital of Central Theater Command, No. 627, Wuluo Road, Wuhan 430030, Hubei Province, P.R. China
| | - Guoming Nie
- Department of Pediatrics, General Hospital of Central Theater Command, No. 627, Wuluo Road, Wuhan 430030, Hubei Province, P.R. China
| | - Hongtao Xu
- Department of Pediatrics, General Hospital of Central Theater Command, No. 627, Wuluo Road, Wuhan 430030, Hubei Province, P.R. China
| | - Minshu Zou
- Department of Pediatrics, General Hospital of Central Theater Command, No. 627, Wuluo Road, Wuhan 430030, Hubei Province, P.R. China
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23
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Zheng J, Li G, Liu W, Deng Y, Xu X. The Expression of Non B Cell-Derived Immunoglobulins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1445:11-36. [PMID: 38967747 DOI: 10.1007/978-981-97-0511-5_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
Although V(D)J recombination and immunoglobulin (Ig) production are traditionally recognised to occur only in B lymphocytes and plasma cells, the expression of Igs in non-lymphoid cells, which we call non B cell-derived Igs (non B Igs), has been documented by growing studies. It has been demonstrated that non B-Igs can be widely expressed in most cell types, including, but not limited to, epithelial cells, cardiomyocytes, hematopoietic stem/progenitor cells, myeloid cells, and cells from immune-privileged sites, such as neurons and spermatogenic cells. In particular, malignant tumour cells express high level of IgG. Moreover, different from B-Igs that mainly localised on the B cell membrane and in the serum and perform immune defence function mainly, non B-Igs have been found to distribute more widely and play critical roles in immune defence, maintaining cell proliferation and survival, and promoting progression. The findings of non B-Igs may provide a wealthier breakthrough point for more therapeutic strategies for a wide range of immune-related diseases.
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Affiliation(s)
- Jie Zheng
- Hematologic Disease Laboratory, Department of Stem Cell Transplantation, Beijing Children's Hospital, Capital Medical University, Beijing, China.
| | - Guohui Li
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Wei Liu
- Department of Immunology, Hebei Medical University, Shijiazhuang, China
| | - Yuqing Deng
- Department of Immunology, Hebei Medical University, Shijiazhuang, China
| | - XiaoJun Xu
- Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China
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24
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Sun W, Chen Z, Huang Z, Wan A, Zhou M, Gao J. Effects of dietary traditional Chinese medicine residues on growth performance, intestinal health and gut microbiota compositions in weaned piglets. Front Cell Infect Microbiol 2023; 13:1283789. [PMID: 38053526 PMCID: PMC10694240 DOI: 10.3389/fcimb.2023.1283789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 10/31/2023] [Indexed: 12/07/2023] Open
Abstract
Weaning stress can induce diarrhea, intestinal damage and flora disorder of piglets, leading to slow growth and even death of piglets. Traditional Chinese medicine residue contains a variety of active ingredients and nutrients, and its resource utilization has always been a headache. Therefore, we aimed to investigate the effects of traditional Chinese medicine residues (Xiasangju, composed of prunellae spica, mulberry leaves, and chrysanthemum indici flos) on growth performance, diarrhea, immune function, and intestinal health in weaned piglets. Forty-eight healthy Duroc× Landrace × Yorkshire castrated males weaned aged 21 days with similar body conditions were randomly divided into 6 groups with eight replicates of one piglet. The control group was fed a basal diet, the antibiotic control group was supplemented with 75 mg/kg chlortetracycline, and the residue treatment groups were supplemented with 0.5%, 1.0%, 2.0% and 4.0% Xiasangju residues. The results showed that dietary Xiasangju residues significantly reduced the average daily feed intake, but reduced the diarrhea score (P < 0.05). The 1.0% and 2.0% Xiasangju residues significantly increased the serum IgM content of piglets, and the 0.5%, 1.0%, 2.0% and 4.0% Xiasangju residues significantly increased the serum IgG content, while the 1.0%, 2.0% and 4.0% Xiasangju residues significantly increased the sIgA content of ileal contents (P < 0.05). Dietary Xiasangju residues significantly increased the villus height and the number of villus goblet cells in the jejunum and ileum, and significantly decreased the crypt depth (P<0.05). The relative mRNA expression of IL-10 in the ileum was significantly increased in the 1% and 2% Xiasangju residues supplemented groups (P < 0.05), while IL-1β in the ileum was downregulated (P < 0.05). Xiasangju residues improved the gut tight barrier, as evidenced by the enhanced expression of Occludin and ZO-1 in the jejunum and ileum. The diets with 1% Xiasangju residues significantly increased the relative abundance of Lactobacillus johnsonii, and 2% and 4% Xiasangju residues significantly increased the relative abundance of Weissella jogaeotgali (P < 0.05). Dietary supplementation with 0.5%, 1.0%, 2% and 4% with Xiasangju residues significantly decreased the relative abundance of Escherichia coli and Treponema porcinum (P < 0.05). In summary, dietary supplementation with Xiasangju residues improves intestinal health and gut microbiota in weaned piglets.
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Affiliation(s)
- Weiguang Sun
- Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou, China
| | - Zhong Chen
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Zhiyun Huang
- Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou, China
| | - Anfeng Wan
- Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou, China
| | - Miao Zhou
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Jing Gao
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
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25
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Zhang L, Liu J, Hou Y. Classification, function, and advances in tsRNA in non-neoplastic diseases. Cell Death Dis 2023; 14:748. [PMID: 37973899 PMCID: PMC10654580 DOI: 10.1038/s41419-023-06250-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 10/14/2023] [Accepted: 10/25/2023] [Indexed: 11/19/2023]
Abstract
tRNA-derived small RNAs (tsRNAs) are non-coding small RNAs produced by specific endonucleases following the processing and splicing of precursor or mature tRNAs upon starvation, oxidative stress, hypoxia, and other adverse conditions. tRNAs are classified into two major categories, tRNA fragments (tRFs) and tRNA-derived stress-induced small RNAs (tiRNAs), based on differences in splice sites. With the development of high-throughput sequencing technologies in recent years, tsRNAs have been found to have important biological functions, including inhibition of apoptosis, epigenetic regulation, cell-cell communication, translation, and regulation of gene expression. Additionally, these molecules have been found to be aberrantly expressed in various diseases and to be involved in several pathological processes. In this article, the classification and nomenclature, biological functions, and potential use of tsRNAs as diagnostic biomarkers and therapeutic targets in non-neoplastic diseases are reviewed. Although tsRNA research is at its infancy, their potential in the treatment of non-tumor diseases warrants further investigation.
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Affiliation(s)
- Liou Zhang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jie Liu
- Translational Research Experiment Department, Science Experiment Center, China Medical University, Shenyang, China.
| | - Yang Hou
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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26
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Liu H, Chen W, Tian C, Deng Y, Xu L, Ouyang W, Qiu R, You Y, Jiang P, Zhou L, Cheng J, Kwan HY, Zhao X, Sun X. The mechanism of Shenbing Decoction II against IgA nephropathy renal fibrosis revealed by UPLC-MS/MS, network pharmacology and experimental verification. Heliyon 2023; 9:e21997. [PMID: 38027651 PMCID: PMC10654229 DOI: 10.1016/j.heliyon.2023.e21997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 12/01/2023] Open
Abstract
Background IgA nephropathy (IgAN) is a major and growing public health problem. Renal fibrosis plays a vital role in the progression of IgAN. This study is to investigate the mechanisms of action underlying the therapeutic effects of Shenbing Decoction II (SBDII) in IgAN renal fibrosis treatment based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), network pharmacology and experimental verification. Method We first used UPLC-MS/MS to explore the main compounds of SBDII, and then used network pharmacology to predict the targets and key pathways of SBDII in the treatment of IgAN renal fibrosis. Next, bovine serum albumin (BSA), lipopolysaccharide (LPS), and carbon tetrachloride (CCL4) were used to induce IgAN in rats, and then biochemical indicators, renal tissue pathology, and renal fibrosis-related indicators were examined. At the same time, part of the results predicted by network pharmacology were also verified. Result A total of 105 compounds were identified in SBDII by UPLC-MS/MS. Network pharmacology results showed that the active compounds such as acacetin, eupatilin, and galangin may mediate the therapeutic effects of SBDII in treating IgAN by targeting tumor protein p53 (TP53) and regulating phosphatidylinositol 3-kinase (PI3K)-Akt kinase (Akt) signaling pathway. Animal experiments showed that SBDII not only significantly improved renal function and fibrosis in IgAN rats, but also significantly downregulated the expressions of p53, p-PI3K and p-Akt. Conclusion This UPLC-MS/MS, network pharmacological and experimental study highlights that the TP53 as a target, and PI3K-Akt signaling pathway are the potential mechanism by which SBDII is involved in IgAN renal fibrosis treatment. Acacetin, eupatilin, and galangin are probable active compounds in SBDII, these results might provide valuable guidance for further studies of IgAN renal fibrosis treatment.
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Affiliation(s)
- Huaxi Liu
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Weijie Chen
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunyang Tian
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yijian Deng
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Liangwo Xu
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Wenkun Ouyang
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Renjie Qiu
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yanting You
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Pingping Jiang
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Lin Zhou
- Endocrinology Department, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jingru Cheng
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hiu Yee Kwan
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiaoshan Zhao
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaomin Sun
- Syndrome Laboratory of Integrated Chinese and Western Medicine, School of Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
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27
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Takada K, Suzukawa M, Igarashi S, Uehara Y, Watanabe S, Imoto S, Ishii M, Morio Y, Matsui H, Akishita M, Ohta K. Serum IgA augments adhesiveness of cultured lung microvascular endothelial cells and suppresses angiogenesis. Cell Immunol 2023; 393-394:104769. [PMID: 37741001 DOI: 10.1016/j.cellimm.2023.104769] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/11/2023] [Accepted: 09/15/2023] [Indexed: 09/25/2023]
Abstract
Immunoglobulin A (IgA) is important in local immunity and is also abundant in the blood. This study aimed to evaluate the effects of serum IgA on cultured lung microvascular endothelial cells (HMVEC-Ls), which are involved in the pathogenesis of inflammatory lung diseases. Serum IgA induced adhesion molecules and inflammatory cytokine production from HMVEC-Ls, and enhanced adhesion of peripheral blood mononuclear cells to HMVEC-Ls. In contrast, migration, proliferation, and tube formation of HMVEC-Ls were significantly suppressed by serum IgA. Experiments with siRNAs and western blotting revealed that two known IgA receptors, β1,4-galactosyltransferase 1 (b4GALT1) and asialoglycoprotein receptor 1 (ASGR1), and mitogen-activated protein kinase and nuclear factor-kappa B pathways were partly involved in serum IgA-induced cytokine production by HMVEC-Ls. Collectively, serum IgA enhanced cytokine production and adhesiveness of HMVEC-L, with b4GALT1 and ASGR1 partially being involved, and suppressed angiogenesis. Thus, serum IgA may be targeted to treat inflammatory lung diseases.
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Affiliation(s)
- Kazufumi Takada
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Maho Suzukawa
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan.
| | - Sayaka Igarashi
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan
| | - Yuuki Uehara
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Shizuka Watanabe
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Sahoko Imoto
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Masaki Ishii
- Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yoshiteru Morio
- Department of Respiratory Medicine, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan
| | - Hirotoshi Matsui
- Department of Respiratory Medicine, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan
| | - Masahiro Akishita
- Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Ken Ohta
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Japan Anti-Tuberculosis Association, JATA Fukujuji Hospital, 3-1-24 Matsuyama, Kiyose-City, Tokyo 204-8522, Japan.
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Zhang Y, Yang H, Jiang M, Nie X. Exploring the pathogenesis and treatment of IgA nephropathy based on epigenetics. Epigenomics 2023; 15:1017-1026. [PMID: 37909120 DOI: 10.2217/epi-2023-0318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2023] Open
Abstract
IgA nephropathy is the most common primary glomerulonephritis worldwide. However, its exact cause remains unclear, with known genetic factors explaining only 11% of the variation. Recently, researchers have turned their attention to epigenetic abnormalities in immune-related diseases, recognizing their significance in IgA nephropathy's development and progression. This emerging field has revolutionized our understanding of epigenetics in IgA nephropathy research. Though in its early stages, studying IgA nephropathy's epigenetics holds promise for unraveling its pathogenesis and identifying new biomarkers and therapies. This review aims to comprehensively analyze epigenetics' role in IgA nephropathy's development and suggest avenues for potential therapeutic interventions. In the future, assessing and modulating epigenetics may become integral in diagnosing, tailoring treatments and assessing prognoses for IgA nephropathy.
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Affiliation(s)
- Yunfan Zhang
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, China
- Department of Pediatrics, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350025, China
| | - Huanhuan Yang
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, China
- Department of Pediatrics, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350025, China
| | - Ming Jiang
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, China
- Department of Pediatrics, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350025, China
| | - Xiaojing Nie
- Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, China
- Department of Pediatrics, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, 350025, China
- Department of Pediatrics, Affiliated Dongfang Hospital, Xiamen University, Fuzhou, 350025, China
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Lian X, Wang Y, Wang S, Peng X, Wang Y, Huang Y, Chen W. Does inflammatory bowel disease promote kidney diseases: a mendelian randomization study with populations of European ancestry. BMC Med Genomics 2023; 16:225. [PMID: 37752523 PMCID: PMC10521387 DOI: 10.1186/s12920-023-01644-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 08/23/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND This study aimed to investigate a causal relationship between IBD and multiple kidney diseases using two-sample Mendelian randomization (MR) analyses. METHODS We selected a group of single nucleotide polymorphisms (SNPs) specific to IBD as instrumental variables from a published genome-wide association study (GWAS) with 86,640 individuals of European ancestry. Summary statistics for multiple kidney diseases were obtained from the publicly available GWAS. Genetic data from one GWAS involving 210 extensive T-cell traits was used to estimate the mediating effect on specific kidney disease. Inverse-variance weighted method were used to evaluate the MR estimates for primary analysis. RESULTS Genetic predisposition to IBD was associated with higher risk of IgA nephropathy (IgAN) (OR, 1.78; 95% CI, 1.45-2.19), but not membranous nephropathy, diabetic nephropathy, glomerulonephritis, nephrotic syndrome, chronic kidney disease, and urolithiasis. CD4 expression on CD4 + T cell had a significant genetic association with the risk of IgAN (OR, 2.72; 95% CI, 1.10-6.72). Additionally, consistent results were also observed when IBD was subclassified as ulcerative colitis (OR, 1.38; 95% CI, 1.10-1.71) and Crohn's disease (OR, 1.37; 95% CI, 1.12-1.68). MR-PRESSO and the MR-Egger intercept did not identify pleiotropic SNPs. CONCLUSIONS This study provides genetic evidence supporting a positive casual association between IBD, including its subclassification as ulcerative colitis and Crohn's disease, and the risk of IgAN. However, no casual association was found between IBD and other types of kidney diseases. Further exploration of IBD interventions as potential preventive measures for IgAN is warranted.
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Affiliation(s)
- Xingji Lian
- Department of Nephrology, The First Affiliated Hospital, NHC Key Laboratory of Nephrology (Sun Yat-sen University), Guangdong Provincial Key Laboratory of Nephrology, Sun Yat-sen University, Guangzhou, 510080, China
- Department of Geriatrics, Guangzhou First People's Hospital, School of Medicine, National Key Clinic Specialty, South China University of Technology, Guangzhou, 510180, China
| | - Yiqin Wang
- Department of Nephrology, The First Affiliated Hospital, NHC Key Laboratory of Nephrology (Sun Yat-sen University), Guangdong Provincial Key Laboratory of Nephrology, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shuyi Wang
- Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xiaohui Peng
- Department of Geriatrics, Guangzhou First People's Hospital, School of Medicine, National Key Clinic Specialty, South China University of Technology, Guangzhou, 510180, China
| | - Yanhui Wang
- Department of Geriatrics, Guangzhou First People's Hospital, School of Medicine, National Key Clinic Specialty, South China University of Technology, Guangzhou, 510180, China
| | - Yuyu Huang
- Department of Geriatrics, Guangzhou First People's Hospital, School of Medicine, National Key Clinic Specialty, South China University of Technology, Guangzhou, 510180, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital, NHC Key Laboratory of Nephrology (Sun Yat-sen University), Guangdong Provincial Key Laboratory of Nephrology, Sun Yat-sen University, Guangzhou, 510080, China.
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Hua MR, Zhao YL, Yang JZ, Zou L, Zhao YY, Li X. Membranous nephropathy: Mechanistic insights and therapeutic perspectives. Int Immunopharmacol 2023; 120:110317. [PMID: 37207447 DOI: 10.1016/j.intimp.2023.110317] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/13/2023] [Accepted: 05/08/2023] [Indexed: 05/21/2023]
Abstract
Membranous nephropathy (MN) is one of the most common causes of non-diabetic nephrotic syndrome in adults. About 80% of cases are renal limited (primary MN) and 20% are associated with other systemic diseases or exposures (secondary MN). Autoimmune reaction is the main pathogenic factor of MN, and the discovery of autoantigens including the phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A has led to new insights into the pathogenesis, they can induce humoral immune responses led by IgG4 makes them suitable for the diagnosis and monitoring of MN. In addition, complement activation, genetic susceptibility genes and environmental pollution are also involved in MN immune response. In clinical practice, due to the spontaneous remission of MN, the combination of supportive therapy and pharmacological treatment is widely used. Immunosuppressive drugs are the cornerstone of MN treatment, and the dangers and benefits of this approach vary from person to person. In summary, this review provides a more comprehensive review of the immune pathogenesis, interventions and unresolved issues of MN in the hope of providing some new ideas for clinical and scientific researchers in the treatment of MN.
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Affiliation(s)
- Meng-Ru Hua
- Xi'an International Medical Center Hospital, Northwest University, No. 777 Xitai Road, Xi'an, Shaanxi 710000, China
| | - Yan-Long Zhao
- Xi'an International Medical Center Hospital, Northwest University, No. 777 Xitai Road, Xi'an, Shaanxi 710000, China
| | - Jun-Zheng Yang
- Guangdong nephrotic drug Engineering Technology Research Center, Institute of Consun Co. for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, No. 71 Dongpeng avenue, Guangzhou, Guangdong 510530, China
| | - Liang Zou
- School of Food and Bioengineering, Chengdu University, No. 2025 Chengluo Avenue, Chengdu, Sichuan 610106, China
| | - Ying-Yong Zhao
- Xi'an International Medical Center Hospital, Northwest University, No. 777 Xitai Road, Xi'an, Shaanxi 710000, China; School of Food and Bioengineering, Chengdu University, No. 2025 Chengluo Avenue, Chengdu, Sichuan 610106, China; School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China.
| | - Xia Li
- Xi'an International Medical Center Hospital, Northwest University, No. 777 Xitai Road, Xi'an, Shaanxi 710000, China.
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Tamura H. IgA nephropathy associated with Crohn's disease. World J Methodol 2023; 13:67-78. [PMID: 37456980 PMCID: PMC10348078 DOI: 10.5662/wjm.v13.i3.67] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/16/2023] [Accepted: 05/12/2023] [Indexed: 06/20/2023] Open
Abstract
The relationship between IgA nephropathy (IgAN) and Crohn’s disease was reported. IgAN is the most common primary glomerulonephritis and one of the leading causes of chronic kidney disease and end-stage renal failure, and up to 50% of cases progressed to end-stage renal disease within 25 years after IgAN diagnosis. However, specific and effective therapeutic strategies are still lacking. In this review, we discuss the possibility of the mechanism involved in IgAN associated with Crohn’s disease based on the findings of basic and clinical studies. Although the etiology of IgAN associated with Crohn’s disease is not permanent and various factors are thought to be involved, the stabilization of the disease condition of Crohn’s disease is believed to help treat IgAN.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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Ma S, Zhao M, Chang M, Shi X, Shi Y, Zhang Y. Effects and mechanisms of Chinese herbal medicine on IgA nephropathy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 117:154913. [PMID: 37307737 DOI: 10.1016/j.phymed.2023.154913] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 05/16/2023] [Accepted: 06/02/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN), is the main cause of end-stage renal disease, that causes serious physical and psychological burden to patients worldwide. Some traditional treatment measures, such as blocking the renin-angiotensin-aldosterone system, controlling blood pressure, and following a low-protein diet, may not achieve satisfactory results. Therefore, more effective and safe therapies for IgAN are urgently needed. PURPOSE The aim of this review is to summarize the clinical efficacy of Chinese herbal medicines (CHMs) and their active ingredients in the treatment and management of IgAN based on the results of clinical trials, systematic reviews, and meta-analyses, to fully understand the advantages and perspectives of CHMs in the treatment of IgAN. STUDY DESIGN AND METHODS For this review, the following electronic databases were consulted: PubMed, ResearchGate, Science Direct, Web of Science, Chinese National Knowledge Infrastructure and Wanfang Data, "IgA nephropathy," "traditional Chinese medicine," "Chinese herbal medicine," "herb," "mechanism," "Meta-analysis," "systematic review," "RCT" and their combinations were the keywords to search the relevant literature. Data were collected from 1990 to 2022. RESULTS This review found that the active ingredients of CHMs commonly act on multiple signaling pathways in the clinical treatment of IgAN, mainly with antioxidant, anti-inflammatory and anti-fibrosis effects, and regulation of autophagy. CONCLUSION Compared with the single-target therapy of modern medicine, CHMs can regulate the corresponding pathways from the aspects of anti-inflammation, anti-oxidation, anti-fibrosis and autophagy to play a multi-target treatment of IgAN through syndrome differentiation and treatment, which has good clinical efficacy and can be used as the first choice or alternative therapy for IgAN treatment. This review provides evidence and research direction for a comprehensive clinical understanding of the protective effect of Chinese herbal medicine on IgAN.
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Affiliation(s)
- Sijia Ma
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Mingming Zhao
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Meiying Chang
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Xiujie Shi
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yue Shi
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yu Zhang
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China.
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Wang F, Li N, Ni S, Min Y, Wei K, Sun H, Fu Y, Liu Y, Lv D. The Effects of Specific Gut Microbiota and Metabolites on IgA Nephropathy-Based on Mendelian Randomization and Clinical Validation. Nutrients 2023; 15:nu15102407. [PMID: 37242290 DOI: 10.3390/nu15102407] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 05/02/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Although recent research suggests that alterations in gut microbiota and metabolites play a critical role in the pathophysiology of immunoglobulin A nephropathy (IgAN), the causal relationship between specific intestinal flora and metabolites and the risk of IgAN remains unclear. METHOD This study employed Mendelian randomization (MR) to investigate the causal association between gut microbiota and IgAN. To explore potential associations between gut microbiota and various outcomes, four MR methods were applied: inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. If the results of the four methods are inconclusive, we prefer the IVW as the primary outcome. Additionally, MR-Egger, MR-PRESSO-Global, and Cochrane's Q tests were used to detect heterogeneity and pleiotropy. The stability of MR findings was assessed using the leave-one-out approach, and the strength of the causal relationship between exposure and outcome was tested using Bonferroni correction. Additional clinical samples were utilized to validate the results of Mendelian randomization, and the outcomes were visualized through an ROC curve, confusion matrix, and correlation analysis. RESULT This study examined a total of 15 metabolites and 211 microorganisms. Among them, eight bacteria and one metabolite were found to be associated with the risk of IgAN (p < 0.05). The Bonferroni-corrected test reveals that only Class. Actinobacteria (OR: 1.20, 95% CI: 1.07-1.36, p = 0.0029) have a significant causal relationship with IgAN. According to Cochrane's Q test, there is no substantial heterogeneity across different single-nucleotide polymorphisms (p > 0.05). Furthermore, MR-Egger and MR-PRESSO-Global tests (p > 0.05) showed no evidence of pleiotropy. No reverse causal association was found between the risk of IgAN and microbiota or metabolites (p > 0.05). Clinical specimens demonstrated the effectiveness and accuracy of Actinobacteria in distinguishing IgAN patients from those with other glomerular diseases (AUC = 0.9, 95% CI: 0.78-1.00). Additionally, our correlation analysis revealed a potential association between Actinobacteria abundance and increased albuminuria (r = 0.85) and poorer prognosis in IgAN patients (p = 0.01). CONCLUSION Through MR analysis, we established a causal link between Actinobacteria and the incidence of IgAN. Moreover, clinical validation using fecal samples indicated that Actinobacteria might be associated with the onset and poorer prognosis of IgAN. This finding could provide valuable biomarkers for early, noninvasive detection of the disease and potential therapeutic targets in IgAN.
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Affiliation(s)
- Fang Wang
- Institute of Nephrology, Liyang Hospital of Chinese Medicine, Liyang 213300, China
- Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Ning Li
- Institute of Nephrology, Southeast University School of Medicine, Nanjing 210009, China
| | - Siming Ni
- Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Yu Min
- Department of Biotherapy and National Clinical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kang Wei
- Yangzhou People's Hospital, Yangzhou University, Yangzhou 225000, China
| | - Hongbin Sun
- Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Yuqi Fu
- Institute of Nephrology, Southeast University School of Medicine, Nanjing 210009, China
| | - Yalan Liu
- Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Dan Lv
- Institute of Nephrology, Liyang Hospital of Chinese Medicine, Liyang 213300, China
- Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210000, China
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Mechanism of Yiqi Yangying Heluo Formula in the Treatment of IgA Nephropathy by Affecting Gd-IgA1 Based on BAFF Molecular Level and T Lymphocyte Immunity. BIOMED RESEARCH INTERNATIONAL 2023; 2023:5124034. [PMID: 36660452 PMCID: PMC9845038 DOI: 10.1155/2023/5124034] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 01/12/2023]
Abstract
Background Galactose-deficient IgA1 (Gd-IgA1) is a critical initiating factor in the pathogenesis of IgA nephropathy (IgAN), which plays an important role in the diagnosis and evaluation of this disease. Moreover, the whole pathogenesis process has an intimate association with the immune response of T and B lymphocytes and their inflammatory factors. There is no specific therapy for IgAN at present. Yiqi Yangyin Formula can significantly reduce urinary protein and hematuria in patients with IgAN. Yiqi Yangying Heluo Formula (YYHF) is optimized on the basis of the above prescription, but its specific mechanism remains to be further studied. Methods The effect of YYHF on urinary protein and urinary red blood cell count in patients with IgAN was observed by a self-controlled clinical study before and after treatment. On this basis, flow cytometry was used to detect the proportion of T lymphocyte subsets in peripheral blood of patients with IgAN before and after treatment and healthy controls. Meanwhile, the levels of Gd-IgA1, B cell activation factor (BAFF), and their cytokines (IL-4, IL-6, and IL-17) in peripheral blood were detected by enzyme-linked immunosorbent assay. The changes in mechanism-related indicators of the two groups were observed and subject to correlation analysis. Results (1) Compared with the levels before treatment, 24-hour urinary protein content decreased by 47.7% and urinary red blood cell number decreased by 67% in patients with IgAN intervened by YYHF after 48 weeks of follow-up. (2) Compared with the healthy control group, patients with IgAN showed a significantly increased proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg, obviously reduced proportion of Th2 cells and Treg cells, and evidently elevated levels of Gd-IgA1, BAFF, and their cytokines (IL-4, IL-6, and IL-17) in the peripheral blood. (3) Following 48 weeks of follow-up after intervention treatment with YYHF, the levels of Gd-IgA1, BAFF, IL-6, and IL-17 were significantly lower, but the level of IL-4 was higher in peripheral blood of patients with IgAN than those before treatment and after 24 weeks of treatment; simultaneously, the proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg decreased while that of Th2 cells and Treg cells increased after 48 weeks of follow-up compared with that before treatment in peripheral blood of patients with IgAN. (4) The results of correlation analysis revealed that the level of Gd-IgA1 in peripheral blood of patients with IgAN was positively correlated with the level of BAFF, as well as the proportion of Th1 cells, Th17 cells, Th1/Th2, IL-6, and IL-17 levels, and negatively correlated with the proportion of Treg cells. In addition, the level of Gd-IgA1 in peripheral blood was positively correlated with proteinuria, yet without correlation with hematuria. Conclusion YYHF can reduce the quantitative level of 24 h urinary protein and urinary red blood cell count in patients with IgAN. Patients with IgAN have obvious T cell immune imbalance. YYHF can significantly reduce the level of Gd-IgA1 in patients with IgAN, and its mechanism may be explained by the reduced level of BAFF in peripheral blood and improved immune balance of T cells.
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Zhang Q, Li J, Wang J, Nie K, Luo Z, Xu S, Lin Y, Feng B, Zhuo Y, Hua L, Che L. Effects of lysophospholipids and multi-enzymes on growth performance, antioxidant capacity, intestinal health, and cecal microflora of male cherry valley ducks. J Anim Sci 2023; 101:skad361. [PMID: 37870076 PMCID: PMC10629945 DOI: 10.1093/jas/skad361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/21/2023] [Indexed: 10/24/2023] Open
Abstract
Improvement of nutrient utilization to promote growth performance is always pursued in poultry. In this study, a total of 360 1-d-old male ducklings was randomly assigned to 3 treatments in terms of diet treatment groups. Three treatments were as follows: basal diet (Con group) or basal diet supplemented with 300 mg/kg multi-enzymes (ENZ group) or 500 mg/kg lysophospholipids (LPL group). On day 42, ducks were slaughtered for samplings. The results revealed that supplementary LPL improved the body weight (BW) at day 14 and average daily gain (ADG) during days 1 to 14 and improved the feed conversion rate (FCR) for the overall period (P < 0.05) by improving nutrient utilization of dry matter and ether extract (P < 0.05) compared with the Con group. Dietary ENZ improved the FCR from days 15-42 and 1-42, and nitrogen utilization (P < 0.05) compared with the Con group. Jejunal villus height and villus height/crypt depth ratio were higher (P < 0.05) in the LPL group and tended to be higher (P < 0.1) in the ENZ group compared to the Con group. Supplementation with either LPL or ENZ reduced interleukin-1β concentration in jejunal mucus (P < 0.05). Both LPL and ENZ enhanced serum total superoxide dismutase activity (P < 0.05), whereas only supplementation with LPL elevated total antioxidant capacity (P < 0.05). In terms of cecal microbiota, microbial richness tended to be reduced by LPL, with low observed-OTUs and Chao1 (0.05 < P < 0.1). Supplementation with ENZ led to higher abundances of cellulolytic bacteria such as Fibrobacterota, [Eubacterium]_xylanophilum_group, and Bifidobacterium. Overall, both LPL and ENZ improved FCR, which may be relevant to ameliorative intestinal health, overall antioxidant ability, and cecal microbiome.
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Affiliation(s)
- Qianqian Zhang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
- Department of Animal Resources and Science, Dankook University, Cheonan 31116, South Korea
| | - Jian Li
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Jianping Wang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Kangkang Nie
- Kemin (China) Technologies Co., Ltd., Zhuhai, China
| | - Zheng Luo
- Kemin (China) Technologies Co., Ltd., Zhuhai, China
| | - Shengyu Xu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Yan Lin
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Bin Feng
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Yong Zhuo
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Lun Hua
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Lianqiang Che
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
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Nihei Y, Suzuki H, Suzuki Y. Current understanding of IgA antibodies in the pathogenesis of IgA nephropathy. Front Immunol 2023; 14:1165394. [PMID: 37114051 PMCID: PMC10126238 DOI: 10.3389/fimmu.2023.1165394] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/27/2023] [Indexed: 04/29/2023] Open
Abstract
Immunoglobulin A (IgA) is the most abundant isotype of antibodies, provides a first line of defense at mucosal surfaces against pathogens, and thereby contributes to mucosal homeostasis. IgA is generally considered as a non-inflammatory antibody because of its main function, neutralizing pathogenic virus or bacteria. Meanwhile, IgA can induce IgA-mediated diseases, such as IgA nephropathy (IgAN) and IgA vasculitis. IgAN is characterized by the deposition of IgA and complement C3, often with IgG and/or IgM, in the glomerular mesangial region, followed by mesangial cell proliferation and excessive synthesis of extracellular matrix in glomeruli. Almost half a century has passed since the first report of patients with IgAN; it remains debatable about the mechanism how IgA antibodies selectively bind to mesangial region-a hallmark of IgAN-and cause glomerular injuries in IgAN. Previous lectin- and mass-spectrometry-based analysis have revealed that IgAN patients showed elevated serum level of undergalactosylated IgA1 in O-linked glycans of its hinge region, called galactose-deficient IgA1 (Gd-IgA1). Thereafter, numerous studies have confirmed that the glomerular IgA from IgAN patients are enriched with Gd-IgA1; thus, the first hit of the current pathogenesis of IgAN has been considered to increase circulating levels of Gd-IgA1. Recent studies, however, demonstrated that this aberrant glycosylation alone is not sufficient to disease onset and progression, suggesting that several additional factors are required for the selective deposition of IgA in the mesangial region and induce nephritis. Herein, we discuss the current understanding of the characteristics of pathogenic IgA and its mechanism of inducing inflammation in IgAN.
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Affiliation(s)
- Yoshihito Nihei
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Department of Nephrology, Juntendo University Urayasu Hospital, Chiba, Japan
- *Correspondence: Yusuke Suzuki, ; Hitoshi Suzuki,
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- *Correspondence: Yusuke Suzuki, ; Hitoshi Suzuki,
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Luvizotto MJ, Menezes-Silva L, Woronik V, Monteiro RC, Câmara NOS. Gut-kidney axis in IgA nephropathy: Role on mesangial cell metabolism and inflammation. Front Cell Dev Biol 2022; 10:993716. [PMID: 36467425 PMCID: PMC9715425 DOI: 10.3389/fcell.2022.993716] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 11/07/2022] [Indexed: 11/15/2023] Open
Abstract
IgA Nephropathy (IgAN) is the commonest primary glomerular disease around the world and represents a significant cause of end-stage renal disease. IgAN is characterized by mesangial deposition of IgA-immune complexes and mesangial expansion. The pathophysiological process includes an abnormally glycosylated IgA1, which is an antigenic target. Autoantibodies specifically recognize galactose-deficient IgA1 forming immune complexes that are amplified in size by the soluble IgA Fc receptor CD89 leading to deposition in the mesangium through interaction with non-classical IgA receptors. The local production of cytokines promotes local inflammation and complement system activation, besides the stimulation of mesangial proliferation. The spectrum of clinical manifestations is quite variable from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. Despite all the advances, the pathophysiology of the disease is still not fully elucidated. The mucosal immune system is quoted to be a factor in triggering IgAN and a "gut-kidney axis" is proposed in its development. Furthermore, many recent studies have demonstrated that food intake interferes directly with disease prognosis. In this review, we will discuss how mucosal immunity, microbiota, and nutritional status could be interfering directly with the activation of intrinsic pathways of the mesangial cells, directly resulting in changes in their function, inflammation and development of IgAN.
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Affiliation(s)
- Mateus Justi Luvizotto
- Department of Nephrology, Faculty of Medicine, University of Sao Paulo, São Paulo, Brazil
| | - Luísa Menezes-Silva
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Viktoria Woronik
- Department of Nephrology, Faculty of Medicine, University of Sao Paulo, São Paulo, Brazil
| | - Renato C. Monteiro
- Centre de Recherche sur l’Inflammation, INSERM and CNRS, Université Paris Cité, Paris, France
| | - Niels Olsen Saraiva Câmara
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
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Imoto S, Suzukawa M, Takada K, Watanabe S, Igarashi S, Kitani M, Nagase T, Ohta K. Immunoglobulin A promotes IL-6 and IL-8 production, proliferation, and migration by the human bronchial smooth muscle cells. Cell Immunol 2022; 381:104612. [PMID: 36130412 DOI: 10.1016/j.cellimm.2022.104612] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/24/2022] [Accepted: 09/11/2022] [Indexed: 11/03/2022]
Abstract
Immunoglobulin A (IgA) is important in biological defense, mainly in the mucosal area, and plays pathogenic roles in various diseases by activating both inflammatory and structural cells. The current study aimed to validate the effects of IgA on the human bronchial smooth muscle cell (BSMC), which plays a major role in airway inflammation and remodeling. Serum IgA induced interleukin (IL)-6 and IL-8 production at both mRNA and protein levels, and enhanced cell proliferation and migration by the BSMCs. The synthetic phenotype markers were regulated and the contractile phenotype markers were downregulated by serum IgA. Mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt, and nuclear factor-κB pathways were involved in IgA-induced IL-6 and IL-8 production. The BSMCs expressed transferrin receptor (TfR), and TfR siRNA transfection inhibited IL-6 and IL-8 production by serum IgA. In summary, serum IgA is a potent activator of the BSMCs at least partially via TfR.
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Affiliation(s)
- Sahoko Imoto
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Maho Suzukawa
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan.
| | - Kazufumi Takada
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Shizuka Watanabe
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Sayaka Igarashi
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan
| | - Masashi Kitani
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan
| | - Takahide Nagase
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Ken Ohta
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan; Japan Anti-Tuberculosis Association, JATA Fukujuji Hospital, 3-1-24 Matsuyama, Kiyose-City, Tokyo 204-8522, Japan.
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Yang N, Li L, He H, Guo X, Yuan X, Li Z, Wang W, Qin B, Du X, Zhang X, Chen S, Lin H. Positive association of serum FUT8 activity with renal tubulointerstitial injury in IgA nephropathy patients. Immun Inflamm Dis 2022; 10:e686. [PMID: 36039648 PMCID: PMC9425009 DOI: 10.1002/iid3.686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND α-1,6 Fucosyltransferase (FUT8) appears to play an essential role in the pathogenesis of renal fibrosis. However, it remained unknown whether FUT8 also contributed to renal fibrosis in immunoglobulin A nephropathy (IgAN). In the present study, we explored the association of serum FUT8 activity with renal tubulointerstitial injury in IgAN patients. METHODS Serum FUT8 activity was measured in 135 IgAN patients and 68 healthy controls from January 2016 to December 2018. The relationships of serum FUT8 activity with clinical and pathological features were analyzed. RESULTS Relative to healthy controls, IgAN patients had significantly higher serum FUT8 activity and upregulation of renal FUT8 protein (p < .05). Among IgAN patients, there was a positive correlation of serum FUT8 activity with renal FUT8 protein expression (p < .05). Multivariable logistic regression analyses showed that serum FUT8 activity was significantly associated with serum creatinine and eGFR (p < .05). Based on a cut-off value determined from ROC curve analysis, we divided IgAN patients into a low serum FUT8 activity group (≤12.2 pmol/h/mL, n = 40) and a high serum FUT8 activity group (>12.2 pmol/h/ml, n = 95). The high serum FUT8 activity group had a higher Oxford T score, increased inflammatory cell infiltration, more severe fibrosis and poor renal function (p < .05). CONCLUSION Serum FUT8 activity was positive association with renal tubulointerstitial injury in IgAN patients.
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Affiliation(s)
- Ning Yang
- Graduate School of Dalian Medical UniversityDalian Medical UniversityDalianChina
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Long‐kai Li
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Hui He
- Graduate School of Dalian Medical UniversityDalian Medical UniversityDalianChina
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xia‐nan Guo
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xue‐feng Yuan
- Graduate School of Dalian Medical UniversityDalian Medical UniversityDalianChina
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Zhi‐tong Li
- Graduate School of Dalian Medical UniversityDalian Medical UniversityDalianChina
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Wei‐dong Wang
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Biao‐jie Qin
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xiang‐ning Du
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xu Zhang
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Shu‐ni Chen
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Hong‐li Lin
- Department of Nephrology, Liaoning Translational Medicine Center of NephrologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
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Storrar J, Chinnadurai R, Sinha S, Kalra PA. The epidemiology and evolution of IgA nephropathy over two decades: A single centre experience. PLoS One 2022; 17:e0268421. [PMID: 36048745 PMCID: PMC9436111 DOI: 10.1371/journal.pone.0268421] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/04/2022] [Indexed: 11/19/2022] Open
Abstract
Background and objectives IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, with an incidence of 2.5 per 100,000 population per year. The 10-year risk of progression to end stage kidney disease (ESKD) or halving of eGFR is 26%. Here we aimed to collect a comprehensive dataset of IgAN patients at our centre over 2 decades to provide real world data, describe outcomes and determine the effects of immunosuppression use. Design, setting, participants and measurements All patients diagnosed with biopsy-proven IgAN at our centre over 2 decades were identified. After exclusions, the total cohort size was 401. Data relating to (i) baseline demographics, (ii) laboratory and urine results, (iii) histological data, and (iv) outcomes of initiation of renal replacement therapy (RRT) and mortality were collected. Results The median age was 45.0 years, with 69.6% male and 57.6% hypertensive; 20.4% received immunosuppression, 29.7% progressed to RRT and 19.7% died, over a median follow up period of 51 months. Baseline eGFR was 46.7ml/min/1.73m2 and baseline uPCR was 183mg/mmol. Median rate of eGFR decline was -1.31ml/min/1.73m2/year. Those with a higher MEST-C score had worse outcomes. Immunosuppression use was associated with an increased rate of improvement in proteinuria, but not with a reduction in RRT or mortality. Factors favouring improved outcomes with immunosuppression use included female gender; lower age, blood pressure and T-score; higher eGFR; and ACEi/ARB use. Conclusions A variety of clinical and histological factors are important in determining risk of progression in IgAN. Therapeutic interventions, particularly use of immunosuppression, should be individualised and guided by these factors.
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Affiliation(s)
- Joshua Storrar
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
- Renal Department, Northern Care Alliance NHS Foundation Trust, Salford Royal Hospital, Salford, United Kingdom
- * E-mail:
| | - Rajkumar Chinnadurai
- Renal Department, Northern Care Alliance NHS Foundation Trust, Salford Royal Hospital, Salford, United Kingdom
| | - Smeeta Sinha
- Renal Department, Northern Care Alliance NHS Foundation Trust, Salford Royal Hospital, Salford, United Kingdom
| | - Philip A. Kalra
- Renal Department, Northern Care Alliance NHS Foundation Trust, Salford Royal Hospital, Salford, United Kingdom
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Crohn's disease may promote inflammation in IgA nephropathy: a case-control study of patients undergoing kidney biopsy. Virchows Arch 2022; 481:553-563. [PMID: 35809093 PMCID: PMC9534821 DOI: 10.1007/s00428-022-03373-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 06/06/2022] [Accepted: 06/24/2022] [Indexed: 11/02/2022]
Abstract
Intestinal immunity has been closely associated with the pathogenesis and progression of renal diseases, a relationship known as the "gut-kidney axis." To determine the association between immunoglobulin A nephropathy (IgAN) and Crohn's disease (CD), a clinico-pathological study was performed on patients who had IgAN with CD (CD-IgAN) and without CD (NOS-IgAN). We enrolled 29 patients diagnosed with IgAN via renal biopsy at the Tokyo Yamate Medical Center from 2009 to 2017. The patients were divided into CD-IgAN (n = 18) and NOS-IgAN (n = 11) and evaluated for clinical and pathological findings. IgA subclasses and galactose-deficient IgA1 (Gd-IgA1) were examined via immunohistochemistry using formalin-fixed paraffin-embedded sections from renal biopsy. Our results showed no significant difference in the extent of mesangial IgA subclasses or Gd-IgA1 deposition according to the presence or absence of CD. Pathologically, however, those with CD-IgAN had remarkably higher percentage of global glomerulosclerosis and extent of interstitial fibrosis and tubular atrophy (IF/TA) compared to those with NOS-IgAN. Moreover, the extent of macrophage infiltration in the glomerulus and interstitium was significantly higher in CD-IgAN than in NOS-IgAN. Clinically, the CD-IgAN group had significantly worse responsiveness to steroid treatment compared to the NOS-IgAN group. In conclusion, the similar immunological characteristics of deposited IgA molecules in the glomeruli between the CD-IgAN and NOS-IgAN groups might suggest their etiological similarity. However, a renal pathology showing advanced glomerular and tubulointerstitial sclerosis accompanying increased macrophage infiltration and highly resistant clinical features in patients with CD-IgAN suggests that some pathophysiological factors in CD, including abnormal intestinal immunity, may promote and activate the inflammatory process in IgAN via undetermined mechanisms.
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Shen Y, Xiao T, Yu Z, Huang Y, He T, Li H, Zhang J, Xiong J, Zhao J. Arteriolar hyalinosis and renal outcomes in patients with immunoglobulin A nephropathy. Ren Fail 2022; 44:994-1003. [PMID: 35658824 PMCID: PMC9176706 DOI: 10.1080/0886022x.2022.2083974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND The relationship between arteriolar hyalinosis and renal progression in immunoglobulin A nephropathy (IgAN) is not fully understood. We aimed to investigate the clinicopathological features and outcomes of IgAN with or without arteriolar hyalinosis. METHODS A total of 762 diagnosed with IgAN patients were retrospectively analyzed. We classified IgAN patients into two groups with or without arteriolar hyalinosis. Then, the clinicopathological characteristics of the two groups were compared. We used Kaplan-Meier survival analysis to compare the composite kidney outcome of the two groups and applied multivariate Cox regression analyses to test the association between arteriolar hyalinosis and composite kidney outcome. RESULTS Overall, 412 (54.1%) patients had arteriolar hyalinosis, including 173 patients diagnosed with hypertension. IgAN patients with arteriolar hyalinosis were older and had higher proteinuria, urea, uric acid, and blood pressure, while lower eGFR than those without arteriolar hyalinosis. Subgroup analysis showed similar results in IgAN patients with hypertension. Kaplan-Meier survival analysis showed that IgAN patients with arteriolar hyalinosis had worse composite kidney outcome than those without arteriolar hyalinosis. In addition, subgroup analysis revealed that patients with hypertension have worse composite kidney outcome than those without hypertension. Multivariate Cox regression analyses confirm that arteriolar hyalinosis (HR 2.57; 95% CI 1.41-4.69; p = 0.002) is an independent risk factor for renal prognosis in IgAN patients. CONCLUSIONS Our study demonstrated that arteriolar hyalinosis is a common vascular lesion in IgAN patients. Arteriolar hyalinosis connects closely with hypertension, and arteriolar hyalinosis is an independent risk factor for renal prognosis in patients with IgAN.
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Affiliation(s)
- Yunzhu Shen
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Tangli Xiao
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - ZhiKai Yu
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Yinghui Huang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Ting He
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Haiyang Li
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Jun Zhang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Jiachuan Xiong
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Jinghong Zhao
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
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The Diagnostic and Predictive Significance of Immune-Related Genes and Immune Characteristics in the Occurrence and Progression of IgA Nephropathy. J Immunol Res 2022; 2022:9284204. [PMID: 35528619 PMCID: PMC9071862 DOI: 10.1155/2022/9284204] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/25/2022] [Accepted: 04/04/2022] [Indexed: 11/18/2022] Open
Abstract
Objective To investigate the potential diagnostic and predictive significance of immune-related genes in IgA nephropathy (IgAN) and discover the abnormal glomerular inflammation in IgAN. Methods GSE116626 was used as a training set to identify different immune-related genes (DIRGs) and establish machine learning models for the diagnosis of IgAN; then, a nomogram model was generated based on GSE116626, and GSE115857 was used as a test set to evaluate its clinical value. Short Time-Series Expression Miner (STEM) analysis was also performed to explore the changing trend of DIRGs with the progression of IgAN lesions. GSE141344 was used with DIRGs to establish the ceRNA network associated with IgAN progression. Finally, ssGSEA analysis was performed on the GSE141295 dataset to discover the abnormal inflammation in IgAN. Results Machine learning (ML) performed excellently in diagnosing IgAN using six DIRGs. A nomogram model was constructed to predict IgAN based on the six DIRGs. Three trends related to IgAN lesions were identified using STEM analysis. A ceRNA network associated with IgAN progression which contained 8 miRNAs, 14 lncRNAs, and 3 mRNAs was established. A higher macrophage ratio and lower CD4+ T cell ratio in IgAN compared to controls were observed, and the correlation between macrophages and monocytes in the glomeruli of IgAN patients was inverse compared to controls. Conclusion This study reveals the diagnostic and predictive significance of DIRGs in IgAN and finds that the imbalance between macrophages and CD4+ immune cells may be an important pathomechanism of IgAN. These results provide potential directions for the treatment and prevention of IgAN.
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Gostomska-Pampuch K, Gamian A, Rawicz-Pruszyński K, Gęca K, Tkaczuk-Włach J, Jonik I, Ożga K, Staniszewska M. Proteins in human body fluids contain in vivo antigen analog of the melibiose-derived glycation product: MAGE. Sci Rep 2022; 12:7520. [PMID: 35525899 PMCID: PMC9079080 DOI: 10.1038/s41598-022-11638-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/27/2022] [Indexed: 01/16/2023] Open
Abstract
Melibiose-derived AGE (MAGE) is an advanced glycation end-product formed in vitro in anhydrous conditions on proteins and protein-free amino acids during glycation with melibiose. Our previous studies revealed the presence of MAGE antigen in the human body and tissues of several other species, including muscles, fat, extracellular matrix, and blood. MAGE is also antigenic and induces generation of anti-MAGE antibody. The aim of this paper was to identify the proteins modified by MAGE present in human body fluids, such as serum, plasma, and peritoneal fluids. The protein-bound MAGE formed in vivo has been isolated from human blood using affinity chromatography on the resin with an immobilized anti-MAGE monoclonal antibody. Using mass spectrometry and immunochemistry it has been established that MAGE epitope is present on several human blood proteins including serum albumin, IgG, and IgA. In serum of diabetic patients, mainly the albumin and IgG were modified by MAGE, while in healthy subjects IgG and IgA carried this modification, suggesting the novel AGE can impact protein structure, contribute to auto-immunogenicity, and affect function of immunoglobulins. Some proteins in peritoneal fluid from cancer patients modified with MAGE were also observed and it indicates a potential role of MAGE in cancer.
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Affiliation(s)
- Kinga Gostomska-Pampuch
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Chalubinskiego 10, 50-368, Wrocław, Poland
- Laboratory of Medical Microbiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114, Wrocław, Poland
| | - Andrzej Gamian
- Laboratory of Medical Microbiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114, Wrocław, Poland
| | - Karol Rawicz-Pruszyński
- Department of Surgical Oncology, Medical University of Lublin, Radziwillowska 13, 20-080, Lublin, Poland
| | - Katarzyna Gęca
- Department of Surgical Oncology, Medical University of Lublin, Radziwillowska 13, 20-080, Lublin, Poland
| | - Joanna Tkaczuk-Włach
- Diagnostic Techniques Unit, Collegium Maximum, Medical University of Lublin, Staszica 4/6, 20-081, Lublin, Poland
| | - Ilona Jonik
- Faculty of Science and Health, The John Paul II Catholic University of Lublin, Konstantynów 1J, 20-708, Lublin, Poland
| | - Kinga Ożga
- Faculty of Science and Health, The John Paul II Catholic University of Lublin, Konstantynów 1J, 20-708, Lublin, Poland
| | - Magdalena Staniszewska
- Faculty of Science and Health, The John Paul II Catholic University of Lublin, Konstantynów 1J, 20-708, Lublin, Poland.
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Ding Y, Li H, Xu L, Wang Y, Yang H. Identification and Validation of Prognostic Biomarkers Specifically Expressed in Macrophage in IgA Nephropathy Patients Based on Integrated Bioinformatics Analyses. Front Mol Biosci 2022; 9:884588. [PMID: 35601837 PMCID: PMC9117719 DOI: 10.3389/fmolb.2022.884588] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/06/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and a frequent cause of end-stage renal disease. The inflammation cascade due to the infiltration and activation of immune cells in glomeruli plays an essential role in the progression of IgAN. In this study, we aimed to identify hub genes involved in immune infiltration and explore potential prognostic biomarkers and therapeutic targets in IgAN. Methods: We combined the single-cell and bulk transcriptome profiles of IgAN patients and controls with clinical data. Through single-cell analysis and weighted gene co-expression network analysis (WGCNA), Gene Ontology (GO) enrichment analysis, and differentially expressed gene (DEG) analysis in the bulk profile, we identified cell-type-specific potential hub genes in IgAN. Real hub genes were extracted via validation analysis and clinical significance analysis of the correlation between the expression levels of genes and the estimated glomerular filtration rate (eGFR) in the external dataset. Gene set enrichment analysis was performed to predict the probable roles of the real hub genes in IgAN. Results: A total of eleven cell clusters were classified via single-cell analysis, among which macrophages showed a variable proportion between the IgAN and normal control samples. We recognized six functional co-expression gene modules through WGCNA, among which the black module was deemed an IgAN-related and immune-involving module via GO enrichment analysis. DEG analysis identified 45 potential hub genes from genes enriched in GO terms. A total of twenty-three potential hub genes were specifically expressed in macrophages. Furthermore, we validated the differential expression of the 23 potential hub genes in the external dataset and identified nine genes with prognostic significance as real hub genes, viz., CSF1R, CYBB, FPR3, GPR65, HCLS1, IL10RA, PLA2G7, TYROBP, and VSIG4. The real hub gens are thought to contribute to immune cell regulation, immunoreaction, and regulation of oxidative stress, cell proliferation, and material metabolism. Conclusion: In this study, we demonstrated that macrophages infiltrated the glomeruli and contributed to the inflammatory response in IgAN. Based on integrated bioinformatics analyses of single-cell and bulk transcriptome data, we highlighted nine genes as novel prognostic biomarkers, which may enable the development of innovative prognostic and therapeutic strategies for IgAN.
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Affiliation(s)
- Yuqing Ding
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hua Li
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lichen Xu
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yukun Wang
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huiying Yang
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Huiying Yang,
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Correlation of Anti-HLA IgA Alloantibodies and Fc Receptor Motives with Kidney Allograft Survival. IMMUNO 2022. [DOI: 10.3390/immuno2020023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Immunoglobulin A (IgA) is the most abundant antibody isotype in humans and anti-HLA IgA was found in sera of transplant recipients. Focusing on patients awaiting kidney re-transplantation, we tested the impact of anti-HLA-class I/II IgA antibodies on graft survival. We analyzed 276 patients with and 238 without allograft failure. Eight motives of the Fcα receptor (FCAR) and Fcγ receptor were analyzed in patients with allograft failure. The distribution of anti-HLA IgA1/A2 and IgG antibodies differed significantly (p < 0.0001) between both patient groups, and IgA1 plus IgA2 antibodies were more abundant in patients with allograft failure. Allograft survival was significantly impaired if anti-HLA-class I plus II IgA was present, in the first 105 months (9 years) of follow-up (median of 43 vs. >105 months, p = 0.007). Patients with anti-HLA IgA and IgG vs. anti-HLA IgG only had a significantly shorter allograft survival within that follow-up period (88 vs. >105 months, p = 0.008). Moreover, allograft survival was shorter (p = 0.02) in carriers of GG vs. AA + AG genotypes of FCAR rs16986050. Thus, the presence of anti-HLA IgA plus IgG vs. IgG only was associated with shorter kidney allograft survival and FCAR motives may impact on graft survival.
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Sun J. Meta-Analysis of the Effectiveness and Safety of Glucocorticoid for the Treatment of IgA Kidney Disease. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:5466331. [PMID: 35295167 PMCID: PMC8920660 DOI: 10.1155/2022/5466331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/25/2021] [Accepted: 01/10/2022] [Indexed: 11/18/2022]
Abstract
Purpose To explore the effect of glucocorticoid on immune globulin A (IgA) nephropathy by meta-analysis. Method Search the data and literature libraries of ScienceDirect, EBSCO, Wiley, PubMed, CBMdisc, and CNKI and collect the literature on the treatment of IgA nephropathy with glucocorticoids as randomized controlled trials published at home and abroad from 1995 to 2021. The standardized mean difference (SMD) and 95% confidence interval (CI) were calculated by fixed-effects model. RevMan 5.0 software was used for meta-analysis of the subgroups of overall curative effect, different degree of proteinuria, different course of treatment, different creatinine level, and combined ACEI. Result ① The overall efficacy of glucocorticoid in the treatment of IgA nephropathy was better than that in the control group (P = 0.00001). ② The efficacy of glucocorticoid treatment in patients with IgA nephropathy with proteinuria greater than 1.50 g/d and less than 1.50 g/d was better than that in the control group (P < 0.01). ③ For IgA nephropathy patients with serum creatinine less than 1.50 mg/dl, the curative effect of glucocorticoid treatment was better than that of the control group (P < 0.01). ④ The effects of short-term treatment (<1 year) and long-term treatment (≥1 year) with glucocorticoid were better than those in the control group (P < 0.01). ⑤ The effect of hormone combined with ACEI drugs on IgA nephropathy was more significant (P < 0.01). Conclusion The overall efficacy of glucocorticoid in the treatment of IgA nephropathy is accurate. Hormone treatment is effective for different degrees of IgA nephropathy. Considering that there is no significant effect on the efficacy of different courses of treatment, it is suggested that the course of hormone treatment can be appropriately shortened. Hormone combined with angiotensin-converting enzyme inhibitors (ACEI) can reduce proteinuria more effectively than ACEI drugs alone.
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Affiliation(s)
- Jieqiong Sun
- Nephrology Department, First People's Hospital of Linping District, Hangzhou, China
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Song Y, Huang X, Yu G, Qiao J, Cheng J, Wu J, Chen J. Pathogenesis of IgA Vasculitis: An Up-To-Date Review. Front Immunol 2021; 12:771619. [PMID: 34858429 PMCID: PMC8630619 DOI: 10.3389/fimmu.2021.771619] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/21/2021] [Indexed: 11/13/2022] Open
Abstract
Immunoglobin A (IgA) vasculitis (IgAV), formerly called the Henoch-Schönlein purpura (HSP), is a small vessel vasculitis, characterized by IgA1-dominant immune deposition at diseased vessel walls. IgAV is the most common form of vasculitis in children; typical symptoms include palpable purpura, arthritis or arthralgia, abdominal pain, and hematuria or proteinuria. Galactose-deficient IgA1 is detected in the tissues of the kidney and skin in patients with IgAV; it forms immune complexes leading to subsequent immune reactions and injuries. This report provides the recent advances in the understanding of environmental factors, genetics, abnormal innate and acquired immunity, and the role of galactose-deficient IgA1 immunocomplexes in the pathogenesis of IgAV.
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Affiliation(s)
- Yan Song
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory Under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Xiaohan Huang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory Under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Guizhen Yu
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory Under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Jianjun Qiao
- Department of Dermatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jun Cheng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory Under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Jianyong Wu
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory Under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory Under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
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Selvaskandan H, Barratt J, Cheung CK. Immunological drivers of IgA nephropathy: Exploring the mucosa-kidney link. Int J Immunogenet 2021; 49:8-21. [PMID: 34821031 DOI: 10.1111/iji.12561] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 10/10/2021] [Accepted: 10/25/2021] [Indexed: 12/14/2022]
Abstract
IgA nephropathy (IgAN) is the most common pattern of primary glomerular disease reported worldwide. Up to 40% of those with IgAN progress to end-stage kidney disease within 20 years of diagnosis, with no currently available disease-specific treatment. This is likely to change rapidly, with evolving insights into the mechanisms driving this disease. IgAN is an immune-complex-mediated disease, and its pathophysiology has been framed by the 'four-hit hypothesis', which necessitates four events to occur for clinically significant disease to develop. However, this hypothesis does not explain the wide variability observed in its presentation or clinical progression. Recently, there has been great interest in exploring the role of the mucosal immune system in IgAN, especially given the well-established link between mucosal infections and disease flares. Knowledge of antigen-mucosal interactions is now being successfully leveraged for therapeutic purposes; the gut-directed drug Nefecon (targeted release formulation-budesonide) is on track to become the first medication to be approved specifically for the treatment of IgAN. In this review, we examine established immunological paradigms in IgAN, explore how antigen-mucosal immune responses drive disease, and discuss how this knowledge is being used to develop new treatments.
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Affiliation(s)
- Haresh Selvaskandan
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Jonathan Barratt
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Chee Kay Cheung
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
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Shen J, Wu Q, Liang T, Zhang J, Bai J, Yuan M, Shen P. TRIM40 inhibits IgA1-induced proliferation of glomerular mesangial cells by inactivating NLRP3 inflammasome through ubiquitination. Mol Immunol 2021; 140:225-232. [PMID: 34763147 DOI: 10.1016/j.molimm.2021.10.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 10/09/2021] [Accepted: 10/17/2021] [Indexed: 12/16/2022]
Abstract
IgA nephropathy, as the most common type of glomerulonephritis, causes chronic renal disease and progresses into kidney failure. Aberrant IgA deposition in the glomerular mesangium induces NLRP3 inflammasome activation for massive local inflammation, and is recognized as the primary pathogenesis in IgA nephropathy. Tripartite motif (TRIM)-containing proteins are E3 ubiquitin ligases that possess crucial regulatory functions in innate immunity, but their functional roles in IgA nephropathy are still unclear. Here, we aimed to identify TRIM-containing proteins that regulate IgA nephropathy and their underlying mechanisms. An in vitro IgA1-induction model was established in glomerular mesangial cells (GMCs) and showed that IgA1 could promote GMC proliferation by activating NLRP3 inflammasome. TRIM40, which was downregulated by IgA1 and interacted with NLRP3, was recognized as a promising candidate. In addition, TRIM40 could suppress IgA1-induced GMC proliferation by inhibiting the activation of NLRP3 inflammasome. Based on coimmunoprecipitation and ubiquitination assays, we confirmed that TRIM40 could mediate the ubiquitination of NLRP3, which explained its regulatory effects on NLRP3 inflammasome and GMC proliferation. More importantly, a dominant-negative mutant of TRIM40 lacking the RING domain (ΔRING) did not affect NLRP3 ubiquitination, and had no effects on IgA1-induced GMC proliferation or NLRP3 inflammasome activation. This study revealed the biological functions of TRIM40 in IgA nephropathy, facilitating its application as therapeutic target for IgA nephropathy and other NLRP3 inflammasome-relevant diseases.
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Affiliation(s)
- Jiaojiao Shen
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China
| | - Qing Wu
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, China
| | - Tingyu Liang
- Department of Pathology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China
| | - Jian Zhang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China
| | - Jiayuan Bai
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China
| | - Meijie Yuan
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China
| | - Peicheng Shen
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, China; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine (20DZ2272200), China.
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