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Wu X, Pan B, Chu C, Zhang Y, Ma J, Xing Y, Ma Y, Zhu W, Zhong H, Alimu A, Zhou G, Liu S, Chen W, Li X, Puyi S. CXCL16/CXCR6/TGF-β Feedback Loop Between M-MDSCs and Treg Inhibits Anti-Bacterial Immunity During Biofilm Infection. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2409537. [PMID: 39716908 PMCID: PMC11831521 DOI: 10.1002/advs.202409537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/29/2024] [Indexed: 12/25/2024]
Abstract
Staphylococcus aureus (S. aureus) is a leading cause of Periprosthetic joint infection (PJI), a severe complication after joint arthroplasty. Immunosuppression is a major factor contributing to the infection chronicity of S. aureus PJI, posing significant treatment challenges. This study investigates the relationship between the immunosuppressive biofilm milieu and S. aureus PJI outcomes in both discovery and validation cohorts. This scRNA-seq analysis of synovium from PJI patients reveals an expansion and heightened activity of monocyte-related myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Treg). Importantly, CXCL16 is significantly upregulated in M-MDSCs, with its corresponding CXCR6 receptor also elevated on Treg. M-MDSCs recruit Treg and enhance its activity via CXCL16-CXCR6 interactions, while Treg secretes TGF-β, inducing M-MDSCs proliferation and immunosuppressive activity. Interfering with this cross-talk in vivo using Treg-specific CXCR6 knockout PJI mouse model reduces M-MDSCs/Treg-mediated immunosuppression and alleviates bacterial burden. Immunohistochemistry and recurrence analysis show that PJI patients with CXCR6high synovium have poor prognosis. This findings highlight the critical role of CXCR6 in Treg in orchestrating an immunosuppressive microenvironment and biofilm persistence during PJI, offering potential targets for therapeutic intervention.
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Affiliation(s)
- Xiaoyu Wu
- Department of Joint SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Clinical Research Center for Orthopedic DiseasesThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Orthopaedics and TraumatologyGuangzhouGuangdong510080China
| | - Baiqi Pan
- Department of Joint SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Clinical Research Center for Orthopedic DiseasesThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Orthopaedics and TraumatologyGuangzhouGuangdong510080China
| | - Chenghan Chu
- Department of Joint SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Clinical Research Center for Orthopedic DiseasesThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Orthopaedics and TraumatologyGuangzhouGuangdong510080China
| | - Yangchun Zhang
- Department of OrthopedicsThe People's Hospital of Baoan ShenzhenShenzhenGuangdong518101China
- Department of OrthopedicsThe Second Affiliated Hospital of Shenzhen UniversityShenzhenGuangdong518101China
| | - Jinjin Ma
- Technology School of MedicineSouth China University of TechnologyGuangzhouGuangdong510640China
- Shien‐ming Wu School of Intelligent EngineeringSouth China University of TechnologyGuangzhouGuangdong510640China
| | - Yang Xing
- Department of Joint SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Clinical Research Center for Orthopedic DiseasesThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Orthopaedics and TraumatologyGuangzhouGuangdong510080China
| | - Yuanchen Ma
- Department of OrthopedicsGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouGuangdong519041China
| | - Wengang Zhu
- Department of Joint OrthopedicsYuebei People's HospitalShaoguanGuangdong512099China
| | - Huan Zhong
- Department of Joint SurgeryAffiliated Hospital of Guangdong Medical UniversityZhanjiangGuangdong524002China
| | - Aerman Alimu
- Department of Joint SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Clinical Research Center for Orthopedic DiseasesThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Orthopaedics and TraumatologyGuangzhouGuangdong510080China
| | - Guanming Zhou
- Department of OrthopedicsFoshan Hospital of Traditional Chinese MedicineGuangzhouGuangdong528051China
| | - Shuying Liu
- Department of Histology and EmbryologyZhongshan School of MedicineSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Weishen Chen
- Department of Joint SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Clinical Research Center for Orthopedic DiseasesThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Orthopaedics and TraumatologyGuangzhouGuangdong510080China
| | - Xiang Li
- Guangdong Provincial Clinical Research Center for Orthopedic DiseasesThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Department of Spine SurgeryThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510080China
| | - Sheng Puyi
- Department of Joint SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Clinical Research Center for Orthopedic DiseasesThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510080China
- Guangdong Provincial Key Laboratory of Orthopaedics and TraumatologyGuangzhouGuangdong510080China
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Ji L, Mei X, Yuan W, Guo H, Zhang Y, Zhang Z, Zou Y, Liu Y, Zhu H, Qian Z, Shen Y. Plasma Interleukin-35 Levels Predict the Prognosis in Patients with HBV-Related Acute-on-Chronic Liver Failure. Viruses 2024; 16:1960. [PMID: 39772266 PMCID: PMC11680333 DOI: 10.3390/v16121960] [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: 11/30/2024] [Revised: 12/13/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
This study aimed to investigate the impact of IL-35 on the prognosis of patients with HBV-ACLF. We recruited 69 patients with HBV-ACLF, 20 patients with chronic hepatitis B (CHB), 17 patients with liver cirrhosis (LC), and 20 healthy controls (HCs) from a regional infectious disease treatment center in China. Plasma levels of IL-35 at baseline were detected using ELISA. Plasma IL-35 levels in the HBV-ACLF group were the highest among all four groups. Furthermore, survivors exhibited significantly higher IL-35 levels than non-survivors (p < 0.001). IL-35 levels correlated with MELD (r = -0.678, p < 0.001), COSSH-ACLF IIs (r = -0.581, p < 0.001), alpha-fetoprotein (AFP) (r = 0.433, p < 0.001), creatinine (Cr) (r =-0.396, p = 0.001), and lactate (r =-0.38, p =0.001). The combination of plasma IL-35 and MELD score had the highest mortality prediction efficiency, with an area under the curve (AUC) of 0.895 (95% CI: 0.812-0.978, p < 0.001), a sensitivity of 80.6%, and a specificity of 93.9%. Additionally, the Kaplan-Meier analysis revealed that lower levels of IL-35 (≤191.5pg/mL) were associated with poorer survival rates in HBV-ACLF patients (p < 0.001). Our results demonstrated that IL-35 could be an effective predictive marker for the prognosis of HBV-ACLF and improve the predictive performance when combined with the MELD score.
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Affiliation(s)
- Liujuan Ji
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Xue Mei
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Wei Yuan
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Hongying Guo
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Yuyi Zhang
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Zhengguo Zhang
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Ying Zou
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Yu Liu
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Hui Zhu
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Zhiping Qian
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; (L.J.); (X.M.); (W.Y.); (H.G.); (Y.Z.); (Z.Z.); (Y.Z.); (Y.L.); (H.Z.)
| | - Yinzhong Shen
- Department of Infection and Immunity, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
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Osuna-Gómez R, Barril S, Mulet M, Zamora Atenza C, Millan-Billi P, Pardessus A, Brough DE, Sabzevari H, Semnani RT, Castillo D, Vidal S. The immunoregulatory role of IL-35 in patients with interstitial lung disease. Immunology 2023; 168:610-621. [PMID: 36273280 DOI: 10.1111/imm.13596] [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: 04/05/2022] [Accepted: 10/20/2022] [Indexed: 11/29/2022] Open
Abstract
Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF-β and IL-35, a recently identified heterodimeric cytokine that belongs to the IL-12 cytokine family. However, the effect of regulatory IL-35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL-35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL-35 and different profibrotic cytokines in fibrotic (F-ILD) and non-fibrotic (NF-ILD) patients by ELISA were compared to that of intracellular IL-35 and IL-17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL-35 (rIL-35) and TGF-β (rTGF-β), which were evaluated by flow cytometry. We observed that BAL concentration of IL-35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF-β (p < 0.001) and IL-17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL-35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL-17 + CD4+ T cells (p < 0.001). The percentage of IL-35 + CD4+ T cells correlated positively with BAL concentration of IL-35 (p = 0.02), but correlated negatively with BAL concentrations of IL-17 (p = 0.007) and TGF-β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF-β: IL-35 ratio of 1:4, an enhanced percentage of IL-35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL-17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL-35 to the BAL from F patients until a 1:4 ratio of TGF-β: IL-35 was reached, a significantly increased percentage of IL-35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL-17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL-35 may induce an anti-fibrotic response, regulating the effect of TGF-β and the inflammatory response on CD4+ T cells. In addition, the TGF-β: IL-35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD.
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Affiliation(s)
- Rubén Osuna-Gómez
- Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Silvia Barril
- Respiratory Department, Institut de Recerca Biomèdica de Lleida (IRBLleida), Hospital Universitari Arnau de Vilanova-Santa María, Translational Research in Respiratory Medicine, Universitat de Lleida (UdL), Lleida, Spain
- Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Maria Mulet
- Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Carlos Zamora Atenza
- Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Paloma Millan-Billi
- Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Respiratory Department, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain
| | - Ana Pardessus
- Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | | | | | - Diego Castillo
- Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Respiratory Department, Institut de Recerca Biomèdica de Lleida (IRBLleida), Hospital Universitari Arnau de Vilanova-Santa María, Translational Research in Respiratory Medicine, Universitat de Lleida (UdL), Lleida, Spain
- Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Silvia Vidal
- Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
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Hildreth AD, Padilla ET, Tafti RY, Legala AR, O'Sullivan TE. Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production. Cell Rep 2023; 42:112141. [PMID: 36807146 PMCID: PMC10435668 DOI: 10.1016/j.celrep.2023.112141] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/02/2022] [Accepted: 02/06/2023] [Indexed: 02/22/2023] Open
Abstract
Tissue-resident immune cells are critical to the initiation and potentiation of inflammation. However, the tissue-protective cellular communication networks initiated by resident immunity during sterile inflammation are not well understood. Using single-cell transcriptomic analysis, we show the liver-resident cell connectome and signalome during acute liver injury. These analyses identify Il12b as a central regulator of liver injury-associated changes in gene expression. Interleukin (IL)-12 produced by conventional type 1 dendritic cells (cDC1s) is required for protection during acute injury through activation of interferon (IFN)-γ production by liver-resident type 1 innate lymphoid cells (ILC1s). Using a targeted in vivo CRISPR-Cas9 screen of innate immune sensing pathways, we find that cDC1-intrinsic cGAS-STING signaling acts upstream of IL-12 production to initiate early protective immune responses. Our study identifies the core communication hubs initiated by tissue-resident innate immune cells during sterile inflammation in vivo and implicates cDC1-derived IL-12 as an important regulator of this process.
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Affiliation(s)
- Andrew D Hildreth
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Eddie T Padilla
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Rana Yakhshi Tafti
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Akshara R Legala
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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Adams DE, Heuer LS, Rojas M, Zhang W, Ridgway WM. Mutated Pkhd1 alone is sufficient to cause autoimmune biliary disease on the nonobese diabetic (NOD) genetic background. Immunogenetics 2023; 75:27-37. [PMID: 36097289 PMCID: PMC9468241 DOI: 10.1007/s00251-022-01276-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/27/2022] [Indexed: 01/21/2023]
Abstract
We previously reported that nonobese diabetic (NOD) congenic mice (NOD.c3c4 mice) developed an autoimmune biliary disease (ABD) with similarities to human primary biliary cholangitis (PBC), including anti-mitochondrial antibodies and organ-specific biliary lymphocytic infiltrates. We narrowed the possible contributory regions in a novel NOD.Abd3 congenic mouse to a B10 congenic region on chromosome 1 ("Abd3") and a mutated Pkhd1 gene (Pkhd1del36-67) upstream from Abd3, and we showed via backcrossing studies that the NOD genetic background was necessary for disease. Here, we show that NOD.Abd3 mice develop anti-PDC-E2 autoantibodies at high levels, and that placing the chromosome 1 interval onto a scid background eliminates disease, demonstrating the critical role of the adaptive immune system in pathogenesis. While the NOD genetic background is essential for disease, it was still unclear which of the two regions in the Abd3 locus were necessary and sufficient for disease. Here, using a classic recombinant breeding approach, we prove that the mutated Pkhd1del36-67 alone, on the NOD background, causes ABD. Further characterization of the mutant sequence demonstrated that the Pkhd1 gene is disrupted by an ETnII-beta retrotransposon inserted in intron 35 in an anti-sense orientation. Homozygous Pkhd1 mutations significantly affect viability, with the offspring skewed away from a Mendelian distribution towards NOD Pkhd1 homozygous or heterozygous genotypes. Cell-specific abnormalities, on a susceptible genetic background, can therefore induce an organ-specific autoimmunity directed to the affected cells. Future work will aim to characterize how mutant Pkhd1 can cause such an autoimmune response.
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Affiliation(s)
- David E Adams
- Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
- Department of Internal Medicine, Cincinnati VA Medical Center, Cincinnati, OH, 45267, USA
| | - Luke S Heuer
- Department of Internal Medicine, Sacramento VA Medical Center, VA Northern California Health Care System, Mather, CA, 95655, USA
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Manuel Rojas
- School of Medicine and Health Sciences, Doctoral Program in Biological and Biomedical Sciences, Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogota, Colombia
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Weici Zhang
- Department of Internal Medicine, Sacramento VA Medical Center, VA Northern California Health Care System, Mather, CA, 95655, USA
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - William M Ridgway
- Department of Internal Medicine, Sacramento VA Medical Center, VA Northern California Health Care System, Mather, CA, 95655, USA.
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA.
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Zhang W, Shao T, Leung PSC, Tsuneyama K, Heuer L, Young HA, Ridgway WM, Gershwin ME. Dual B-cell targeting therapy ameliorates autoimmune cholangitis. J Autoimmun 2022; 132:102897. [PMID: 36029718 PMCID: PMC10311358 DOI: 10.1016/j.jaut.2022.102897] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVE The ability to regulate B cell development has long been recognized to have therapeutic potential in a variety of autoimmune diseases. However, despite the presence of a classic autoantibody in primary biliary cholangitis (PBC), B cell depleting therapy and indeed therapy with other biologic agents has been disappointing. Unsuccessful treatment using Rituximab is associated with elevation of B-cell activating factor (BAFF) level. Indeed, therapies for PBC remain directed at modulating bile salt biology, rather than targeting effector pathways. With these data in mind, we proposed that targeting two major stages of B cell development, namely long-lived memory B cells and short-lived peripheral autoreactive plasma cells would have therapeutic potential. METHODS To address this thesis, we administrated anti-BAFF and anti-CD20 monoclonal antibody to ARE-Del mice, a well-characterized murine model of human PBC. We evaluated and compared the therapeutic efficacy of the two agents individually and the combination of anti-BAFF and anti-CD20 in female mice with well-established disease. RESULTS Our data demonstrate that there was an increased level of B cell depletion that resulted in a significantly more effective clinical and serologic response using the combination of agents as compared with the use of the individual agents. The combination of anti-BAFF and anti-CD20 treatment was more effective in reducing serum levels of antimitochondrial antibody (AMA), total IgM and IgG compared to mice treated with the 2 individual agents. Combination treatment efficiently depleted B cells in the peripheral blood, peritoneal cavity and spleen. Importantly, we identified a unique IgM+ FCRL5+ B cell subset which was sensitive to dual B-cell targeting therapy and depletion of this unique population was associated with reduced portal infiltration and bile duct damage. Taken together, our data indicate that dual B cell targeting therapy with anti-BAFF and anti-CD20 not only led to the efficient depletion of B cells both in the peripheral blood and tissues, but also led to significant clinical improvement. These findings highlight the potential application of combination of anti-BAFF and anti-CD20 in treating patients with PBC. However, additional studies in other animal models of PBC should be undertaken before considering human trials in those PBC patients who have incomplete responses to conventional therapy.
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Affiliation(s)
- Weici Zhang
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California Davis, CA, USA.
| | - Tihong Shao
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California Davis, CA, USA; Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University; Hefei, China.
| | - Patrick S C Leung
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California Davis, CA, USA.
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School; Tokushima, Japan.
| | - Luke Heuer
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California Davis, CA, USA.
| | - Howard A Young
- Center for Cancer Research, National Cancer Institute-Frederick; Frederick, MD, USA.
| | - William M Ridgway
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California Davis, CA, USA.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California Davis, CA, USA.
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The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis. J Immunol Res 2022; 2022:7111445. [PMID: 35300072 PMCID: PMC8922149 DOI: 10.1155/2022/7111445] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/31/2021] [Accepted: 01/06/2022] [Indexed: 11/18/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease primarily featured by autoimmune-mediated damage of intrahepatic small- and medium-sized bile ducts. Elevated serum proinflammatory cytokines, serum anti-mitochondrial antibodies (AMAs), liver inflammation, and fibrosis are also hallmarks of PBC disease. However, whether the elevated proinflammatory cytokines play a role in autoimmune cholangitis remains unknown. Herein, we utilized the p40-/-IL-2Rα-/- PBC mouse model to investigate the roles of proinflammatory cytokines IL-18, IL-21, and IFN-γ in the onset and progression of PBC. IL-18-/-, IFN-γ-/-, and IL-21-/- mice were crossed with p40-/-IL-2Ra+/- mice, respectively, to produce corresponding cytokine-deficient PBC models. Autoantibody level, liver inflammation, and bile duct injury were analyzed. We found that livers from p40-/-IL-2Rα-/- mice exhibit similar transcriptomic characters of PBC patients. In p40-/-IL-2Rα-/- mice, deletion of IL-18 has no remarkable effect on disease progression, while deletion of IL-21 indicates that it is necessary for AMA production but independent of liver inflammation and cholangitis. IFN-γ is responsible for both AMA production and liver inflammation in our model. Our results demonstrate that different proinflammatory cytokines can regulate different effector functions in PBC pathogenesis and need to be considered in PBC treatment.
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Li Z, Zhu L, Zheng H, Jiang W, Wang Y, Jiang Z, Xu J. Serum IL-35 levels is a new candidate biomarker of cancer-related cachexia in stage IV non-small cell lung cancer. Thorac Cancer 2022; 13:716-723. [PMID: 35142058 PMCID: PMC8888146 DOI: 10.1111/1759-7714.14307] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/21/2022] Open
Abstract
Background Cancer‐related cachexia is a major cause of treatment resistance and poor prognosis, which is characterized by anorexia and skeletal muscle depletion. To date, there have been no reports on the relationship between IL‐35 and cancer‐related cachexia in patients with stage IV non‐small cell lung cancer. Methods Serum IL‐35 levels in 86 patients with stage IV NSCLC were measured and statistically analyzed based on patients' clinicopathological parameters. Serum albumin levels, C‐reactive protein, and skeletal muscle index (SMI) of the patients were also determined. In vivo studies using a mouse model were also conducted by subcutaneously injecting immunodeficiency (SCID) mice with overexpressing IL‐35 cell lines and determining their daily food intake, bodyweight and muscle atrophy. Cachexia indicators were measured again after administering the mice with an anti‐IL35 neutralizing antibody. Results Patients with stage IV NSCLC had significantly higher serum IL‐35 levels than the healthy controls. Similarly, circulating IL‐35 levels were significantly higher in patients with cachexia than those without. The SMI values of patients with high serum IL‐35 levels were significantly lower than those with low serum IL‐35 levels. Mice subcutaneously injected with LLC PLV‐IL‐35 cell lines exhibited anorexia, weight loss, and muscle atrophy. Moreover, these symptoms were significantly reduced after administering the mice with an anti‐IL35 neutralizing antibody. Conclusions This study reveals that high serum IL‐35 expression is associated with non‐small cell lung cancer cachexia and skeletal muscle atrophy. These findings highlight its potential as a biomarker and therapeutic target for controlling cachexia of advanced lung cancer.
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Affiliation(s)
- Zengxun Li
- Department of Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Lei Zhu
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Han Zheng
- Department of Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wenna Jiang
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yifei Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zhansheng Jiang
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jie Xu
- Department of Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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9
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Wu D, Wang L, Hong D, Zheng C, Zeng Y, Ma H, Lin J, Chen J, Zheng R. Interleukin 35 contributes to immunosuppression by regulating inflammatory cytokines and T cell populations in the acute phase of sepsis. Clin Immunol 2022; 235:108915. [PMID: 34995813 DOI: 10.1016/j.clim.2021.108915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 02/17/2021] [Accepted: 12/22/2021] [Indexed: 12/30/2022]
Abstract
Cytokines interact closely with each other and play a crucial role in the progression of sepsis. We focused on the associations of a cytokine network with IL-35 in sepsis. First, the retrospective study included 42 patients with sepsis and 23 healthy controls. Blood samples were collected from patients on days 1, 2, 4. Levels of IL-35, IL-1β, IL-4, IL-6, IL-10, IL-17A, TNF-α and IFN-γ were measured. They all increased to various extend on days 1, 2, 4, and strongly associated with markers of disease severity. Network analysis revealed a network formed by IL-35, with IL-6, IL-10, IL-17A, TNF-α and IFN-γ throughout the acute phase of sepsis(days 1, 2 and4). Then, the CLP-induced septic rats were used. The recombinant human IL-35(rIL-35) upregulated the levels of IL-10, but downregulated IL-4, IL-6, IL-17A, TNF-α and IFN-γ, while it had no significant effect on IL-1β, and upregulated the percentages of CD4+CD25+Tregs, and iTR35, but downregulated Teff cells in the peripheral blood. The rIL-35 reduced inflammation damage and improved prognosis of the septic rats. IL-35 forms a network with other cytokines and plays a major role in the immunopathogenesis of sepsis.
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Affiliation(s)
- Dansen Wu
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China.
| | - Liming Wang
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China
| | - Donghuang Hong
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China
| | - Caifa Zheng
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China
| | - Yongping Zeng
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China
| | - Huolan Ma
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China
| | - Jing Lin
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China
| | - Jialong Chen
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China
| | - Ronghui Zheng
- Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Provincial Center for Critical Care Medicine, Fujian Medical University, Fuzhou 350001, Fujian, China
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10
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Reuveni D, Brezis MR, Brazowski E, Vinestock P, Leung PSC, Thakker P, Gershwin ME, Zigmond E. Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis. Front Immunol 2021; 12:718841. [PMID: 34484224 PMCID: PMC8414574 DOI: 10.3389/fimmu.2021.718841] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/29/2021] [Indexed: 12/30/2022] Open
Abstract
Background and Aims Primary Biliary Cholangitis (PBC) is an organ-specific autoimmune liver disease. Mononuclear phagocytes (MNPs), comprise of monocyte, dendritic cells and monocyte-derived macrophages, constitute major arm of the innate immune system known to be involved in the pathogenesis of autoimmune disorders. MNPs were shown to accumulate around intra-hepatic bile ducts in livers of PBC patients. Interleukin 23 (IL-23) is a pro-inflammatory cytokine. IL-23-positive cells were detected in livers of patients with advanced stage PBC and IL-23 serum levels found to be in correlation with PBC disease severity. Our overall goal was to assess the importance of IL-23 derived from MNPs in PBC pathogenesis. Methods We utilized an inducible murine model of PBC and took advantage of transgenic mice targeting expression of IL-23 by specific MNP populations. Analysis included liver histology assessment, flow cytometry of hepatic immune cells and hepatic cytokine profile evaluation. Specific MNPs sub-populations were sorted and assessed for IL-23 expression levels. Results Flow cytometry analysis of non-parenchymal liver cells in autoimmune cholangitis revealed massive infiltration of the liver by MNPs and neutrophils and a decrease in Kupffer cells numbers. In addition, a 4-fold increase in the incidence of hepatic IL-17A producing CD4+ T cells was found to be associated with an increase in hepatic IL23-p19 and IL17A expression levels. Disease severity was significantly ameliorated in both CD11ccreP19flox/flox and CX3CR1creP19 flox/flox mice as assessed by reduced portal inflammation and decreased hepatic expression of various inflammatory cytokines. Amelioration of disease severity was associated with reduction in IL-17A producing CD4+ T cells percentages and decreased hepatic IL23-p19 and IL17A expression levels. qRT-PCR analysis of sorted hepatic MNPs demonstrated high expression levels of IL-23 mRNA specifically by CX3CR1hiCD11c+ monocyte-derived macrophages. Conclusion Our results indicate a major role for IL-23 produced by hepatic monocyte-derived macrophages in the pathogenesis of PBC. These results may pave the road for the development of new immune-based and cell specific therapeutic modalities for PBC patients not responding to current therapies.
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Affiliation(s)
- Debby Reuveni
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Miriam R Brezis
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eli Brazowski
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Philip Vinestock
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Paresh Thakker
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, United States
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Ehud Zigmond
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Center for Autoimmune Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
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11
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Kotlinowski J, Hutsch T, Czyzynska-Cichon I, Wadowska M, Pydyn N, Jasztal A, Kij A, Dobosz E, Lech M, Miekus K, Pośpiech E, Fu M, Jura J, Koziel J, Chlopicki S. Deletion of Mcpip1 in Mcpip1 fl/flAlb Cre mice recapitulates the phenotype of human primary biliary cholangitis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166086. [PMID: 33513427 PMCID: PMC8938941 DOI: 10.1016/j.bbadis.2021.166086] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease characterized by progressive destruction of the intrahepatic bile ducts. The immunopathology of PBC involves excessive inflammation; therefore, negative regulators of inflammatory response, such as Monocyte Chemoattractant Protein-1-Induced Protein-1 (MCPIP1) may play important roles in the development of PBC. The aim of this work was to verify whether Mcpip1 expression protects against development of PBC. Genetic deletion of Zc3h12a was used to characterize the role of Mcpip1 in the pathogenesis of PBC in 6–52-week-old mice. We found that Mcpip1 deficiency in the liver (Mcpip1fl/flAlbCre) recapitulates most of the features of human PBC, in contrast to mice with Mcpip1 deficiency in myeloid cells (Mcpip1fl/flLysMCre mice), which present with robust myeloid cell-driven systemic inflammation. In Mcpip1fl/flAlbCre livers, intrahepatic bile ducts displayed proliferative changes with inflammatory infiltration, bile duct destruction, and fibrosis leading to cholestasis. In plasma, increased concentrations of IgG, IgM, and AMA autoantibodies (anti-PDC-E2) were detected. Interestingly, the phenotype of Mcpip1fl/flAlbCre mice was robust in 6-week-old, but milder in 12–24-week-old mice. Hepatic transcriptome analysis of 6-week-old and 24-week-old Mcpip1fl/flAlbCre mice showed 812 and 8 differentially expressed genes, respectively, compared with age-matched control mice, and revealed a distinct set of genes compared to those previously associated with development of PBC. In conclusion, Mcpip1fl/flAlbCre mice display early postnatal phenotype that recapitulates most of the features of human PBC.
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Affiliation(s)
- Jerzy Kotlinowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
| | - Tomasz Hutsch
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Pawińskiego 3c, 02-106 Warsaw, Poland; Veterinary Diagnostic Laboratory ALAB bioscience, Stępińska 22/30, 00-739 Warszawa, Poland
| | - Izabela Czyzynska-Cichon
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Marta Wadowska
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Natalia Pydyn
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Agnieszka Jasztal
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Agnieszka Kij
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Ewelina Dobosz
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Maciej Lech
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Department of Medicine IV, LMU Hospital, Munich, Germany
| | - Katarzyna Miekus
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Ewelina Pośpiech
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
| | - Mingui Fu
- Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, Kansas City, USA
| | - Jolanta Jura
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Joanna Koziel
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Chair of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, 31-531 Krakow, Poland
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12
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Zhao N, Liu X, Guo H, Zhao X, Qiu Y, Wang W. Interleukin-35: An emerging player in the progression of liver diseases. Clin Res Hepatol Gastroenterol 2021; 45:101518. [PMID: 33387857 DOI: 10.1016/j.clinre.2020.07.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 07/31/2020] [Indexed: 02/04/2023]
Abstract
Interleukin-35(IL-35), a newly identified immunosuppressive cytokine, has recently been shown to play a significant role in the progression of various autoimmune diseases and malignant tumors. The liver is the largest organ in the body and is generally regarded as an important lymphoid organ by an increasing number of immunologists. A number of reports have demonstrated that IL-35 plays essential roles in maintaining the immune homeostasis of the liver microenvironment. This review summarizes the existing studies of IL-35 in liver diseases, including viral hepatitis, immune liver injury, liver cirrhosis and carcinoma. We aimed to provide a comprehensive overview of the vital roles of IL-35 in hepatic damage and explore new alternative therapeutic targets for these diseases.
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Affiliation(s)
- Na Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Xin Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hao Guo
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xiangnan Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yujie Qiu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Wei Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
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13
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Di Gregorio J, Robuffo I, Spalletta S, Giambuzzi G, De Iuliis V, Toniato E, Martinotti S, Conti P, Flati V. The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders. Front Cell Dev Biol 2020; 8:607483. [PMID: 33409282 PMCID: PMC7779530 DOI: 10.3389/fcell.2020.607483] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is a chronic and progressive disorder characterized by excessive deposition of extracellular matrix, which leads to scarring and loss of function of the affected organ or tissue. Indeed, the fibrotic process affects a variety of organs and tissues, with specific molecular background. However, two common hallmarks are shared: the crucial role of the transforming growth factor-beta (TGF-β) and the involvement of the inflammation process, that is essential for initiating the fibrotic degeneration. TGF-β in particular but also other cytokines regulate the most common molecular mechanism at the basis of fibrosis, the Epithelial-to-Mesenchymal Transition (EMT). EMT has been extensively studied, but not yet fully explored as a possible therapeutic target for fibrosis. A deeper understanding of the crosstalk between fibrosis and EMT may represent an opportunity for the development of a broadly effective anti-fibrotic therapy. Here we report the evidences of the relationship between EMT and multi-organ fibrosis, and the possible therapeutic approaches that may be developed by exploiting this relationship.
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Affiliation(s)
- Jacopo Di Gregorio
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Iole Robuffo
- Institute of Molecular Genetics, National Research Council, Section of Chieti, Chieti, Italy
| | - Sonia Spalletta
- Department of Clinical Pathology, E. Profili Hospital, Fabriano, Ancona, Italy
| | - Giulia Giambuzzi
- Department of Medical and Oral Sciences and Biotechnologies, University “G. d’Annunzio”, Chieti, Italy
| | - Vincenzo De Iuliis
- Department of Medical and Oral Sciences and Biotechnologies, University “G. d’Annunzio”, Chieti, Italy
| | - Elena Toniato
- Department of Medical and Oral Sciences and Biotechnologies, University “G. d’Annunzio”, Chieti, Italy
| | - Stefano Martinotti
- Department of Medical and Oral Sciences and Biotechnologies, University “G. d’Annunzio”, Chieti, Italy
| | - Pio Conti
- Postgraduate Medical School, University of Chieti-Pescara, Chieti, Italy
| | - Vincenzo Flati
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
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14
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Ullrich KAM, Schulze LL, Paap EM, Müller TM, Neurath MF, Zundler S. Immunology of IL-12: An update on functional activities and implications for disease. EXCLI JOURNAL 2020; 19:1563-1589. [PMID: 33408595 PMCID: PMC7783470 DOI: 10.17179/excli2020-3104] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/07/2020] [Indexed: 12/15/2022]
Abstract
As its first identified member, Interleukin-12 (IL-12) named a whole family of cytokines. In response to pathogens, the heterodimeric protein, consisting of the two subunits p35 and p40, is secreted by phagocytic cells. Binding of IL-12 to the IL-12 receptor (IL-12R) on T and natural killer (NK) cells leads to signaling via signal transducer and activator of transcription 4 (STAT4) and subsequent interferon gamma (IFN-γ) production and secretion. Signaling downstream of IFN-γ includes activation of T-box transcription factor TBX21 (Tbet) and induces pro-inflammatory functions of T helper 1 (TH1) cells, thereby linking innate and adaptive immune responses. Initial views on the role of IL-12 and clinical efforts to translate them into therapeutic approaches had to be re-interpreted following the discovery of other members of the IL-12 family, such as IL-23, sharing a subunit with IL-12. However, the importance of IL-12 with regard to immune processes in the context of infection and (auto-) inflammation is still beyond doubt. In this review, we will provide an update on functional activities of IL-12 and their implications for disease. We will begin with a summary on structure and function of the cytokine itself as well as its receptor and outline the signal transduction and the transcriptional regulation of IL-12 secretion. In the second part of the review, we will depict the involvement of IL-12 in immune-mediated diseases and relevant experimental disease models, while also providing an outlook on potential translational approaches.
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Affiliation(s)
- Karen A.-M. Ullrich
- Department of Medicine and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
| | - Lisa Lou Schulze
- Department of Medicine and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
| | - Eva-Maria Paap
- Department of Medicine and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
| | - Tanja M. Müller
- Department of Medicine and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
| | - Markus F. Neurath
- Department of Medicine and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
| | - Sebastian Zundler
- Department of Medicine and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
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15
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Wu N, Baiocchi L, Zhou T, Kennedy L, Ceci L, Meng F, Sato K, Wu C, Ekser B, Kyritsi K, Kundu D, Chen L, Meadows V, Franchitto A, Alvaro D, Onori P, Gaudio E, Lenci I, Francis H, Glaser S, Alpini G. Functional Role of the Secretin/Secretin Receptor Signaling During Cholestatic Liver Injury. Hepatology 2020; 72:2219-2227. [PMID: 32737904 PMCID: PMC8957864 DOI: 10.1002/hep.31484] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 07/02/2020] [Indexed: 12/19/2022]
Abstract
The gastrointestinal peptide, secretin (Sct) is an important homeostatic regulator of pancreatic and liver secretory function. With regard to the liver, discoveries have been made, in the last decades, indicating a key role for the secretin/secretin receptor axis during normal or cholestatic conditions. Since large cholangiocytes are the only cells to express secretin receptor in the liver, research on secretin also expanded our knowledge on biliary epithelia. In this review we examined in detail the role of the secretin/secretin receptor axis, not only on biliary secretion, but also on cholangiocyte proliferation and senescence, as well as in prompting fibrotic processes involving biliary epithelia. Relevant data on human chronic cholestatic liver diseases, such as primary biliary cholangitis or primary sclerosing cholangitis, and obtained in animal models mimicking the diseases or in correlative studies on human are also reported. The aim of this review is to provide an update on the progress regarding the interactions between secretin and the biliary epithelia in normal and pathological conditions, underlining the aspects that suggests modulation of secretin pathway as a possible therapeutic approach for chronic cholestatic human liver disease.
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Affiliation(s)
- Nan Wu
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Leonardo Baiocchi
- Liver Unit, Department of Medicine, University of Rome "Tor Vergata,", Rome, Italy
| | - Tianhao Zhou
- Department of Medical Physiology, Texas A&M University, Bryan, TX
| | - Lindsey Kennedy
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Ludovica Ceci
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Fanyin Meng
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Gastroenterology, Medicine, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN
| | - Keisaku Sato
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Konstantina Kyritsi
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Debjyoti Kundu
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Lixian Chen
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | - Vik Meadows
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
| | | | - Domenico Alvaro
- Department of Internal Medicine and Medical Specialties, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Ilaria Lenci
- Liver Unit, Department of Medicine, University of Rome "Tor Vergata,", Rome, Italy
| | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Gastroenterology, Medicine, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, Bryan, TX
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN
- Gastroenterology, Medicine, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN
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16
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Liu SP, Bian ZH, Zhao ZB, Wang J, Zhang W, Leung PSC, Li L, Lian ZX. Animal Models of Autoimmune Liver Diseases: a Comprehensive Review. Clin Rev Allergy Immunol 2020; 58:252-271. [PMID: 32076943 DOI: 10.1007/s12016-020-08778-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Autoimmune liver diseases (AILDs) are potentially life-threatening chronic liver diseases which include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and recently characterized IgG4-related sclerosing cholangitis. They are caused by immune attack on hepatocytes or bile ducts, with different mechanisms and clinical manifestations. The etiologies of AILDs include a susceptible genetic background, environment insults, infections, and changes of commensal microbiota, but remain complicated. Understanding of the underlying mechanisms of AILDs is mandatory for early diagnosis and intervention, which is of great importance for better prognosis. Thus, animal models are developed to mimic the pathogenesis, find biomarkers for early diagnosis, and for therapeutic attempts of AILDs. However, no animal models can fully recapitulate features of certain AILD, especially the late stages of diseases. Certain limitations include different living condition, cell composition, and time frame of disease development and resolution. Moreover, there is no IgG4 in rodents which exists in human. Nevertheless, the understanding and therapy of AILDs have been greatly advanced by the development and mechanistic investigation of animal models. This review will provide a comprehensive overview of traditional and new animal models that recapitulate different features and etiologies of distinct AILDs.
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Affiliation(s)
- Shou-Pei Liu
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Zhen-Hua Bian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.,School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Zhi-Bin Zhao
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Jinjun Wang
- College of Environmental Science and Engineering, Yangzhou University, Yangzhou, 225127, Jiangsu, China
| | - Weici Zhang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Patrick S C Leung
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Liang Li
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China. .,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.
| | - Zhe-Xiong Lian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China. .,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.
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17
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Sahu R, Mishra R, Majee C. An insight into primary biliary cholangitis and its recent advances in treatment: semi-synthetic analogs to combat ursodeoxycholic-acid resistance. Expert Rev Gastroenterol Hepatol 2020; 14:985-998. [PMID: 32674617 DOI: 10.1080/17474124.2020.1797485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease which on progression causes cirrhosis; various studies also suggested that several diseases can co-exist in patients. In existing depiction of disease PBC, apart from entire use of ursodeoxycholic acid (UDCA), several patients need to step forward to liver-transplantation or death due to resistance or non-responder with UDCA monotherapy. AREAS COVERED To overcome this non-respondent treatment, novel bile acid semi-synthetic analogs have been identified which shows their potency against for farnesoid X receptor and transmembrane G protein-coupled receptor-5 which are identified as target for many developing analogs which have desirable pharmacokinetic profiles. EXPERT OPINION A range of studies suggests that adding semisynthetic analogs in therapeutic regime improves liver biochemistries in patients with suboptimal response to UDCA. Thus, the aspire of this review is to abridge and compare therapeutic value and current markets affirm of various bile acids semi-synthetic analogs which certainly are having promising effects in PBC monotherapy or in pooled treatment with UDCA for PBC.
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Affiliation(s)
- Rakesh Sahu
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
| | - Rakhi Mishra
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
| | - Chandana Majee
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
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18
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Hu H, Fu Y, Li M, Xia H, Liu Y, Sun X, Hu Y, Song F, Cheng X, Li P, Wu Y. Interleukin-35 pretreatment attenuates lipopolysaccharide-induced heart injury by inhibition of inflammation, apoptosis and fibrotic reactions. Int Immunopharmacol 2020; 86:106725. [PMID: 32679538 DOI: 10.1016/j.intimp.2020.106725] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 06/07/2020] [Accepted: 06/17/2020] [Indexed: 12/14/2022]
Abstract
Previous studies have demonstrated that targeting inflammation is a promising strategy for treating lipopolysaccharide (LPS)-induced sepsis and related heart injury. Interleukin-35 (IL-35), which consists of two subunits, Epstein-Barr virus-induced gene 3 (EBI3) and p35, is an immunosuppressive cytokine of the IL-12 family and exhibits strong anti-inflammatory activity. However, the role of IL-35 in LPS-induced heart injury reains obscure. In this study, we explored the role of IL-35 in heart injury induced by LPS and its potential mechanisms. Mice were treated with a plasmid encoding IL-35 (pIL-35) and then injected intraperitoneally (ip) with LPS (10 mg/kg). Cardiac function was assessed by echocardiography 12 h later. LPS apparently decreased the expression of EBI3 and p35 and caused cardiac dysfunction and pathological changes, which were significantly improved by pIL-35 pretreatment. Moreover, pIL-35 pretreatment significantly decreased the levels of cardiac proinflammatory cytokines including TNF-α, IL-6, and IL-1β, and the NLRP3 inflammasome. Furthermore, decreased number of apoptotic myocardial cells, increased BCL-2 levels and decreased BAX levels inhibited apoptosis, and LPS-induced upregulation of the expression of cardiac pro-fibrotic genes (MMP2 and MMP9) and fibrotic factor (Collagen type I) was inhibited. Further investigation indicated that pIL-35 pretreatment might suppressed the activation of the cardiac NF-κBp65 and TGF-β1/Smad2/3 signaling pathways in LPS-treated mice. Similar cardioprotective effects of IL-35 pretreatment were observed in mouse myocardial fibroblasts challenged with LPS in vitro. In summary, IL-35 pretreatment can attenuate cardiac inflammation, apoptosis, and fibrotic reactions induced by LPS, implicating IL-35 as a promising therapeutic target in sepsis-related cardiac injury.
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Affiliation(s)
- Huan Hu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Yang Fu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Meng Li
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Huasong Xia
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Yue Liu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Xiaopei Sun
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Yang Hu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Fulin Song
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Xiaoshu Cheng
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Ping Li
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Yanqing Wu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
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19
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Yazdani Z, Rafiei A, Golpour M, Zafari P, Moonesi M, Ghaffari S. IL‐35, a double‐edged sword in cancer. J Cell Biochem 2019; 121:2064-2076. [DOI: 10.1002/jcb.29441] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 10/08/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Zahra Yazdani
- Department of Immunology, School of Medicine Mazandaran University of Medical Sciences Sari Iran
| | - Alireza Rafiei
- Department of Immunology, School of Medicine Mazandaran University of Medical Sciences Sari Iran
| | - Monireh Golpour
- Students Research Committee Mazandaran University of Medical Sciences Sari Iran
| | - Parisa Zafari
- Department of Immunology, School of Medicine Mazandaran University of Medical Sciences Sari Iran
- Students Research Committee Mazandaran University of Medical Sciences Sari Iran
| | - Mohammadreza Moonesi
- Department of Hematology, School of Medicine Tabriz University of Medical Science, Tabriz Iran
| | - Sasan Ghaffari
- Student Scientific Research Center Tehran University of Medical Sciences Tehran Iran
- Cell‐Based Therapies Research Center, Digestive Disease Research Institute Tehran University of Medical Sciences Tehran Iran
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20
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, Vierling JM, Adams D, Alpini G, Banales JM, Beuers U, Björnsson E, Bowlus C, Carbone M, Chazouillères O, Dalekos G, De Gottardi A, Harada K, Hirschfield G, Invernizzi P, Jones D, Krawitt E, Lanzavecchia A, Lian ZX, Ma X, Manns M, Mavilio D, Quigley EM, Sallusto F, Shimoda S, Strazzabosco M, Swain M, Tanaka A, Trauner M, Tsuneyama K, Zigmond E, Gershwin ME. The challenges of primary biliary cholangitis: What is new and what needs to be done. J Autoimmun 2019; 105:102328. [PMID: 31548157 DOI: 10.1016/j.jaut.2019.102328] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/18/2019] [Accepted: 08/20/2019] [Indexed: 02/06/2023]
Abstract
Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino, Lugano, Switzerland; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; European Reference Network ERN RARE-LIVER.
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - David Adams
- Birmingham NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesMedical School, University of Birmingham, Birmingham, UK
| | - Gianfranco Alpini
- Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastián, Spain
| | - Ulrich Beuers
- European Reference Network ERN RARE-LIVER; Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Einar Björnsson
- Division of Gastroenterology and Hepatology, Landspitali the National University Hospital of Iceland, Reykjavík, Iceland
| | - Christopher Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Marco Carbone
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - Olivier Chazouillères
- European Reference Network ERN RARE-LIVER; Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France
| | - George Dalekos
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research, Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Andrea De Gottardi
- European Reference Network ERN RARE-LIVER; Epatocentro Ticino & Division of Gastroenterology and Hepatology Ente Ospedaliero Cantonale and Università della Svizzera Italiana, Lugano, Switzerland
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Gideon Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | - Pietro Invernizzi
- European Reference Network ERN RARE-LIVER; Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - David Jones
- Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK
| | - Edward Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA
| | | | - Zhe-Xiong Lian
- Institutes for Life Sciences, South China University of Technology, Higher Education Mega Center, Guangzhou, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Italy
| | - Eamon Mm Quigley
- Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA
| | - Federica Sallusto
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
| | - Shinji Shimoda
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Mario Strazzabosco
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA
| | - Mark Swain
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Ehud Zigmond
- Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California, USA.
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21
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Shen K, Zhang S, Ma S, Zhang H. Molecular Markers and Diagnostic Model Specific for Barrett's Esophagus. J Comput Biol 2019; 26:1367-1378. [PMID: 31259619 DOI: 10.1089/cmb.2019.0064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Biomarkers involved in the progression of Barrett's esophagus (BE) have not been extensively studied. We aimed to identify novel molecular markers for the early diagnosis of BE. The expression profiles of GSE100843 including BE segment and normal squamous mucosa samples before and after vitamin D3 supplementation were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified using the limma package. Principal component analysis was performed using Minitab, and DEGs in the top three principal components were clustered into different gene sets by the mclust package. Pathways and functions enriched by these gene sets were evaluated by deregulation score analysis. Key genes associated with BE were identified by coexpression analysis and a genetic algorithm. Using the xgboost package, an XGBoost classifier specific for BE was further constructed based on the key genes. A total of 2598 DEGs were identified, which were further clustered into nine gene sets. According to the deregulation scores of pathways and functions enriched by these gene sets, nine functional and pathway terms were significantly deregulated in BE. Among the DEGs, CREB3L1, HNF1B, and IL35 were genes with high fitness levels and connectivity degrees, predicting that they were key genes associated with BE. The XGBoost classifier constructed using the key genes was efficient and robust in BE prediction. The accuracies for prediction were 93% and 87% for training and validation datasets, respectively. Key genes may serve as novel biomarkers of BE, and the XGBoost classifier may contribute to the diagnosis of BE in future clinical practice.
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Affiliation(s)
- Kexin Shen
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Shujuan Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Shurong Ma
- Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Haishan Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
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22
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Ronca V, Chen QB, Lygoura V, Ben-Mustapha I, Shums Z, Trifa M, Carbone M, Mancuso C, Milani C, Bernuzzi F, Ma X, Agrebi N, Norman GL, Chang C, Gershwin ME, Barbouche MR, Invernizzi P. Autoantibodies in patients with interleukin 12 receptor beta 1 deficiency. J Dig Dis 2019; 20:363-370. [PMID: 31111679 DOI: 10.1111/1751-2980.12790] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 05/07/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Interleukin 12 receptor beta 1 (IL-12Rβ1) deficiency is a primary immunodeficiency that exposes affected individuals to an augmented risk of intracellular pathogen-mediated infections. The paradoxical presence of autoimmune manifestations in immune-deficient patients has been recognized, but the basis of this phenomenon is unclear, with the role of frequent infections being a possible trigger to break tolerance. Our study aimed to analyze extensively a profile of autoantibodies in a clinically well-defined case series of patients with IL-12Rβ1 deficiency. METHODS Eight patients with IL-12Rβ1 deficiency referred to Children's Medical Center in Tunis, Tunisia, during 1995-2012 were enrolled in the study. Sixteen age- and gender-matched blood donors served as controls. Serum, liver-related autoantibodies immunoglobulin (Ig)G, IgM, IgA were tested by ELISA and by standard indirect immunofluorescence on Hep-2 cells. RESULTS We found a significant prevalence of liver autoantibodies in the study group. Regarding primary biliary cholangitis (PBC), two of eight patients were positive for MIT3 autoantibodies, both confirmed by immunofluorescence, and one patient was positive for PBC-specific antinuclear antibodies, sp100. Moreover, two patients had significantly increased gamma-glutamyltransferase levels and one had IgM levels twice the upper limit of normal. Intriguingly two patients were positive for anti-actin antibodies; a typical feature of autoimmune hepatitis type 1, along with a significant increase in IgG levels. CONCLUSIONS This is the first report of a serological analysis in patients with an IL-12Rβ1 deficiency. Despite the difficulty in interpreting the role of the IL-12, the evidence of liver-specific autoantibodies confirms the importance its signal in liver autoimmunity.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Qu Bo Chen
- Clinical Laboratory, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guandong Province, China
| | - Vasiliky Lygoura
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Imen Ben-Mustapha
- Laboratory of Immunology, Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia
| | - Zakera Shums
- Department of Research and Development, Inova Diagnostics, San Diego, California, USA
| | - Mehdi Trifa
- Department of Anesthesia and Intensive Care, Tunis and Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Clara Mancuso
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Chiara Milani
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Francesca Bernuzzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Xiong Ma
- Key Laboratory of Gastroenterology and Hepatology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Nourhen Agrebi
- Laboratory of Immunology, Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia
| | - Gary L Norman
- Department of Research and Development, Inova Diagnostics, San Diego, California, USA
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Mohamed-Ridha Barbouche
- Laboratory of Immunology, Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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23
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Kennedy L, Francis H, Invernizzi P, Venter J, Wu N, Carbone M, Gershwin ME, Bernuzzi F, Franchitto A, Alvaro D, Marzioni M, Onori P, Gaudio E, Sybenga A, Fabris L, Meng F, Glaser S, Alpini G. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis. FASEB J 2019; 33:10269-10279. [PMID: 31251081 DOI: 10.1096/fj.201802606r] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Primary biliary cholangitis (PBC) primarily targets cholangiocytes and is characterized by liver fibrosis and biliary proliferation. Activation of the secretin (Sct)/secretin receptor (SR) axis, expressed only by cholangiocytes, increases biliary proliferation, liver fibrosis, and bicarbonate secretion. We evaluated the effectiveness of SR antagonist treatment for early-stage PBC. Male and female dominant-negative TGF-β receptor II (dnTGF-βRII) (model of PBC) and wild-type mice at 12 wk of age were treated with saline or the SR antagonist, Sec 5-27, for 1 wk. dnTGF-βRII mice expressed features of early-stage PBC along with enhanced Sct/SR axis activation and Sct secretion. dnTGF-βRII mice had increased biliary proliferation or senescence, inflammation, and liver fibrosis. In dnTGF-βRII mice, there was increased microRNA-125b/TGF-β1/TGF-β receptor 1/VEGF-A signaling. Human early-stage PBC patients had an increase in hepatobiliary Sct and SR expression and serum Sct levels. Increased biliary Sct/SR signaling promotes biliary and hepatic damage during early-stage PBC.-Kennedy, L., Francis, H., Invernizzi, P., Venter, J., Wu, N., Carbone, M., Gershwin, M. E., Bernuzzi, F., Franchitto, A., Alvaro, D., Marzioni, M., Onori, P., Gaudio, E., Sybenga, A., Fabris, L., Meng, F., Glaser, S., Alpini, G. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.
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Affiliation(s)
- Lindsey Kennedy
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA.,Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA.,Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA.,Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott and White Health, Temple, Texas, USA
| | | | - Julie Venter
- Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA
| | - Nan Wu
- Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA
| | - Marco Carbone
- Humanitas Clinical and Research Center, Rozzano (MI), Italy
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California-Davis, Davis, California, USA
| | | | | | - Domenico Alvaro
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Universita Politecnica delle Marche, Ancona, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Amelia Sybenga
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy.,Digestive Disease Section, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA.,Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott and White Health, Temple, Texas, USA
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA.,Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott and White Health, Temple, Texas, USA
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA.,Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA.,Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott and White Health, Temple, Texas, USA
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24
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Xue W, Yan D, Kan Q. Interleukin-35 as an Emerging Player in Tumor Microenvironment. J Cancer 2019; 10:2074-2082. [PMID: 31205568 PMCID: PMC6548173 DOI: 10.7150/jca.29170] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 03/05/2019] [Indexed: 12/15/2022] Open
Abstract
IL-35 is the newest member of IL-12 family. A dimeric protein consisting of two separate subunits has manifested suppressive actions on immune system, which is counterproductive in the context of cancers. Various reports have confirmed its inhibitory role on immune system which is carried out via formation of IL-35-producing regulatory T cells (iTr35), increased Treg development and suppressive Th17 cells growth. Although last decade has seen a great deal of scientific interest on this subject, the exact role, precise signal transduction and elaborative functions of IL-35 in tumor microenvironment (TME) remained elusive. Search for anti-IL-35 therapies have exhibited limited success in animal models. Contrarily, few studies have denied the idea that IL-35 plays a role in cancer. The purpose of this review is to analyze the reported scientific data on continuous symphony of IL-35 in cancers since the inception of former.
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Affiliation(s)
- Wenhua Xue
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Dan Yan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Quancheng Kan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
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25
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Nie Y, Yu K, Li B, Hu Y, Zhang H, Xin R, Xiong Y, Zhao P, Chai G. S-allyl-l-cysteine attenuates bleomycin-induced pulmonary fibrosis and inflammation via AKT/NF-κB signaling pathway in mice. J Pharmacol Sci 2019; 139:377-384. [DOI: 10.1016/j.jphs.2019.03.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/28/2019] [Accepted: 03/04/2019] [Indexed: 12/30/2022] Open
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26
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Luo M, Peng H, Chen P, Zhou Y. The immunomodulatory role of interleukin-35 in fibrotic diseases. Expert Rev Clin Immunol 2019; 15:431-439. [PMID: 30590954 DOI: 10.1080/1744666x.2019.1564041] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Fibrosis makes numerous diseases in all organs more complicated and leads to severe consequences in the lung, liver, heart, kidney, and skin. In essence, fibrosis results from excessive, persistent and oftentimes nonreversible aggregation of extracellular matrix (ECM) or simply as collagen during the process of tissue injury and repair. Recent studies suggest the pathology of fibrosis, especially in pulmonary and liver fibrosis, involves various types of immune cells and soluble mediators including interleukin (IL)-35, a recently identified heterodimeric cytokine that belongs to the IL-12 cytokine family. Furthermore, IL-35 may inhibit fibrotic diseases. However, the side effects of inhibiting IL-35 also need attention and we have a long way to go to make better use of it in fibrotic diseases. Areas covered: This review focuses on recent evidence regarding the role of IL-35 in the pathogenesis of pulmonary, hepatic, cardiac, renal and skin fibrosis. It also discusses targeting of IL-35 as a promising novel strategy for treatment of fibrotic diseases. Expert commentary: Understanding as fully as possible the relationship between IL-35 and fibrotic diseases is important for the development of new therapeutic approaches.
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Affiliation(s)
- Man Luo
- a Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital , Central South University , Changsha , China.,b Research Unit of Respiratory Disease , Central South University , Changsha , China.,c Diagnosis and Treatment Center of Respiratory Disease , Central South University , Changsha , China
| | - Hong Peng
- a Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital , Central South University , Changsha , China.,b Research Unit of Respiratory Disease , Central South University , Changsha , China.,c Diagnosis and Treatment Center of Respiratory Disease , Central South University , Changsha , China
| | - Ping Chen
- a Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital , Central South University , Changsha , China.,b Research Unit of Respiratory Disease , Central South University , Changsha , China.,c Diagnosis and Treatment Center of Respiratory Disease , Central South University , Changsha , China
| | - Yong Zhou
- d Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine , University of Alabama at Birmingham , Birmingham , AL , USA
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27
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Guo J, Gu M, Zhang W, Liu Y, Qian C, Deng A. Aberrant IL-35 levels in patients with primary Sjogren's syndrome. Scand J Immunol 2019; 88:e12718. [PMID: 30589451 DOI: 10.1111/sji.12718] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2018] [Indexed: 12/28/2022]
Abstract
OBJECTIVE IL-35 is a newly discovered immunoregulatory cytokine that possesses the ability to inhibit CD4 + effector T cells and alleviate autoimmune diseases. The objective of this study was to investigate IL-35 levels in patients with primary Sjogren's syndrome (pSS) and explore the roles of IL-35 in the pathogenesis of pSS. METHODS Thirty-four hospitalized patients with pSS were recruited, and 34 volunteers were enrolled as healthy controls. An ELISA was adopted to measure plasma IL-35 levels. The levels of P35 and EBI3 mRNAs in peripheral blood mononuclear cells (PBMCs) were determined using real-time quantitative PCR. The percentage of CD4 + EBI3 + T cells and CD19 + EBI3 + B cells was analysed using flow cytometry. Correlations between IL-35 levels, P35 and EBI3 mRNAs, numbers of CD4 + EBI3 + T cells, CD19 + EBI3 + B cells and clinical parameters were analysed. RESULTS Significantly lower plasma IL-35 levels, P35 and EBI3 mRNA levels, and percentages of CD4 + EBI3 + T cells but increased percentages of CD19 + EBI3 + B cells were observed in patients with pSS than in healthy controls. IL-35 levels, EBI3 mRNA expression and the percentage of CD4 + EBI3 + T cells exhibited negative correlations with the ESSDAI score, whereas levels of the IL-35 protein and EBI3 mRNA were negatively correlated with the ESR. Patients who were positive for anti-SSB antibodies presented with lower IL-35 levels and percentages of CD4 + EBI3 + T cells. CONCLUSIONS Based on these results, a decrease in the IL-35 levels may play an important role in the pathogenesis of pSS. IL-35 may act as a potential therapeutic agent against inflammation in patients with pSS.
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Affiliation(s)
- Jie Guo
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Mingli Gu
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Weiwei Zhang
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yun Liu
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Cheng Qian
- Department of Laboratory Diagnosis, The 100th Hospital of Chinese People's Liberation Army, Suzhou, China
| | - Ammei Deng
- Department of Clinical Experiment, Changhai Hospital, Second Military Medical University, Shanghai, China
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28
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Tam PKH, Yiu RS, Lendahl U, Andersson ER. Cholangiopathies - Towards a molecular understanding. EBioMedicine 2018; 35:381-393. [PMID: 30236451 PMCID: PMC6161480 DOI: 10.1016/j.ebiom.2018.08.024] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 08/06/2018] [Accepted: 08/09/2018] [Indexed: 12/14/2022] Open
Abstract
Liver diseases constitute an important medical problem, and a number of these diseases, termed cholangiopathies, affect the biliary system of the liver. In this review, we describe the current understanding of the causes of cholangiopathies, which can be genetic, viral or environmental, and the few treatment options that are currently available beyond liver transplantation. We then discuss recent rapid progress in a number of areas relevant for decoding the disease mechanisms for cholangiopathies. This includes novel data from analysis of transgenic mouse models and organoid systems, and we outline how this information can be used for disease modeling and potential development of novel therapy concepts. We also describe recent advances in genomic and transcriptomic analyses and the importance of such studies for improving diagnosis and determining whether certain cholangiopathies should be viewed as distinct or overlapping disease entities.
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Affiliation(s)
- Paul K H Tam
- Department of Surgery, Li Ka Shing Faculty of Medicine, and Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, and The University of Hong Kong, Hong Kong.
| | - Rachel S Yiu
- Department of Surgery, Li Ka Shing Faculty of Medicine, and Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, and The University of Hong Kong, Hong Kong
| | - Urban Lendahl
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
| | - Emma R Andersson
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden; Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
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29
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Liaskou E, Patel SR, Webb G, Bagkou Dimakou D, Akiror S, Krishna M, Mells G, Jones DE, Bowman SJ, Barone F, Fisher BA, Hirschfield GM. Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells. J Autoimmun 2018; 94:143-155. [PMID: 30119881 DOI: 10.1016/j.jaut.2018.07.020] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/30/2018] [Accepted: 07/31/2018] [Indexed: 02/06/2023]
Abstract
IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren's syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals. Our data revealed that TLR stimulation of PBC (n = 17) and pSS monocytes (n = 6) resulted in significant induction of IL12A mRNA (p < 0.05, p < 0.01, respectively) compared to PSC monocytes (n = 13) and at similar levels to HC monocytes (n = 8). PSC monocytes expressed significantly less IL-12p70 (108 pg/ml, mean) and IL-23 (358 pg/ml) compared to HC (458 pg/ml and 951 pg/ml, respectively) (p < 0.01, p < 0.05). Treg cells from patients with PBC (n = 16) and pSS (n = 3) but not PSC (n = 10) and HC (n = 8) responded to low dose (10 ng/ml) IL-12 stimulation by significant upregulation of IFNγ (mean 277 and 254 pg/ml, respectively) compared to PSC and HC Treg cells (mean 22 and 77 pg/ml, respectively)(p < 0.05). This effect was mediated by the rapid and strong phosphorylation of STAT4 on Treg cells from patients with PBC and pSS (p < 0.05) but not PSC and HC. In the liver of patients with PBC (n = 7) a significantly higher proportion of IL-12Rβ2+Tregs (16% on average) was detected (p < 0.05) compared to other liver disease controls (5%)(n = 18) which also showed ex vivo high IFNG and TBET expression. CONCLUSION: Our data show an increased sensitivity of PBC and pSS Treg cells to low dose IL-12 stimulation, providing ongoing support for the importance of the IL12-IL-12Rβ2-STAT4 pathway on Treg cells in disease pathogenesis and potentially treatment.
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Affiliation(s)
- Evaggelia Liaskou
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Samita R Patel
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Gwilym Webb
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Danai Bagkou Dimakou
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Sarah Akiror
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Mahesh Krishna
- Weiss School of Natural Sciences, Rice University, Houston, TX, USA
| | - George Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Dave E Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK; NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle-upon-Tyne, UK
| | - Simon J Bowman
- Institute of Inflammation and Ageing and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Francesca Barone
- Institute of Inflammation and Ageing and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Benjamin A Fisher
- Institute of Inflammation and Ageing and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Gideon M Hirschfield
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; University Hospitals Birmingham, Birmingham, UK; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada.
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30
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Tanaka A, Leung PSC, Gershwin ME. Evolution of our understanding of PBC. Best Pract Res Clin Gastroenterol 2018; 34-35:3-9. [PMID: 30343708 DOI: 10.1016/j.bpg.2018.05.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 05/10/2018] [Indexed: 01/31/2023]
Abstract
The discovery of mitochondrial autoantigens recognized by antimitochondrial antibodies (AMAs) in 1987 marked the dawn of a new era in primary biliary cholangitis (PBC) research. Since then, there has been substantial progress in our understanding of PBC partly bestowed by the development of innovative technologies in molecular biology, immunology, and genetics. Here, we review this evolutionary progress in understanding PBC. We now recognize that the epitopes of AMAs, CD4+, and CD8+ T cells are all mapped to the same region of the inner lipoyl domain of pyruvate dehydrogenase complex E2 subunit (PDC-E2), and that intrahepatic biliary epithelial cells (BECs) are exclusively targeted in PBC. BECs express PDC-E2 on apotopes in an immunologically intact form during apoptosis, but not other epithelial cells, which could explain the tissue specificity of PBC. In addition, genetic factors, environmental triggers, and epigenetic modifications play crucial roles in the development of PBC. Intact lipoylated PDC-E2, presumably after modification with xenobiotics such as 2-octynamide or 2-nonyamide that are abundantly present in the environment, is endocytosed by antigen-presenting cells and are presented to CD4+ or CD8+ T cells. An immune complex consisting of PDC-E2 and anti-PDC-E2 autoantibodies cross-present autoantigens in a more efficient manner. Finally, an adenylate uridine-rich element (ARE) Del -/- mouse model has been established, which presents a disease modeling human PBC, including female dominance as one of its most important features, and can be used to dissect the immunopathology of PBC. Expanding our knowledge of the pathology from a very early stage of the disease will provide the key to cure PBC.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
| | - Patrick S C Leung
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA.
| | - M Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA.
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31
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Guo H, Zhao N, Gao H, He X. Mesenchymal Stem Cells Overexpressing Interleukin-35 Propagate Immunosuppressive Effects in Mice. Scand J Immunol 2017; 86:389-395. [PMID: 28888053 DOI: 10.1111/sji.12613] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 09/04/2017] [Indexed: 12/20/2022]
Abstract
To explore generation of interleukin (IL)-35-expressing mouse adipocyte-derived mesenchymal stem cells (Ad-MSCs) using lentiviral vector and their potential immunosuppressive effects in mice. Ad-MSCs were isolated and cultured in vitro and transfected with a lentivirus vector for overexpression of the therapeutic murine IL-35 gene. IL-35 expression in transfected MSCs (IL-35-MSCs) was quantified by enzyme-linked immunosorbent assay (ELISA). The lymphocytes subsets after one-way mixed lymphocyte culture and in vivo intravenous transplantation were analysed by flow cytometry to evaluate the immunosuppressive effects of IL-35-MSCs. ELISA was performed to examine IL-10, IL-17A and IL-35 expression in lymphocyte culture. Mouse Ad-MSCs were isolated and cultured. IL-35 was expressed in the MSC supernatant and serum after IL-35 transduction into Ad-MSCs by lentiviral vector transfection in vitro and in vivo. The percentage of CD4+ CD25+ T regulatory (Treg) cells in mice treated with IL-35-MSCs significantly increased. IL-35-MSCs upregulated the CD4+ CD25+ Treg cells in the allogeneic mixed lymphocyte reaction system, and lowered the percentage of CD4+ T cells compared with the other two control groups (P < 0.01). IL-17A expression significantly decreased and IL-10 expression significantly increased in IL-35-MSCs and MSCs when compared by ELISA to the control groups (P < 0.01). IL-35-transduced Ad-MSCs in vivo can enhance proliferation of CD4+ CD25+ Treg cells and suppress the function of effector T cells such as T helper (Th) 1, Th2 and Th17 cells and may reduce the development of allograft rejection. Our data suggest that transduced Ad-MSCs overexpressing IL-35 may provide a useful approach for basic research on cell-based immunotolerance therapy for inducing transplantation tolerance.
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Affiliation(s)
- H Guo
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - N Zhao
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - H Gao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - X He
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
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Tanakaa A, Leung PS, Young HA, Gershwin ME. Toward solving the etiological mystery of primary biliary cholangitis. Hepatol Commun 2017; 1:275-287. [PMID: 29057387 PMCID: PMC5646686 DOI: 10.1002/hep4.1044] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti‐mitochondrial antibody (AMA) autoantibody, female predominance, and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens recognized by AMA have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relatively high concordance rate in identical twins, genome‐wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed, including spontaneous models, models induced by chemical xenobiotic immunization, and by “designer” mice with altered interferon metabolism. Herein, we describe five such models, including 1) NOD.c3c4 mice, 2) dominant negative form of transforming growth factor receptor type II mice, 3) interleukin‐2R α−/− mice, 4) adenylate‐uridylate‐rich element Del−/− mice, and 5) 2‐octynoic acid‐conjugated bovine serum albumin immunized mice. Individually there is no perfect murine model, but collectively the models point to loss of tolerance to PDC‐E2, the major mitochondrial autoantigen, as the earliest event that occurs before clinical disease is manifest. Although there is no direct association of AMA titer and PBC disease progression, it is noteworthy that the triad of PBC monocytes, biliary apotopes, and AMA leads to an intense proinflammatory cytokine burst. Further, the recurrence of PBC after liver transplantation indicates that, due to major histocompatibility complex restriction, disease activity must include not only adaptive immunity but also innate immune mechanisms. We postulate that successful treatment of PBC may require a personalized approach with therapies designed for different stages of disease. (Hepatology Communications 2017;1:275–287)
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Affiliation(s)
- Atsushi Tanakaa
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Patrick Sc Leung
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA
| | - Howard A Young
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA
| | - M Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA
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Pandey A, Raj P, Goru SK, Kadakol A, Malek V, Sharma N, Gaikwad AB. Esculetin ameliorates hepatic fibrosis in high fat diet induced non-alcoholic fatty liver disease by regulation of FoxO1 mediated pathway. Pharmacol Rep 2017; 69:666-672. [PMID: 28527877 DOI: 10.1016/j.pharep.2017.02.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 01/20/2017] [Accepted: 02/03/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder is associated with oxidative stress, inflammation and fibrotic cascades. In this study, we aimed to examine the effects of Esculetin, a well-known anti-oxidant on TGF-β1 mediated liver fibrosis and FoxO1 activity. METHODS A non-genetic murine model for NAFLD was developed by chronic high fat diet (HFD) (58% calories from fats) feeding in Wistar rats. The plasma biochemical parameters, liver function tests, oxidative stress, and histopathological alterations were assessed. The alterations in extracellular matrix (ECM) deposition and FoxO1 activity were assessed by immunohistochemistry. RESULTS The aberrations in plasma parameters, liver functioning, morphometric and microscopic changes in liver structure of HFD fed rats were significantly improved by treatment with Esculetin. Liver fibrosis, identified in the form of collagen deposition and expression of fibrotic proteins like TGF-β1 and fibronectin was also markedly controlled by Esculetin. The expression of phospho-FoxO1 was found to be reduced in HFD fed rats' liver, showing an increase in activation of FoxO1 under insulin resistant and hyperglycemic states. Esculetin treatment could improve phospho-FoxO1 expression, thus showing its ability to act on Akt/PI3K/FoxO1 pathway. CONCLUSIONS As per the previous studies, a potential therapy for NAFLD may be the one with multi-faceted actions on insulin resistance, oxidative stress, inflammation and fibrosis. This study demonstrates the efficiency of Esculetin in improving liver fibrosis in HFD induced NAFLD.
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Affiliation(s)
- Anuradha Pandey
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Priyank Raj
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Santosh Kumar Goru
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Almesh Kadakol
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Vajir Malek
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India.
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Choi J, Leung PSC, Bowlus C, Gershwin ME. IL-35 and Autoimmunity: a Comprehensive Perspective. Clin Rev Allergy Immunol 2016; 49:327-32. [PMID: 25619872 DOI: 10.1007/s12016-015-8468-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Interleukin 35 (IL-35) is the most recently identified member of the IL-12 family of cytokines and offers the potential to be a target for new therapies for autoimmune, inflammatory, and infectious diseases. Similar to other members of the IL-12 family including IL-12, IL-23, and IL-27, IL-35 is composed of a heterodimer of α and β chains, which in the case of IL-35 are the p35 and Epstein-Barr virus-induced gene 3 (EBI3) proteins. However, unlike its proinflammatory relatives, IL-35 has immunosuppressive effects that are mediated through regulatory T and B cells. Although there are limited data available regarding the role of IL-35 in human autoimmunity, several murine models of autoimmunity suggest that IL-35 may have potent effects in regulating immunoreactivity via IL-10-dependent mechanisms. We suggest that similar effects are operational in human disease and IL-35-directed therapies hold significant promise. In particular, we emphasize that IL-35 has immunosuppressive ability that are mediated via regulatory T and B cells that are IL-10 dependent. Further, although deletion of IL-35 does not result in spontaneous breach of tolerance, recombinant IL-35 can improve autoimmune responses in several experimental models.
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Affiliation(s)
- Jinjung Choi
- Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA, 95616, USA.,Division of Rheumatology, CHA University Medical Center, Bundang, 463-712, Korea
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA, 95616, USA
| | - Christopher Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, 95817, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA, 95616, USA.
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35
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Yang GX, Sun Y, Tsuneyama K, Zhang W, Leung PSC, He XS, Ansari AA, Bowlus C, Ridgway WM, Gershwin ME. Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice. Clin Exp Immunol 2016; 185:154-64. [PMID: 27148790 PMCID: PMC4955007 DOI: 10.1111/cei.12806] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 04/26/2016] [Accepted: 04/27/2016] [Indexed: 12/30/2022] Open
Abstract
During chronic inflammation, interleukin (IL)-22 expression is up-regulated in both CD4 and CD8 T cells, exerting a protective role in infections. However, in autoimmunity, IL-22 appears to have either a protective or a pathogenic role in a variety of murine models of autoimmunity and, by extrapolation, in humans. It is not clear whether IL-22 itself mediates inflammation or is a by-product of inflammation. We have taken advantage of the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice that develop both inflammatory bowel disease and autoimmune cholangitis and studied the role and the biological function of IL-22 by generating IL-22(-/-) dnTGF-βRII mice. Our data suggest that the influence of IL-22 on autoimmunity is determined in part by the local microenvironment. In particular, IL-22 deficiency exacerbates tissue injury in inflammatory bowel disease, but has no influence on either the hepatocytes or cholangiocytes in the same model. These data take on particular significance in the previously defined effects of IL-17A, IL-12p40 and IL-23p19 deficiency and emphasize that, in colitis, there is a dominant role of IL-23/T helper type 17 (Th17) signalling. Furthermore, the levels of IL-22 are IL-23-dependent. The use of cytokine therapy in patients with autoimmune disease has significant potential, but must take into account the overlapping and often promiscuous effects that can theoretically exacerbate inflammation.
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Affiliation(s)
- G-X Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Y Sun
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
- Diagnostic and Treatment Center for Non-Infectious Liver Diseases, 302nd Military Hospital, Beijing, China
| | - K Tsuneyama
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
| | - W Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - P S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - X-S He
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - A A Ansari
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - C Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Sacramento, CA, USA
| | - W M Ridgway
- Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
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Hou C, Wu Q, Ouyang C, Huang T. Effects of an intravitreal injection of interleukin-35-expressing plasmid on pro-inflammatory and anti-inflammatory cytokines. Int J Mol Med 2016; 38:713-20. [PMID: 27460435 PMCID: PMC4990317 DOI: 10.3892/ijmm.2016.2688] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 06/27/2016] [Indexed: 12/23/2022] Open
Abstract
In order to explore the potential effects of interleukin (IL)-35 on IL-10, transforming growth factor-β (TGF-β), interferon-γ (INF)-γ, IL-12 and IL-17, a pcDNA3.1‑IL-35 plasmid was injected into the vitreous cavity of BALB/c mice. Enzyme-linked immunosorbent assay, western blot analysis and quantitative PCR analysis were performed to confirm the successful expression of IL-35. Slit-lamp biomicroscopy, hematoxylin and eosin staining and immunofluorescence were employed to detect the status of eyes, and western blot analysis was performed to examine the expression of corneal graft rejection-related cytokines. There were no abnormalities in the eyes pre-mydriasis or post-mydriasis and no injuries to the cornea or retina following the injection of IL-35-expressing plasmid. An immunofluorescence assay detected the positive expression of IL-35 in corneal epithelial cells from IL-35‑injected mice and negative staining in the control group. Further study revealed that IL-35 enhanced the expression of IL-10 and TGF-β which reached their highest levels at 1 and 2 weeks after injection, respectively (p<0.01). Moreover, the expression of INF-γ and IL-12 was decreased significantly at 2 weeks after the injection of IL-35-expressing plasmid (p<0.05), and the expression of IL-17 was suppressed notably at 4 weeks after the injection (p<0.05). The intravitreal injection of IL-35-expressing plasmid in mice downregulates the expression of pro-inflammatory cytokines and upregulates the expression of anti-inflammatory cytokines. Thus, IL-35 may further be assessed as a potential target for the treatment of corneal graft rejection.
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Affiliation(s)
- Chao Hou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510030, P.R. China
| | - Qianni Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510030, P.R. China
| | - Chen Ouyang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510030, P.R. China
| | - Ting Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510030, P.R. China
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Li P, Lu G, Cui Y, Wu Z, Chen S, Li J, Wen X, Zhang H, Mu S, Zhang F, Li Y. Association of IL12A Expression Quantitative Trait Loci (eQTL) With Primary Biliary Cirrhosis in a Chinese Han Population. Medicine (Baltimore) 2016; 95:e3665. [PMID: 27175695 PMCID: PMC4902537 DOI: 10.1097/md.0000000000003665] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Genome-wide association studies in European individuals have revealed that IL12A is strongly associated with primary biliary cirrhosis (PBC). However, this association was not detected in replicative studies conducted in Chinese Han and Japanese populations.To verify contributions of genetic variants of IL12A to the pathogenesis of PBC in Chinese populations, a replicative study of 22 single nucleotide polymorphisms (SNPs) around the IL12A gene locus was performed in a cohort of 586 PBC cases and 726 healthy controls. Three out of the 22 SNPs were significantly associated with PBC. The 2 SNPs with the most significant association signal were rs4679868 (P = 6.59E-05, odds ratio [OR] = 1.554 [1.253-1.927]) and rs6441286 (P = 8.00E-05, OR = 1.551 [1.250-1.924]). These 2 SNPs were strongly linked to each other (r = 0.981), and both were found to be significantly associated with PBC in European populations.An expression quantitative trait loci (eQTL) analysis was performed based on the observation that these 2 SNPs were located in proximity to 2 enhancers verified by luciferase reporter systems in the HEK293 cell line. The results of eQTL analysis, conducted using the publically accessible data, showed that the risk alleles of rs4679868 and rs6441286 were significantly associated with decreased expression of IL12A in lymphoblastoid cell lines derived from individuals of Chinese Han ancestry (P = 0.0031 for rs4679868 and P = 0.0073 for rs6441286). In addition, the risk alleles of the 2 SNPs were significantly associated with down-regulation of SCHIP1, a celiac disease susceptible gene, 91.5 kb upstream of IL12A.These results not only demonstrated that IL12A is associated with PBC in the Chinese Han population but also identified a potential mechanism for its involvement in the pathogenesis of PBC.
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Affiliation(s)
- Ping Li
- From the Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing (PL, GL, ZW, SC, JL, XW, HZ, FZ, YL) and Department of Blood Transfusion, Tangdu Hospital, The Fourth Military Medical University, Xi'an (GL, YC, MJ), China
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Leung PSC, Choi J, Yang G, Woo E, Kenny TP, Gershwin ME. A contemporary perspective on the molecular characteristics of mitochondrial autoantigens and diagnosis in primary biliary cholangitis. Expert Rev Mol Diagn 2016; 16:697-705. [PMID: 26953925 DOI: 10.1586/14737159.2016.1164038] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disease characterized by immune mediated destruction of the intrahepatic small bile ducts and the presence of antimitochondrial antibodies (AMAs). The mitochondrial autoantigens have been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complex, including the E2 subunits of pyruvate dehydrogenase, branched-chain 2-oxo acid dehydrogenase complex, oxoglutarate dehydrogenase complex, E3 binding protein and PDC E1 alpha subunit. The AMA epitope is mapped within the E2 lipoic acid binding domain, which is particularly important for oxidative phosphorylation. In addition, lipoic acid, which serves as a swinging arm to capture electrons, is particularly susceptible to an electrophilic attack and may provide clues to the etiology of PBC. This review emphasizes the molecular characteristics of AMAs, including detection, immunochemistry and the putative role in disease. These data have significance not only specifically for PBC, but generically for autoimmunity.
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Affiliation(s)
- Patrick S C Leung
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California at Davis School of Medicine , Davis , CA , USA
| | - Jinjung Choi
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California at Davis School of Medicine , Davis , CA , USA
| | - Guoxiang Yang
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California at Davis School of Medicine , Davis , CA , USA
| | - Elena Woo
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California at Davis School of Medicine , Davis , CA , USA
| | - Thomas P Kenny
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California at Davis School of Medicine , Davis , CA , USA
| | - M Eric Gershwin
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California at Davis School of Medicine , Davis , CA , USA
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Webb GJ, Hirschfield GM. Using GWAS to identify genetic predisposition in hepatic autoimmunity. J Autoimmun 2016; 66:25-39. [PMID: 26347073 DOI: 10.1016/j.jaut.2015.08.016] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 08/23/2015] [Indexed: 12/20/2022]
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major hepatic autoimmune conditions. Patient morbidity and mortality remain high across these three diseases, and an unmet need for rational therapy exists. Disease understanding has focused on combining clinical and laboratory based science to provide better insights into the joint host and environmental factors necessary for the initiation, and perpetuation, of hepato-biliary inflammation. Twin studies, family studies, population studies and an inter-relationship with other autoimmune phenomena suggest a genetic component to risk for each disease. Until recently, understanding of this genetic risk has been limited to HLA haplotypes. Associations with risk-conferring and protective HLA haplotypes are present in all three diseases. Over the last few years, genome-wide association studies (GWAS), and related genetic association studies, have greatly increased understanding of the genetic risk signature of these three diseases and autoimmunity in general. Here we consider the rationale for GWAS in general and with specific reference to hepatic autoimmunity. We consider the process of GWAS, and highlight major findings to date. Potential functional implications of key findings are discussed including the IL-12/STAT4 pathway in PBC and the CD28/IL-2 pathway in PSC. We describe the marked pleiotropy demonstrated by PBC and PSC, which is consistent with other autoimmune diseases. Further, we focus on specific gene associations including SH2B3, which is common to all three diseases, and FUT2 in PSC, which represents a link between environment and genetics. We review attempts to translate GWAS findings into basic laboratory models including in vivo systems and highlight where clinical observations relate to genetics. Finally we describe deficiencies in GWAS to date and consider future study of genetics in hepatic autoimmunity.
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Affiliation(s)
- G J Webb
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - G M Hirschfield
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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Extrahepatic malignancies in primary biliary cirrhosis: a comparative study at two European centers. Clin Rev Allergy Immunol 2016; 48:254-62. [PMID: 25205363 DOI: 10.1007/s12016-014-8446-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Limited information and divergent results are available on the prevalence/incidence, survival, and risk factors for developing extrahepatic malignancies (EMs) in primary biliary cirrhosis (PBC). The aim of the study was to analyze the epidemiology and survival rates for EM in PBC patients. The study was conducted on two series of patients followed up at two European centers (361 in Padova, Italy, and 397 in Barcelona, Spain) for a mean 7.7 ± 7 and 12.2 ± 7 years, respectively. The cancer incidence was compared with the standardized incidence ratios (SIRs) calculated using the Cancer Registry of the Veneto Region (Italy) and the Cancer Registry of Tarragona (Spain). Seventy-two patients developed EM. The prevalence of cases was similar in Padova (9.7 %) and Barcelona (9.4 %). The overall cancer incidence was similar to the expected incidence for the general population in the same geographical area (SIR = 1.2), and so was the crude EM rate (855.01 vs 652.86 per 100,000 patient-years, respectively, RR = 1.3). Logistic regression analysis showed that advanced histological stage and extrahepatic autoimmune diseases were significantly associated with the onset of EM. Survival was similar for PBC patients with and without EM (p = n.s.), and actual survival was similar to the one predicted by the Mayo model. The incidence of EM in PBC patients was found similar in Italy and Spain and no different from that of the general population. Advanced histological stage and extrahepatic autoimmune disease were risk factors significantly associated with EM developing in PBC. The onset of cancer in PBC patients does not influence the natural history of their liver disease.
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Floreani A, Franceschet I, Cazzagon N, Spinazzè A, Buja A, Furlan P, Baldo V, Gershwin ME. Extrahepatic autoimmune conditions associated with primary biliary cirrhosis. Clin Rev Allergy Immunol 2016; 48:192-7. [PMID: 24809534 DOI: 10.1007/s12016-014-8427-x] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
There is a paucity of information on extrahepatic autoimmune (EHA) conditions associated with primary biliary cirrhosis (PBC) and on the impact of EHA conditions on PBC patients' survival. Our goal was to assess the association between PBC and other autoimmune diseases and the impact of EHA conditions on the natural history of PBC. We took advantage of 361 consecutive PBC patients enrolled between 1975 and 2012 (22 males, 339 females; mean follow-up 8 ± 6.9 years). Any associated EHA conditions, PBC histological stage at diagnosis, biochemical data, physiological history, and extrahepatic malignancies developing during the follow-up were recorded. Survival was analyzed by means of Kaplan-Meier curves. Importantly, 221 patients (61.2 %) had at least one EHA conditions: 45 patients (20.4 %) had Hashimoto thyroiditis; 7 (3.2 %) had Graves' thyroiditis; 65 (29.4 %) had Raynaud's phenomenon; 124 (56.1 %) had Sjogren's syndrome; 8 (3.6 %) had systemic lupus erythematosus; 22 (9.9 %) had scleroderma; 22 (9.9 %) had rheumatoid arthritis; 18 (8.1 %) had cutaneous autoimmune diseases; 8 (3.6 %) had vasculitis; 5 (1.4 %) had celiac disease; and 25 (13.1 %) had other EHA conditions. The proportion of patients with associated EHA conditions enrolled during representative periods (1975-1980, 1981-1990, 1991-2000, 2001-2010, 2011-2012) remained stable. No differences emerged between patients with versus without EHA conditions in terms of mean age at PBC diagnosis, antimitochondrial antibody (AMA), or antinuclear antibody (ANA) positivity, histological stage at diagnosis, smoking habits, alcohol consumption, or BMI >25. Multiple logistic regression analysis showed that only female gender was significantly associated with positivity for EHA conditions (OR 4.8; 95 % CI 1.6-13.7, p = 0.004). The mean survival after the diagnosis of PBC was much the same in patients with and without EHA conditions. In conclusion, EHA conditions are often associated with PBC, especially in female patients, but they do not reduce patient survival.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology-DiSCOG, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy,
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Sun Y, Haapanen K, Li B, Zhang W, Van de Water J, Gershwin ME. Women and primary biliary cirrhosis. Clin Rev Allergy Immunol 2016; 48:285-300. [PMID: 25241227 DOI: 10.1007/s12016-014-8449-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Primary biliary cirrhosis occurs more frequently in women, and previous studies indicated that the average age of primary biliary cirrhosis (PBC) onset makes pregnancy in PBC patients uncommon. However, more recently, improved diagnostic testing has enabled detection of PBC in younger women, including those of childbearing age. This has led investigators to become increasingly interested in the relationship between the ontogeny of PBC and pregnancy. Published cases indicate that the typical age for pregnant women to be diagnosed with PBC is in the early 30s, and that during gestation, pruritus and jaundice are the most common symptoms. During gestation, susceptible women may experience onset of PBC resulting from the drastic changes in female hormones; this would include not only the mitochondrial damage due to accumulation of bile acids but also changes in the immune response during the different stages of pregnancy that might play an important role in the breakdown of self-tolerance. The mechanisms underlying the potential relationship between PBC and pregnancy warrant further investigation. For women first diagnosed with PBC during gestation, or those for whom first appearance of a flare up occurs during and postpartum, investigation of the immune response throughout gestation could provide new avenues for immunologic therapeutic intervention and the discovery of new treatment strategies for PBC.
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Affiliation(s)
- Ying Sun
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
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Abstract
Primary biliary cirrhosis (PBC) is characterized histologically by the presence of chronic non-suppurative destructive cholangitis of the small interlobular bile duct, leading to chronic progressive cholestasis. Most PBC patients are asymptomatic and have a reasonable prognosis, but a few develop esophageal varices or jaundice, rapidly leading to liver failure within a short period. As multiple factors appear to be involved in the onset of PBC, its clinical course may be complicated. Therefore, the use of an animal model would be valuable for clarifying the pathogenesis of PBC. Here, we review recent data of selected PBC models, particularly spontaneous models, xenobiotic immunized models, and infection-triggered models. There are a number of spontaneous models: the NOD.c3c4, dominant-negative TGF-β receptor II, IL-2Rα-/-, Scurfy, and Ae2a,b-/- mice. These animal models manifest distinct clinical and immunological features similar, but also often different, from those of human PBC. It is clear that a combination of genetic predisposition, environmental factors, and immunological dysfunction contribute to the pathogenesis of PBC. The diverse clinical course and complexity of the immunological mechanisms of PBC cannot be fully recapitulated solely any single animal model. The challenge remains to develop a progressive PBC disease model that exhibits fibrosis, and ultimately hepatic failure.
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Abstract
Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized.
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Affiliation(s)
- Aliya F. Gulamhusein
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
| | - Brian D. Juran
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. Phone: (507) 538-4877. Fax: (507) 284-0762
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Shi T, Zhang T, Zhang L, Yang Y, Zhang H, Zhang F. The Distribution and the Fibrotic Role of Elevated Inflammatory Th17 Cells in Patients With Primary Biliary Cirrhosis. Medicine (Baltimore) 2015; 94:e1888. [PMID: 26554784 PMCID: PMC4915885 DOI: 10.1097/md.0000000000001888] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
T helper (Th) 17 cells were reported to have the property of proinflammation and profibrosis. We first investigate the levels of Th17 cells in primary biliary cirrhosis (PBC) patients, and then explore their distribution and fibrotic role in the disease.We compared the circulating Th17 and hepatic interleukin (IL)-17-positive cells between patients and healthy controls (HCs) at different disease stages by flow cytometry and immunohistochemistry, respectively. The levels of chemokine (c-c motif) ligand (CCL) 20 were then measured. For exploration of the reason why Th17 cells increased, CD4CD161 populations were sorted and cultured with IL-23 and IL-1β to analyze their proliferation and IL-17 secretions. The serum IL-23 and IL-1β were tested by enzyme-linked immunosorbent assay. The proliferation and expressions of α-smooth muscle actin and IL-8 of hepatic stellate cells (HSCs) were identified after stimulated by different concentrations of IL-17.Circulating and hepatic Th17 cells were elevated in PBC patients compared with HCs. Early PBC patients presented with more Th17 cells in periphery blood and less in the liver than advanced PBC patients. Accordingly, the levels of both serum and hepatic CCL20 for Th17 cells were higher, especially in those with advanced disease. The progenitor of Th17, CD4CD161 cell was increased in PBC. Moreover, the percentage of Th17 cells was positively related with CD4CD161 cell. After stimulation with IL-23 and IL-1β which were improved in PBC patients, CD4CD161 cells from PBC patients expressed more IL-17, although their proliferation were not different between 2 groups. IL-17 can promote the proliferation of HSCs at a dose-dependent method, and also increase the IL-8 expression in a dose/time-dependent way. Anti-IL-17 can neutralize the above reactions.CD4CD161 cells are a source of increased Th17 in PBC patients. With disease progression, Th17 population decreased in the circulation, accompanied by greater accumulation in the liver, which is regulated by CCL20 in advanced patients. IL-17 may be involved in the process of PBC fibrosis.
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Affiliation(s)
- TianYan Shi
- From the Department of Rheumatology and Clinical Immunology, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
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Webb GJ, Siminovitch KA, Hirschfield GM. The immunogenetics of primary biliary cirrhosis: A comprehensive review. J Autoimmun 2015; 64:42-52. [PMID: 26250073 PMCID: PMC5014907 DOI: 10.1016/j.jaut.2015.07.004] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 07/06/2015] [Indexed: 12/20/2022]
Abstract
Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.
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Affiliation(s)
- G J Webb
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - K A Siminovitch
- Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto General Research Institute, and Departments of Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - G M Hirschfield
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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Cheng LS, Liu Y, Jiang W. Restoring homeostasis of CD4⁺ T cells in hepatitis-B-virus-related liver fibrosis. World J Gastroenterol 2015; 21:10721-10731. [PMID: 26478664 PMCID: PMC4600574 DOI: 10.3748/wjg.v21.i38.10721] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 06/19/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
Immune-mediated liver injury is widely seen during hepatitis B virus (HBV) infection. Unsuccessful immune clearance of HBV results in chronic hepatitis and increases the risk of liver cirrhosis and hepatocellular carcinoma. HBV-related liver fibrosis (HBVLF), occurring as a result of HBV-induced chronic hepatitis, is a reversible, intermediate stage of chronic hepatitis B (CHB) and liver cirrhosis. Therefore, defining the pathogenesis of HBVLF is of practical significance for achieving better clinical outcomes. Recently, the homeostasis of CD4(+) T cells was considered to be pivotal in the process of HBVLF. To better uncover the underlying mechanisms, in this review, we systematically retrospect the impacts of different CD4(+) T-cell subsets on CHB and HBVLF. We emphasize CD4(+) T-cell homeostasis and the important balance between regulatory T (Treg) and T helper 17 (Th17) cells. We discuss some cytokines associated with Treg and Th17 cells such as interleukin (IL)-17, IL-22, IL-21, IL-23, IL-10, IL-35 and IL-33, as well as surface molecules such as programmed cell death protein 1, cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin domain and mucin domain-containing molecule 3 and cannabinoid receptor 2 that have potential therapeutic implications for the homeostasis of CD4(+) T cells in CHB and HBVLF.
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Yang JB, Wang YH, Yang W, Lu FT, Ma HD, Zhao ZB, Jia YJ, Tang W, Tsuneyama K, Ridgway WM, Gershwin ME, Lian ZX. Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy. J Autoimmun 2015; 66:108-17. [PMID: 26432598 DOI: 10.1016/j.jaut.2015.09.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 09/10/2015] [Accepted: 09/14/2015] [Indexed: 01/26/2023]
Abstract
There is a significant unmet need in the treatment of primary biliary cirrhosis (PBC) despite significant data on the effector pathways that lead to biliary duct damage. We focused attention on a murine model of PBC, the dominant negative transforming growth factor β receptor II (Tg) mice. To further define the pathways that lead to biliary pathology in these mice, we developed Tg mice deleted of CD4 cells (CD4(-/-)Tg). Interestingly, these mice developed more severe cholangitis than control Tg mice. These mice, which lack CD4 cells, manifested increased levels of IFN-γ produced by effector CD8 cells. It appears that increased cholangitis is due to the absence of CD4 Treg cells. Based on these data, we parabiosed CD4(-/-)Tg mice with established disease at 8-9 weeks of age with C57BL/6 control mice. Such parabiotic "twins" had a significant reduction in autoimmune cholangitis, even though they had established pathology at the time of surgery. We prepared mixed bone marrow chimera mice constructed from CD4(-/-)Tg and CD8(-/-) mice and not only was cholangitis improved, but a decrease in terminally differentiated CD8(+) T effector cells in the presence of wild type CD4 cells was noted. In conclusion, "correcting" the CD4 T cell subset, even in the presence of pathogenic CD8 T cells, is effective in treating autoimmune cholangitis.
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Affiliation(s)
- Jing-Bo Yang
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Yin-Hu Wang
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Wei Yang
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Fang-Ting Lu
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Hong-Di Ma
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Zhi-Bin Zhao
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Yan-Jie Jia
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Wei Tang
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Koichi Tsuneyama
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan.
| | - William M Ridgway
- Division of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, OH 45220, USA.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
| | - Zhe-Xiong Lian
- Liver Immunology Laboratory, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
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49
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Epigenetics and Primary Biliary Cirrhosis: a Comprehensive Review and Implications for Autoimmunity. Clin Rev Allergy Immunol 2015; 50:390-403. [DOI: 10.1007/s12016-015-8502-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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50
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Tanaka H, Yang GX, Tomiyama T, Tsuneyama K, Zhang W, Leung PSC, Coppel RL, Joh T, Nadler SG, Ansari AA, Bowlus C, Gershwin ME. Immunological potential of cytotoxic T lymphocyte antigen 4 immunoglobulin in murine autoimmune cholangitis. Clin Exp Immunol 2015; 180:371-82. [PMID: 25581259 DOI: 10.1111/cei.12581] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2015] [Indexed: 12/13/2022] Open
Abstract
Cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig) is an important regulator of T cell activation and a fusion protein directed at CD80 and CD86; it blocks co-stimulatory signalling and T cell activation. We have taken advantage of a murine model of human primary biliary cirrhosis (PBC), mice expressing a transforming growth factor (TGF)-β receptor II dominant negative (dnTGF-βRII) transgene to address the potential therapeutic efficacy of CTLA-4 Ig. To mimic patients with PBC at different stages or duration of disease, we treated mice with either CTLA-4 Ig or control IgG three times weekly from 3 to 12 or 24 weeks of age, or from 12 to 24 weeks of age. CTLA-4 Ig treatment from 3 weeks of age significantly reduced liver inflammation to 12 weeks of age. Treatment initiated at 12 weeks of age also ameliorated the autoimmune cholangitis at 24 weeks of age. However, in mice treated at 3 weeks of age, suppression of liver inflammation was not sustained and colitis was aggravated when treatment was extended to 24 weeks of age. Our data indicate that, in dnTGF-βRII mice, CTLA-4 Ig treatment has short-term beneficial effects on autoimmune cholangitis, but the effect varies according to duration of treatment and the time in which therapy was initiated. Further dissection of the events that lead to the reduction in therapeutic effectiveness of CTLA-4 Ig will be critical to determining whether such efforts can be applied to human PBC.
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Affiliation(s)
- H Tanaka
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.,Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - G-X Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - T Tomiyama
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.,Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - K Tsuneyama
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.,Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
| | - W Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - P S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - R L Coppel
- Department of Microbiology, Monash University, Melbourne, Victoria, Australia
| | - T Joh
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - S G Nadler
- Department of Immunology, Bristol Myers Squibb, Princeton, NJ, USA
| | - A A Ansari
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - C Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Sacramento, CA, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
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