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Nugteren S, Wang H, van Kooten C, Gelderman KA, Trouw LA. Autoantibodies and therapeutic antibodies against complement factor H. Immunol Lett 2025; 274:107002. [PMID: 40118156 DOI: 10.1016/j.imlet.2025.107002] [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: 12/24/2024] [Revised: 03/11/2025] [Accepted: 03/19/2025] [Indexed: 03/23/2025]
Abstract
The complement system is a crucial part of our immune defense as, upon recognition, it can kill pathogens fast and effectively. However, misguided complement activation could cause damage to host tissues. Therefore, a well-controlled regulation of the complement system is a necessity to prevent collateral damage. Regulation is achieved by several complement inhibitory proteins, acting at different levels of the complement system. One of these complement regulators is factor H, the main regulator of the alternative complement activation pathway. Factor H can regulate the complement system both in fluid-phase and on the host cell surface by, for example, acting as co-factor for factor I, inactivating C3b. The functional properties of factor H are located within different regions of the protein. Functional impairment of factor H, either because of genetic variants, competing proteins such as the factor H-related proteins and proteins from certain pathogens, but also the presence of autoantibodies will impact on complement activation. However, exact consequences are dependent on the region within factor H that is affected. Autoantibodies binding to factor H have been shown to inhibit several regulatory functions of factor H, which is observed in diseases such as membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome. As more recently the presence of anti-factor H autoantibodies has also been discovered in several other diseases, ranging from autoimmune diseases to cancer, this review provides an overview of the presence of factor H autoantibodies described in these diseases. Factor H autoantibodies are reported to have inhibitory, or enhancing, effects on factor H, depending on the epitopes that are recognized. Formal conclusions about the pathogenicity of the factor H autoantibodies in some of these diseases cannot be drawn yet. Importantly, understanding the binding and functional impact of anti-factor H (auto)antibodies will allow targeted interventions to diminish pathological consequences of anti-factor H autoantibodies but may also open up additional avenues for the use of anti-factor H antibodies as therapeutic agents.
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Affiliation(s)
- Saskia Nugteren
- Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
| | - Haiyu Wang
- Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
| | - Cees van Kooten
- Department of Internal Medicine section Nephrology, Center of Expertise for Lupus, Vasculitis and Complement- mediated Systemic Autoimmune Diseases, Leiden University Medical Center, Leiden, the Netherlands
| | - Kyra A Gelderman
- Erasmus Medical Center, Department of Immunology, Laboratory Medical Immunology, Rotterdam, the Netherlands
| | - Leendert A Trouw
- Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands.
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2
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Zipfel PF, Heidenreich K. The 4 functional segments of Factor H: Role in physiological target recognition and contribution to disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf065. [PMID: 40356067 DOI: 10.1093/jimmun/vkaf065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/07/2025] [Indexed: 05/15/2025]
Abstract
Factor H controls proximal complement activation, and its dysfunction leads to diseases that often manifest in the kidney. Structural and functional analyses have identified 4 distinct functional segments: an N-terminal regulatory unit, a cell binding unit, a segment with combined low-affinity C3b and heparin sites, and a C-terminal recognition or sensor unit with overlapping C3b/C3d and heparin sites. Three segments are linked to diseases. The regulatory segment is affected in C3 glomerulopathy and antineutrophil cytoplasmic antibody-associated vasculitis. The second segment includes the Y402H polymorphism of age-related macular degeneration, is associated with different types of cancer, and is targeted by pathogens. The C-terminal sensor segment is involved in atypical hemolytic uremic syndrome, in FHR1:FHR3 deficient and autoantibody-positive hemolytic uremic syndrome form and is exploited by pathogens. Factor H function is modulated by Factor H like protein 1 and FHR1, 2 plasma proteins that share segments with Factor H. This interplay is critical for fine-tuning local complement. Understanding Factor H's physiological role, as well as the impact of its absence, mutations, or autoantibody targeting, provides insights into disease mechanisms and provides opportunities for therapeutic intervention by using full-length Factor H, its fragments, or complement-modulatory compounds.
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Affiliation(s)
- Peter F Zipfel
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
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Lafayette RA, Charu V, Glassock RJ. Expert Discussion on Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Challenges and Considerations. Adv Ther 2025; 42:2003-2014. [PMID: 40146368 PMCID: PMC12006263 DOI: 10.1007/s12325-025-03167-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/04/2025] [Indexed: 03/28/2025]
Abstract
Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is a rare pattern of kidney injury and a progressive nephropathy characterized by the glomerular deposition of immune complexes and complement proteins. The IC-MPGN pattern of injury exhibits a membranoproliferative glomerulonephritis appearance by light microscopy and occurs secondary to various conditions or, more rarely, idiopathically, when no underlying etiology can be determined. Kidney biopsy is the only method for identifying IC-MPGN, distinguishing between IC-MPGN and complement 3 glomerulopathy (C3G), and for providing critical pathologic insights that guide further clinical evaluation for underlying etiologies and inform patient management. Given the progressive nature of IC-MPGN, it is crucial to identify patients early and to define the underlying pathophysiology for timely and appropriate treatment. However, several challenges remain in the accurate interpretation of kidney biopsy specimens and the effective treatment of idiopathic disease. In this commentary, two nephrologists and a nephropathologist review best practices in the clinical and histopathologic evaluation of IC-MPGN and discuss the central role of kidney biopsy in the differentiation of IC-MPGN and C3G. The challenges and considerations discussed are explored through an illustrative case of idiopathic disease, drawn from the authors' clinical experiences. Finally, remaining unmet needs are highlighted, and future perspectives on targeted treatments under investigation for patients with idiopathic IC-MPGN are provided.
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Affiliation(s)
| | - Vivek Charu
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Richard J Glassock
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- , 3329 Bahia Blanca East, Unit B, Laguna Woods, CA, 92637, USA.
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Matola AT, Csuka D, Szilágyi Á, Rudnicki M, Prohászka Z, Józsi M, Uzonyi B. Autoantibodies Against Factor B and Factor H Without Pathogenic Effects in a Patient with Immune Complex-Mediated Membranoproliferative Glomerulonephritis. Biomedicines 2025; 13:648. [PMID: 40149624 PMCID: PMC11939916 DOI: 10.3390/biomedicines13030648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 02/24/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Membranoproliferative glomerulonephritis (MPGN) is an umbrella term for chronic disorders affecting the glomeruli. MPGN is often accompanied by the presence of autoantibodies against complement components. However, the actual pathogenic effects of such autoantibodies, if any, are rarely studied. In this work, we investigated the role of anti-complement autoantibodies in an IC-MPGN patient. Methods: The presence of autoantibodies, their binding site, isotype, and titer were analyzed in ELISA. Antibody-antigen complexes were detected in the patient's serum using Western blot. Autoantibodies were studied in functional assays to analyze their effects on C3 convertase, complement deposition, cofactor activity, C3b binding, and hemolysis. Results: We identified autoantibodies against factor B (FB) and factor H (FH) in the patient's serum. Both FB-, and FH-autoantibodies were of IgG2, IgG3, IgG4, and IgGκ, IgGλ isotypes. FB-autoantibodies bound to the Ba and the enzymatically active Bb part of FB. FH-autoantibodies bound to the N- and C-termini of FH and cross-reacted with FHL-1 and FHR-1 proteins. In vivo formed complexes of the autoantibodies with both FB and FH were detected in the IgG fraction isolated from the serum. The autoantibodies did not influence solid-phase C3 convertase assembly and its FH-mediated decay. The free autoantibodies had no effect on complement deposition and on FH cofactor activity but slightly reduced C3b binding to FH. The IgG fraction of the patient dose-dependently inhibited complement-mediated rabbit red blood cell lysis, and the free autoantibodies decreased the solid phase C3 convertase activity. Conclusions: This case highlights that FB- and FH-autoantibodies are not necessarily pathogenic in IC-MPGN.
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Affiliation(s)
- Alexandra T. Matola
- Department of Immunology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, H-1117 Budapest, Hungary
| | - Dorottya Csuka
- Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
- HUN-REN-SE Research Group for Immunology and Hematology, Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
| | - Ágnes Szilágyi
- Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
- HUN-REN-SE Research Group for Immunology and Hematology, Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
| | - Michael Rudnicki
- Department of Internal Medicine IV, Medical University of Innsbruck, A-6020 Innsbruck, Austria
| | - Zoltán Prohászka
- Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
- HUN-REN-SE Research Group for Immunology and Hematology, Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, H-1117 Budapest, Hungary
| | - Barbara Uzonyi
- Department of Immunology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, H-1117 Budapest, Hungary
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Welsh SJ, Zhang Y, Smith RJH. Acquired drivers of C3 glomerulopathy. Clin Kidney J 2025; 18:sfaf022. [PMID: 40052168 PMCID: PMC11883229 DOI: 10.1093/ckj/sfaf022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Indexed: 03/09/2025] Open
Abstract
C3 glomerulopathy (C3G) is a group of heterogeneous ultrarare kidney diseases characterized by dysregulated activation of the complement alternative pathway (AP) leading to excessive C3 cleavage. Diagnosis relies on kidney biopsy showing predominant C3 deposition in the glomerular basement membrane, with electron microscopy differentiating between dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The main drivers of AP dysregulation in C3G are acquired rather than genetic and consist primarily of autoantibodies called nephritic factors (C3Nefs, C4Nefs and C5Nefs) that bind to and stabilize complement convertases, causing complement overactivation. Current therapies are largely supportive, and existing complement-targeting treatments, such as eculizumab, demonstrate limited efficacy. Challenges in studying C3G include variability in autoantibody detection and a lack of standardized assays, which complicates clinical interpretation. Comprehensive assessment involving autoantibody panels, complement biomarkers, functional assays and genetic testing provides a more complete understanding of disease dynamics; however, key knowledge gaps remain regarding Nef origins, mechanisms and their pathogenic role. In this review we discuss acquired drivers of C3G with an emphasis on C3Nefs and C5Nefs and suggest areas of interest that might benefit from future research.
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Affiliation(s)
- Seth J Welsh
- Department of Internal Medicine, Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Yuzhou Zhang
- Department of Internal Medicine, Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Richard J H Smith
- Department of Internal Medicine, Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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Heidenreich K, Goel D, Priyamvada PS, Kulkarni S, Chakurkar V, Khullar D, Singh R, Bale C, Zipfel PF. C3 glomerulopathy: a kidney disease mediated by alternative pathway deregulation. FRONTIERS IN NEPHROLOGY 2024; 4:1460146. [PMID: 39534179 PMCID: PMC11554616 DOI: 10.3389/fneph.2024.1460146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 09/17/2024] [Indexed: 11/16/2024]
Abstract
C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease caused by to the deregulation of the alternative pathway (AP) of proximal complement. Consequently, all effector loops of the complement are active and can lead to pathologies, such as C3a- and C5a-mediated inflammation, C3b opsonization, surface C3b-mediated AP C3 convertase assembly, C3 cleavage product deposition in the glomerulus, and lytic C5b-9/MAC cell damage. The most common pathologic mechanisms are defective chronic alternative pathway deregulation, mostly occurring in the plasma, often causing C3 consumption, and chronic complement-mediated glomerular damage. C3G develops over several years, and loss of renal function occurs in more than 50% of patients. C3G is triggered by both genetic and autoimmune alterations. Genetic causes include mutations in individual complement genes and chromosomal variations in the form of deletions and duplications affecting genes encoding complement modulators. Many genetic aberrations result in increased AP C3 convertase activity, either due to decreased activity of regulators, increased activity of modulators, or gain-of-function mutations in genes encoding components of the convertase. Autoimmune forms of C3G do also exist. Autoantibodies target individual complement components and regulators or bind to neoepitopes exposed in the central alternative pathway C3 convertase, thereby increasing enzyme activity. Overactive AP C3 convertase is common in C3G patients. Given that C3G is a complement disease mediated by defective alternative pathway action, complement blockade is an emerging concept for therapy. Here, we summarize both the causes of C3G and the rationale for complement inhibition and list the inhibitors that are being used in the most advanced clinical trials for C3G. With several inhibitors in phase II and III trials, it is expected that effectice treatment for C3G will become availabe in the near future.
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Affiliation(s)
| | | | - P. S. Priyamvada
- Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Sagar Kulkarni
- Department of Nephrology, King Edward Memorial Hospital, Pune, Maharashtra, India
| | - Vipul Chakurkar
- Department of Nephrology, King Edward Memorial Hospital, Pune, Maharashtra, India
| | - Dinesh Khullar
- Department of Nephrology and Renal Transplantation, Max Super Speciality Hospital Saket, New Delhi, India
| | - Ravi Singh
- Department of Nephrology and Renal Transplant, Jaypee Hospital, Noida, Uttar Pradesh, India
| | - Charan Bale
- Department of Nephrology, Dr. D.Y. Patil Medical College & Research Centre, Pune, Maharashtra, India
| | - Peter F. Zipfel
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany
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7
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Liang S, Liang D, Zhu X, Liang D, Xu F, Tu Y, Zeng C. Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a clinicopathological study of three cases. J Clin Pathol 2024; 77:551-556. [PMID: 37137693 DOI: 10.1136/jcp-2023-208795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/17/2023] [Indexed: 05/05/2023]
Abstract
AIMS To explore the clinical and pathological features of light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID-LC). METHODS From January 2010 to December 2022, patients who were diagnosed with PGNMID-LC were selected, and their clinical and pathological features were retrospectively analysed. RESULTS Three males aged 42-61 years old were enrolled. Hypertension was present in three patients, oedema in three patients, anaemia in two patients, proteinuria in three patients, nephrotic syndrome in one patient, microscopic haematuria in three patients, renal insufficiency in two patients and hypocomplementaemia of C3 in one patient. Elevated serum-free LC ratios and plasmacytosis on bone marrow smears were observed in three patients, and κ was identified by serum protein immunofixation electrophoresis in one patient. Renal biopsy showed membranoproliferative glomerulonephritis in two patients and endocapillary proliferative glomerulonephritis in one patient on light microscopy. Immunofluorescence indicated restricted κ LC and C3 distributed in glomeruli. By electron microscopy, electron-dense deposits without substructure were identified predominantly in the mesangial and subendothelial regions and were variable in the subepithelial region. Two patients were treated with plasma cell-directed chemotherapy and achieved haematological complete response or very good partial response, and one of them achieved a renal status of complete remission. One patient treated with immunosuppressive therapy only did not achieve haematological or renal remission. CONCLUSIONS PGNMID-LC is a rare and uniform disease with a high frequency of a detectable pathogenic plasma cell clone and is characterised by glomerular deposition of restricted LC and C3 in renal pathology. Plasma cell-directed chemotherapy may improve haematological and renal prognosis.
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Affiliation(s)
- Shaoshan Liang
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Dongmei Liang
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Xiaodong Zhu
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Dandan Liang
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Feng Xu
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Yuanmao Tu
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
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8
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Bartoli G, Dello Strologo A, Grandaliano G, Pesce F. Updates on C3 Glomerulopathy in Kidney Transplantation: Pathogenesis and Treatment Options. Int J Mol Sci 2024; 25:6508. [PMID: 38928213 PMCID: PMC11204074 DOI: 10.3390/ijms25126508] [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: 04/23/2024] [Revised: 06/01/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
C3 glomerulopathy is a rare disease, characterized by an abnormal activation of the complement's alternative pathway that leads to the accumulation of the C3 component in the kidney. The disease recurs in more than half of kidney transplant recipients, with a significant impact on graft survival. Recurrence of the primary disease represents the second cause of graft loss after organ rejection. In C3 glomerulopathy, there are several risk factors which can promote a recurrence during transplantation, such as delayed graft function, infection and monoclonal gammopathy. All these events can trigger the alternative complement pathway. In this review, we summarize the impact of C3 glomerulopathy on kidney grafts and present the latest treatment options. The most widely used treatments for the disease include corticosteroids and mycophenolate mofetil, which are already used chronically by kidney transplant recipients; thus, additional treatments for C3 glomerulopathy are required. Currently, several studies using anti-complement drugs (i.e., eculizumab, Ravalizumab, avacopan) for C3 glomerulopathy in kidney transplant patients are ongoing with encouraging results.
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Affiliation(s)
- Giulia Bartoli
- Department of Translational Medicine and Surgery, Università Cattolica dl Sacro Cuore, 00168 Rome, Italy; (G.B.); (A.D.S.); (G.G.)
| | - Andrea Dello Strologo
- Department of Translational Medicine and Surgery, Università Cattolica dl Sacro Cuore, 00168 Rome, Italy; (G.B.); (A.D.S.); (G.G.)
| | - Giuseppe Grandaliano
- Department of Translational Medicine and Surgery, Università Cattolica dl Sacro Cuore, 00168 Rome, Italy; (G.B.); (A.D.S.); (G.G.)
- Nephrology, Dialysis and Transplantation Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Pesce
- Department of Translational Medicine and Surgery, Università Cattolica dl Sacro Cuore, 00168 Rome, Italy; (G.B.); (A.D.S.); (G.G.)
- Division of Renal Medicine, “Ospedale Isola Tiberina—Gemelli Isola”, 00186 Rome, Italy
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9
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Al Jurdi A, Cohen Bucay A, Riella LV, Yee AJ, Abdelmalek C, Klepeis V, Kimura S, Safa K. Successful Treatment of Posttransplant Monoclonal Gammopathy-associated C3 Glomerulopathy With Plasma Cell Clone-directed Therapy. Transplant Direct 2024; 10:e1616. [PMID: 38606352 PMCID: PMC11005891 DOI: 10.1097/txd.0000000000001616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 04/13/2024] Open
Affiliation(s)
- Ayman Al Jurdi
- Division of Nephrology, Massachusetts General Hospital, Boston, MA
| | | | | | - Andrew J. Yee
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA
| | - Cherif Abdelmalek
- Division of Hematology and Oncology, Southern New Hampshire Health, Nashua, NH
| | - Veronica Klepeis
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Shoko Kimura
- Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA
| | - Kassem Safa
- Division of Nephrology, Massachusetts General Hospital, Boston, MA
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10
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Abstract
The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic-uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.
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Affiliation(s)
- Vojtech Petr
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Joshua M Thurman
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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11
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Ekladious A, Bhandari R, Javaid MM. Association of monoclonal gammopathy of undetermined significance and C3 glomerulopathy. Intern Med J 2023; 53:1712-1715. [PMID: 37665716 DOI: 10.1111/imj.16222] [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: 02/14/2023] [Accepted: 07/12/2023] [Indexed: 09/06/2023]
Abstract
Monoclonal gammopathy of undetermined significance (MGUS) is usually an asymptomatic pre-malignant condition caused by the proliferation of clonal plasma cells. Often considered a benign condition, it has the potential to progress to malignant plasma cell or lymphoproliferative disorders. Moreover, MGUS can rarely cause glomerular disease by activating the alternative complement pathway resulting in immunoglobulin-negative C3-positive glomerulonephritis called C3 glomerulopathy. Because of its rarity, the diagnosis might not be considered by the treating physicians, leading to delayed diagnosis or misdiagnosis. Untreated C3 glomerulopathy can lead to irreversible glomerular damage and end-stage renal failure, and a high index of suspicion is essential for timely diagnosis and management. Here, we present the case of a patient with a prior diagnosis of MGUS who presented with proteinuria and microscopic haematuria and was diagnosed with C3 glomerulopathy. The patient had complete resolution of the disease after receiving treatment with a combination of dexamethasone, lenalidomide and bortezomib for the underlying MGUS.
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Affiliation(s)
- Adel Ekladious
- Department of General Medicine and Acute Assessment Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia
- Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Ritesh Bhandari
- Department of General Medicine, Royal Hobart Hospital, Hobart, Tasmania, Australia
| | - Muhammad M Javaid
- Department of Renal Medicine, Woodlands Health, Singapore, Singapore
- School of Medicine, Monash University, Melbourne, Victoria, Australia
- School of Medicine, Deakin University, Burwood, Victoria, Australia
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12
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Relapse of Monoclonal Gammopathy of Renal Significance after mRNA COVID-19 Vaccination: A Case Report. Life (Basel) 2023; 13:life13030734. [PMID: 36983889 PMCID: PMC10057448 DOI: 10.3390/life13030734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
This case report represents the first suspected case of light chain deposition disease relapse associated with mRNA COVID-19 vaccination. The 75-year-old female patient of Greek ethnicity was admitted to the clinic for the investigation of worsening renal function detected on routine lab examinations, two weeks after she received the second dose of the Moderna COVID-19 vaccine (mRNA-1273). Rapidly progressive glomerulonephritis and anemia were the most notable findings. She had a history of LCDD, which had remained stable for four years. Serum protein immunofixation showed monoclonal kappa zones, and a bone marrow biopsy revealed 5% plasma cell infiltration. These, along with other investigations, established the diagnosis of LCDD recurrence. The patient was started on chemotherapy, which improved her immunological profile, but not her renal function. The patient has remained on hemodialysis since. The association between mRNA vaccinations and LCDD relapse may be grounds for investigations into the pathophysiology of MGRS, given the patient’s previous long-term remission. This case report is not intended to directly inform changes in clinical practice. We must stress the importance of following all standardized vaccination protocols, especially in immunocompromised patients.
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13
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Genest DS, Patriquin CJ, Licht C, John R, Reich HN. Renal Thrombotic Microangiopathy: A Review. Am J Kidney Dis 2022; 81:591-605. [PMID: 36509342 DOI: 10.1053/j.ajkd.2022.10.014] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 10/03/2022] [Indexed: 12/14/2022]
Abstract
Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies.
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Affiliation(s)
- Dominique Suzanne Genest
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Christopher J Patriquin
- Division of Medical Oncology & Hematology, University Health Network, Toronto, Ontario, Canada; Department of Medicine, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada
| | - Christoph Licht
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Medicine, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada; Division of Nephrology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rohan John
- Division of Laboratory Medicine and Pathology, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada
| | - Heather N Reich
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Medicine, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
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14
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Kao S, Silinsky Krupnikova SD, AlMackenzie M, Atefi G. Renal injury in scleromyxoedema due to monoclonal gammopathy associated C3 glomerulonephritis. BMJ Case Rep 2022; 15:e250296. [PMID: 36450416 PMCID: PMC9716891 DOI: 10.1136/bcr-2022-250296] [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] [Accepted: 11/14/2022] [Indexed: 12/03/2022] Open
Abstract
Scleromyxoedema is a rare mucinosis that primarily affects the skin. It is associated with monoclonal gammopathy and has many extracutaneous manifestations, however, renal involvement is rare. We report the case of a woman with monoclonal gammopathy and scleromyxoedema presenting with progressive exertional dyspnoea and acute renal failure. Workup of her renal failure revealed monoclonal gammopathy associated C3 glomerulonephritis. She was treated with intravenous steroids and discharged with plans to pursue annual monoclonal gammopathy laboratory monitoring. Given the rarity of renal scleromyxoedema, careful investigation of extracutaneous manifestations and comorbidities is critical to discern the primary pathological process in patients with scleromyxoedema who develop renal insufficiency.
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Affiliation(s)
- Stephanie Kao
- Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | | | - Maha AlMackenzie
- Division of Rheumatology, Department of Medicine, Medical Cities of the Ministry of the Interior, Riyadh, Saudi Arabia
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15
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An Exceptional Case of Light Chain Only Variant of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits Secondary to Chronic Lymphocytic Leukemia: A Case Report and Review of the Literature. Case Rep Nephrol 2022; 2022:9207282. [PMID: 36312462 PMCID: PMC9605840 DOI: 10.1155/2022/9207282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
We present the case of an 86-year-old Caucasian male with an 11-year history of low-grade chronic lymphocytic leukemia (CLL) presenting with nephrotic syndrome (NS). Renal biopsy findings showed a diffuse mesangial and endocapillary proliferative glomerulonephritis (GN) lesion with fine granular deposits, consistent with a rare morphologic variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)-lambda light chain (LC) only. Monthly combination therapy of rituximab (500 mg/m2 on day 1), fludarabine (30 mg/m2 on days 1–3), and cyclophosphamide (750 mg/m2 on days 1–3) was administered. Five courses of this regimen resulted in hematological remission, as well as a partial renal response with a reduction in the spot urine protein-to-creatinine ratio (UPCR) of 815.3 mg/g (reduction > 50% proteinuria without improvement in kidney function). This condition is a rare morphological variant of PGNMID, poorly described in CLL patients. We review the literature and suggest that this case provides sheds light on the unknown pathophysiological mechanisms of monoclonal immunoglobulins (MIg)-mediated glomerular damage in CLL patients, and may be helpful for the investigation of a more effective treatment.
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16
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Overview on the role of complement-specific autoantibodies in diseases. Mol Immunol 2022; 151:52-60. [PMID: 36084516 DOI: 10.1016/j.molimm.2022.08.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/03/2022] [Accepted: 08/15/2022] [Indexed: 11/24/2022]
Abstract
The complement system is recognized as a major pathogenic or contributing factor in an ever-growing number of diseases. In addition to inherited factors, autoantibodies to complement proteins have been detected in various systemic and organ-specific disorders. These include antibodies directed against complement components, regulators and receptors, but also protein complexes such as autoantibodies against complement convertases. In some cases, the autoantibodies are relatively well characterized and a pathogenic role is incurred and their detection has diagnostic value. In other cases, the relevance of the autoantibodies is rather unclear. This review summarizes what we know of complement specific autoantibodies in diseases and identifies unresolved questions regarding their functional effect and relevance.
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17
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Bangolo A, Akhter M, Jarri A, Kaur M, Atoot A, Jandir P, Ibrahim M, Manandhar L, Atoot A. A Case Report of Premalignant Plasma Cell Dyscrasia-Induced Renal Failure in a 31-Year-Old Female. Case Rep Hematol 2022; 2022:2497380. [PMID: 35711966 PMCID: PMC9197607 DOI: 10.1155/2022/2497380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 05/24/2022] [Indexed: 01/14/2023] Open
Abstract
Monoclonal gammopathy of renal significance (MGRS) is a rare disorder in which monoclonal immunoglobulin secreted by nonmalignant B cell or plasma cell clone causes kidney damage. Although MGRS is a premalignant condition, it can cause severe kidney disease and end-stage renal disease (ESRD) at any age. Herein, we present a 31-year-old female with past medical history of lupus nephritis who presented with signs of volume overload and worsening renal function despite adequate immunosuppressive therapy. Renal biopsy revealed heavy and light chain deposition consistent with MGRS. This case report demonstrates the importance of including MGRS in the differential diagnosis of worsening renal function despite adequate treatment, raising awareness of this premalignant yet morbid condition.
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Affiliation(s)
- Ayrton Bangolo
- Hackensack, Meridian Health Palisades Medical Center, Department of Internal Medicine, North Bergen, NJ, USA
| | - Mahabuba Akhter
- Hackensack, Meridian Health Palisades Medical Center, Department of Internal Medicine, North Bergen, NJ, USA
| | - Amer Jarri
- Hackensack, Meridian Health Palisades Medical Center, Department of Internal Medicine, North Bergen, NJ, USA
| | - Manpreet Kaur
- Hackensack, Meridian Health Palisades Medical Center, Department of Internal Medicine, North Bergen, NJ, USA
| | - Ali Atoot
- Hackensack University Medical Center, Department of Anesthesia, Hackensack, NJ, USA
| | - Parul Jandir
- Hackensack, Meridian Health Palisades Medical Center, Department of Internal Medicine, North Bergen, NJ, USA
| | - Mahmood Ibrahim
- Hackensack, Meridian Health Palisades Medical Center, Department of Internal Medicine, North Bergen, NJ, USA
| | - Lochana Manandhar
- Hackensack Meridian Health Palisades Medical Center, Department of Nephrology, North Bergen, NJ, USA
| | - Adam Atoot
- Hackensack, Meridian Health Palisades Medical Center, Department of Internal Medicine, North Bergen, NJ, USA
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18
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Hesius E, Bunthof K, Steenbergen E, de Kort E, Klein I, Wetzels J. Monoclonal gammopathy of renal significance presenting with cryoglobulinemia type I associated severe thrombotic microangiopathy. Clin Kidney J 2022; 15:1425-1428. [PMID: 35756736 PMCID: PMC9217659 DOI: 10.1093/ckj/sfac078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Indexed: 11/28/2022] Open
Abstract
We report a 53-year-old man who presented with acute renal failure. His medical history revealed a spondyloarthropathy, for which secukinumab was started recently, and a monoclonal gammopathy of unknown significance. Kidney function deteriorated despite the withdrawal of secukinumab and dialysis was started. In the serum, type 1 cryoglobulins were present and a kidney biopsy showed ischaemic glomeruli, with thrombosis of the larger interlobular arteries. Other causes of thrombotic microangiopathy were excluded. Bone marrow immunophenotyping showed 1% monoclonal plasma cells. A diagnosis of monoclonal gammopathy of renal significance was made. Haematological treatment resulted in haematological and renal response.
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Affiliation(s)
- Eva Hesius
- Radboudumc, Department of Hematology, Nijmegen, The Netherlands
| | - Kim Bunthof
- Radboudumc, Department of Nephrology, Nijmegen, The Netherlands
- Bravis Hospital, Department of Internal Medicine, Roosendaal, The Netherlands
| | | | | | - Inge Klein
- Slingeland Hospital, Department of Nephrology, Doetinchem, The Netherlands
| | - Jack Wetzels
- Radboudumc, Department of Nephrology, Nijmegen, The Netherlands
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19
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Ma T, Wang H, Su T, Wang S. Case Report: Chronic Lymphocytic Leukemia With Recurrent Complement-Mediated Thrombotic Microangiopathy and C3 Glomerulonephritis. Front Med (Lausanne) 2022; 9:813439. [PMID: 35223908 PMCID: PMC8866726 DOI: 10.3389/fmed.2022.813439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/13/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a monoclonal B cell lymphocytosis that produces nephrotoxic monoclonal immunoglobulin (MIg). However, the role of MIg in CLL and how it affects CLL patient survival are still unknown. Here, we report a case of MIg with renal significance (MGRS) associated with CLL. A 59-year-old Chinese woman complaining of abdominal pain, skin purpura, and typical soy-colored urine was admitted to the hospital for investigation. Laboratory tests revealed that she had microangiopathic hemolytic anemia, thrombocytopenia, acute kidney injury (AKI), and hypocomplementemia. She also reported cryoglobulinemia, thrombotic microangiopathy (TMA), and AKI 2 years previously. Peripheral blood smears at that time showed 4% schistocytes, a negative Coombs' test, and elevated lactate dehydrogenase (LDH). Based on a diagnosis of complement-mediated TMA, the patient was treated by plasmapheresis and achieved clinical disease remission. However, the serum hypocomplement 4 and cryoglobulinemia persisted. Further investigation showed elevated B lymphocytes and monoclonal serum IgMκ; however, the cryoprecipitate contained monoclonal IgMκ and polyclonal IgG, as well as immunoglobulins κ and λ. After plasmapheresis, her LDH, platelets, and complement 3 (C3) levels returned to normal. Biopsies of the bone marrow and an enlarged subclavicular lymph node revealed CLL/SLL. Renal pathological findings indicated significant arteriolar endothelial cells myxoid edema and glomerular endothelial cells swelling, however no thromboli, cryoglobulin formation and vasculitis were observed. We also found mild mesangial proliferative C3 glomerulonephritis and renal interstitial CLL cells infiltration. Collectively, these clinical and pathological manifestations were attributed to monoclonal IgMκ, which triggered C3 activation. MGRS associated with CLL was finally confirmed. Six cycles of rituximab, cyclophosphamide, verodoxin, and dexamethasone therapy were administered, after which she received ibrutinib. The patient experienced disease remission, and her serum C4 level returned to normal. Cryoglobulin and IgMκ were not detected. This is a special presentation of CLL/SLL with monoclonal IgMκ, which is a type of MGRS. Activation of the complement system by MIg led to TMA with C3 glomerulonephritis. Treatment for TMA and CLL/SLL should be initiated in a timely manner to improve patient prognosis.
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Affiliation(s)
- Tiantian Ma
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Education, Beijing, China
| | - Hui Wang
- Laboratory of Electron Microscopy, Ultrastructural Pathology Center, Peking University First Hospital, Beijing, China
| | - Tao Su
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Education, Beijing, China
| | - Suxia Wang
- Laboratory of Electron Microscopy, Ultrastructural Pathology Center, Peking University First Hospital, Beijing, China
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20
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Andeen NK, Abdulameer S, Charu V, Zuckerman JE, Troxell M, Kambham N, Alpers CE, Najafian B, Nicosia RF, Smith KD, Kung VL, Avasare RS, Vallurupalli A, Jefferson JA, Hecox D, Swetnam L, Yamashita M, Lin M, Bissonnette ML, Akilesh S, Hou J. A Diverse Spectrum of Immune Complex- and Complement-Mediated Kidney Diseases Is Associated With Mantle Cell Lymphoma. Kidney Int Rep 2022; 7:568-579. [PMID: 35257069 PMCID: PMC8897291 DOI: 10.1016/j.ekir.2021.12.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 12/13/2021] [Indexed: 11/20/2022] Open
Abstract
Introduction There are limited reports on kidney biopsy findings in patients with mantle cell lymphoma (MCL). Methods We initiated a multi-institutional, retrospective review of kidney biopsy findings in patients with active and treated MCL. Results A total of 30 patients with MCL and kidney biopsies were identified, with a median age of 67 (range 48-87) years, 73% of whom were men. A total of 20 patients had active MCL at the time of biopsy, of whom 14 (70%) presented with acute kidney injury (AKI), proteinuria and/or hematuria, and biopsy findings potentially attributable to lymphoma. Of the 14, 11 had immune complex (IC) or complement-mediated (C3) disease including proliferative glomerulonephritis (GN) with monotypic Ig deposits (PGNMID [2]), C3GN, (2), secondary membranous nephropathy (MN [3]), tubular basement membrane (TBM) deposits (2), and modest lupus-like GN (2). Lymphomatous infiltration was present in 8 of the 20 patients, 5 with coincident IC or C3 lesions. A total of 6 patients with available follow-up were treated for MCL, all with clinical remission of GN (2 PGNMID, 2 C3GN, and 2 MN). Conclusion MCL is associated with diverse monoclonal and polyclonal glomerular and extra-glomerular IC and C3 disease. For patients with active MCL and kidney dysfunction requiring biopsy, 70% had findings due or potentially due to lymphoma, including 55% with IC or C3 disease and 40% had lymphomatous kidney infiltration. IC and C3GN in the setting of active MCL was responsive to lymphoma-directed therapy.
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Affiliation(s)
- Nicole K. Andeen
- Department of Pathology, Oregon Health & Science University, Portland, Oregon, USA
| | - Shahad Abdulameer
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Vivek Charu
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Jonathan E. Zuckerman
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Megan Troxell
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Neeraja Kambham
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Charles E. Alpers
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Behzad Najafian
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Roberto F. Nicosia
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Kelly D. Smith
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Vanderlene L. Kung
- Department of Pathology, Oregon Health & Science University, Portland, Oregon, USA
| | - Rupali S. Avasare
- Division of Nephrology, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Anusha Vallurupalli
- Center for Hematologic Malignancies, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - J. Ashley Jefferson
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | | | - Leah Swetnam
- Nephrology, Kaiser Permanente, Portland, Oregon, USA
| | - Michifumi Yamashita
- Department of Pathology, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Mercury Lin
- Department of Pathology, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Mei Lin Bissonnette
- Department of Pathology, St Paul’s Hospital, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Shreeram Akilesh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Jean Hou
- Department of Pathology, Cedars Sinai Medical Center, Los Angeles, California, USA
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21
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Filippone EJ, Newman ED, Li L, Gulati R, Farber JL. Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review. Front Immunol 2021; 12:780107. [PMID: 34858436 PMCID: PMC8631422 DOI: 10.3389/fimmu.2021.780107] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/22/2021] [Indexed: 12/25/2022] Open
Abstract
Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.
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Affiliation(s)
- Edward J Filippone
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Eric D Newman
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Li Li
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Rakesh Gulati
- Divsion of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - John L Farber
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
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22
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Zhang X, Yu XJ, Li DY, Wang SX, Zhou FD, Zhao MH. C3 glomerulonephritis associated with monoclonal gammopathy: a retrospective case series study from a single institute in China. Ren Fail 2021; 43:1437-1445. [PMID: 34658305 PMCID: PMC8525950 DOI: 10.1080/0886022x.2021.1990949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Objective To investigate the demographic and clinicopathological features and renal outcomes of Chinese patients with C3 glomerulonephritis in the setting of monoclonal gammopathy. Methods Patients with renal biopsy-proven C3 glomerulonephritis and detectable serum and/or urine monoclonal immunoglobulin from 2006 to 2018 in Peking University First Hospital were included, their clinical data, renal pathology type, treatment, and prognosis were collected and analyzed. Results Nineteen patients were enrolled, accounting for 24% of C3GN patients in the study period. The mean age of onset was 55 years old and the gender ratio was 4/15 (female/male). The mean eGFR at biopsy was 49.55 ± 29.81 ml/min/1.73m2. The prominent clinical manifestations included nephrotic syndrome (58%), anemia (68%), microscopic hematuria and leukocyturia (58%), and hypocomplementemia (13, 68%). The IgG was the most common isotype of monoclonal Ig on immunofixation electrophoresis. Kidney biopsies revealed a relatively prominent MPGN pattern. Only two patients had direct evidence of monocle immunoglobulins acting as C3GN pathogenic factors. Two patients had concurrent TMA-like renal injuries. The median renal survival was 12 and 15 months, respectively in patients receiving conservative therapy and immunosuppressant therapy, without statistical significance. The efficacy of clone-targeted therapy needed further investigation. Plasma exchange therapy only improved one patient’s renal outcome. Conclusions This is the first case series report of C3GN combined with monoclonal Ig in northern China. The renal prognosis of these patients is poor, and immunosuppressant therapies show no advantage over supportive therapy in renal prognosis, while the benefit of clone-targeted chemotherapy is still requiring investigation.
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Affiliation(s)
- Xin Zhang
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China.,Renal Pathology Center, Key laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Juan Yu
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China.,Renal Pathology Center, Key laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Chinese Academy of Medical Sciences, Beijing, China
| | - Dan-Yang Li
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China.,Renal Pathology Center, Key laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Chinese Academy of Medical Sciences, Beijing, China
| | - Su-Xia Wang
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China.,Renal Pathology Center, Key laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Chinese Academy of Medical Sciences, Beijing, China.,Laboratory of Electron Microscopy, Pathological Centre, Peking University First Hospital, Beijing, China
| | - Fu-de Zhou
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China.,Renal Pathology Center, Key laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming-Hui Zhao
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China.,Renal Pathology Center, Key laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Chinese Academy of Medical Sciences, Beijing, China.,Peking-Tsinghua Center for Life Science, Beijing, China
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23
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Uzonyi B, Szabó Z, Trojnár E, Hyvärinen S, Uray K, Nielsen HH, Erdei A, Jokiranta TS, Prohászka Z, Illes Z, Józsi M. Autoantibodies Against the Complement Regulator Factor H in the Serum of Patients With Neuromyelitis Optica Spectrum Disorder. Front Immunol 2021; 12:660382. [PMID: 33986750 PMCID: PMC8111293 DOI: 10.3389/fimmu.2021.660382] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/31/2021] [Indexed: 02/02/2023] Open
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by pathogenic, complement-activating autoantibodies against the main water channel in the CNS, aquaporin 4 (AQP4). NMOSD is frequently associated with additional autoantibodies and antibody-mediated diseases. Because the alternative pathway amplifies complement activation, our aim was to evaluate the presence of autoantibodies against the alternative pathway C3 convertase, its components C3b and factor B, and the complement regulator factor H (FH) in NMOSD. Four out of 45 AQP4-seropositive NMOSD patients (~9%) had FH autoantibodies in serum and none had antibodies to C3b, factor B and C3bBb. The FH autoantibody titers were low in three and high in one of the patients, and the avidity indexes were low. FH-IgG complexes were detected in the purified IgG fractions by Western blot. The autoantibodies bound to FH domains 19-20, and also recognized the homologous FH-related protein 1 (FHR-1), similar to FH autoantibodies associated with atypical hemolytic uremic syndrome (aHUS). However, in contrast to the majority of autoantibody-positive aHUS patients, these four NMOSD patients did not lack FHR-1. Analysis of autoantibody binding to FH19-20 mutants and linear synthetic peptides of the C-terminal FH and FHR-1 domains, as well as reduced FH, revealed differences in the exact binding sites of the autoantibodies. Importantly, all four autoantibodies inhibited C3b binding to FH. In conclusion, our results demonstrate that FH autoantibodies are not uncommon in NMOSD and suggest that generation of antibodies against complement regulating factors among other autoantibodies may contribute to the complement-mediated damage in NMOSD.
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Affiliation(s)
- Barbara Uzonyi
- MTA-ELTE Immunology Research Group, Eötvös Loránd Research Network (ELKH), Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Zsóka Szabó
- MTA-ELTE "Lendület" Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Eszter Trojnár
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.,Research Group for Immunology and Haematology, Semmelweis University-Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary
| | - Satu Hyvärinen
- Department of Bacteriology and Immunology, Medicum, and Immunobiology Research Program Unit, University of Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Katalin Uray
- MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd Research Network (ELKH), ELTE Eötvös Loránd University, Budapest, Hungary
| | - Helle H Nielsen
- Department of Neurology, Odense University Hospital and Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Anna Erdei
- MTA-ELTE Immunology Research Group, Eötvös Loránd Research Network (ELKH), Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - T Sakari Jokiranta
- Department of Bacteriology and Immunology, Medicum, and Immunobiology Research Program Unit, University of Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Zoltán Prohászka
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.,Research Group for Immunology and Haematology, Semmelweis University-Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary
| | - Zsolt Illes
- Department of Neurology, Odense University Hospital and Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.,Department of Neurology, Medical School, University of Pécs, Pécs, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE "Lendület" Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Eötvös Loránd Research Network (ELKH), Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
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The Clone Wars: Diagnosing and Treating Dysproteinemic Kidney Disease in the Modern Era. J Clin Med 2021; 10:jcm10081633. [PMID: 33921394 PMCID: PMC8069250 DOI: 10.3390/jcm10081633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 11/17/2022] Open
Abstract
Dysproteinemic kidney diseases are disorders that occur as the result of lymphoproliferative (B cell or plasma cell) disorders that cause kidney damage via production of nephrotoxic monoclonal immunoglobulins or their components. These monoclonal immunoglobulins have individual physiochemical characteristics that confer specific nephrotoxic properties. There has been increased recognition and revised characterization of these disorders in the last decade, and in some cases, there have been substantial advances in disease understanding and treatments, which has translated to improved patient outcomes. These disorders still present challenges to nephrologists and patients, since they are rare, and the field of hematology is rapidly changing with the introduction of novel testing and treatment strategies. In this review, we will discuss the clinical presentation, kidney biopsy features, hematologic characteristics and treatment of dysproteinemic kidney diseases.
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Steinberg AG, Fox LC, Bender S, Batrouney A, Juneja S, Sirac C, Touchard G, Blombery P, Finlay MJ, Bridoux F, Barbour TD. Proliferative Glomerulonephritis With Fibrils, Monoclonal κ Light Chain, and C3 Deposits. Am J Kidney Dis 2021; 78:459-463. [PMID: 33774080 DOI: 10.1053/j.ajkd.2021.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 01/07/2021] [Indexed: 11/11/2022]
Abstract
There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.
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Affiliation(s)
- Adam G Steinberg
- Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
| | - Lucy C Fox
- Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
| | - Sebastien Bender
- Centre National de la Recherche Scientifique UMR CNRS 7276/INSERM U1262, Université de Limoges, Limoges, France
| | - Ahida Batrouney
- Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Surender Juneja
- Department of Hematology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Christophe Sirac
- Centre National de la Recherche Scientifique UMR CNRS 7276/INSERM U1262, Université de Limoges, Limoges, France
| | - Guy Touchard
- Service de Néphrologie, Hémodialyse et Transplantation Rénale, CIC INSERM 1402, Centre de référence pour l'amylose AL et autres maladies par dépôt d'immunoglobulines monoclonales, CHU Poitiers, Poitiers, France
| | - Piers Blombery
- Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
| | - Moira J Finlay
- Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | - Frank Bridoux
- Centre National de la Recherche Scientifique UMR CNRS 7276/INSERM U1262, Université de Limoges, Limoges, France; Service de Néphrologie, Hémodialyse et Transplantation Rénale, CIC INSERM 1402, Centre de référence pour l'amylose AL et autres maladies par dépôt d'immunoglobulines monoclonales, CHU Poitiers, Poitiers, France
| | - Thomas D Barbour
- Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
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Bettacchioli E, Le Gaffric C, Mazeas M, Borghi MO, Frostegard J, Barturen G, Makowska Z, Babei S, Lesche R, PRECISESADS Clinical Consortium, Meroni PL, Alarcon-Riquelme ME, Renaudineau Y. An elevated polyclonal free light chain level reflects a strong interferon signature in patients with systemic autoimmune diseases. J Transl Autoimmun 2021; 4:100090. [PMID: 33817614 PMCID: PMC8010703 DOI: 10.1016/j.jtauto.2021.100090] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 02/21/2021] [Indexed: 12/17/2022] Open
Abstract
High amount of polyclonal free light chains (FLC) are reported in systemic autoimmune diseases (SAD) and we took advantage of the PRECISESADS study to better characterize them. Serum FLC levels were explored in 1979 patients with SAD (RA, SLE, SjS, Scl, APS, UCTD, MCTD) and 614 healthy controls. Information regarding clinical parameters, disease activity, medications, autoantibodies (Ab) and the interferon α and/or γ scores were recorded. Among SAD patients, 28.4% had raised total FLC (from 12% in RA to 30% in SLE and APS) with a normal kappa/lambda ratio. Total FLC levels were significantly higher in SAD with inflammation, active disease in SLE and SjS, and an impaired pulmonary functional capacity in SSc, while independent from kidney impairment, infection, cancer and treatment. Total FLC concentrations were positively correlated among the 10/17 (58.8%) autoantibodies (Ab) tested with anti-RNA binding protein Ab (SSB, SSA-52/60 kDa, Sm, U1-RNP), anti-dsDNA/nucleosome Ab, rheumatoid factor and negatively correlated with complement fractions C3/C4. Finally, examination of interferon (IFN) expression as a potential driver of FLC overexpression was tested showing an elevated level of total FLC among patients with a high IFNα and IFNγ Kirou's score, a strong IFN modular score, and the detection in the sera of B-cell IFN dependent factors, such as TNF-R1/TNFRSF1A and CXCL10/IP10. In conclusion, an elevated level of FLC, in association with a strong IFN signature, defines a subgroup of SAD patients, including those without renal affectation, characterized by increased disease activity, autoreactivity, and complement reduction.
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Key Words
- APS, primary antiphospholipid syndrome
- AUC, area under the curve
- Ab, autoantibody
- Autoantibodies
- Autoimmune diseases
- CCP, cyclic citrulinated peptide
- CXCL10, C-X-C motif chemokine 10
- F, female
- FLC, free light chains
- Free light chains
- HC, healthy controls
- IFN, interferon
- Interferon signature
- M, male
- MCTD, mixed connective tissue disease
- MDA, malondialdehyde
- NK, natural killer
- PC, phosphorylcholine
- RA, rheumatoid arthritis
- RF, rheumatoid factor
- RNP, ribonucleoprotein
- ROC, Receiver Operating Characteristics
- SAD, systemic autoimmune diseases
- SD, standard deviation
- SLE, systemic lupus erythematosus
- Scl, systemic sclerosis
- SjS, Sjögren's syndrome
- TH1, T helper type 1
- TNF-R1, tumor necrosis factor receptor 1
- UCTD, undetermined connective tissue disease
- VAS, visual analogical scale
- κ, kappa
- λ, lambda
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Affiliation(s)
| | | | - Margaux Mazeas
- Laboratory of Immunology and Immunotherapy, CHRU Morvan, Brest, France
| | - Maria Orietta Borghi
- Immunorheumatology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Johan Frostegard
- Section of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Guillermo Barturen
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada, 18016, Spain
| | | | | | | | | | - Pier Luigi Meroni
- Immunorheumatology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Marta E. Alarcon-Riquelme
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada, 18016, Spain
| | - Yves Renaudineau
- Laboratory of Immunology and Immunotherapy, CHRU Morvan, Brest, France
- Univ Brest, INSERM, LBAI, 29238, Brest Cedex 3, France
- Corresponding author. Laboratory of Immunology and Immunotherapy, CHRU Morvan, Brest, France.
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Livson S, Jarva H, Kalliala I, Lokki AI, Heikkinen-Eloranta J, Nieminen P, Meri S. Activation of the Complement System in the Lower Genital Tract During Pregnancy and Delivery. Front Immunol 2021; 11:563073. [PMID: 33505390 PMCID: PMC7829332 DOI: 10.3389/fimmu.2020.563073] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 11/24/2020] [Indexed: 12/29/2022] Open
Abstract
Background Human pregnancy alters profoundly the immune system. The local involvement and mechanisms of activation of the complement system in the cervicovaginal milieu during pregnancy and delivery remain unexplored. Objectives To determine whether normal pregnancy and delivery are associated with local activation of complement or changes in the immunoglobulin profile in the cervix. Study Design This study was designed to assess IgA, IgG, and complement activation in the cervicovaginal area in three groups of patients: i) 49 pregnant women (week 41+3–42+0) not in active labor, ii) 24 women in active labor (38+4–42+2), and iii) a control group of nonpregnant women (n=23) at child-bearing age. We collected mucosal samples from the lateral fornix of the vagina and external cervix during routine visits and delivery. The Western blot technique was used to detect complement C3 and its activation products. For semiquantitative analysis, the bands of the electrophoresed proteins in gels were digitized on a flatbed photo scanner and analyzed. IgA and IgG were analyzed by Western blotting and quantified by ELISA. One-way ANOVA and Tukey’s Multiple Comparison tests were used for statistical comparisons. Results A higher abundance but lower activation level of C3 in both the external cervix (P<0.001) and lateral fornix of the vagina (P<0.001) was observed during delivery (58 ± 22, n= 24) in comparison to the groups of nonpregnant (72 ± 13%; mean ± SD, n=23) and pregnant women (78 ± 22%, n=49). Complement activating IgG was detected in higher abundance than IgA in the cervicovaginal secretions of pregnant women. In a small proportion samples also C3-IgG complexes were detected. Conclusions Our results reveal an unexpectedly strong activation of the complement system and the presence IgG immunoglobulins in the cervicovaginal area during pregnancy, active labor, and among nonpregnant women. In contrast to the higher amounts of C3 in the cervicovaginal secretions during labor, its activation level was lower. Complement activating IgG was detected in higher concentrations than IgA in the mucosal secretions during pregnancy and labor. Taken together our results imply the presence a locally operating humoral immune system in the cervicovaginal mucosa.
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Affiliation(s)
- Sivan Livson
- Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.,Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Hanna Jarva
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.,HUS Diagnostic Center, Helsinki University Hospital Laboratory, Helsinki University Hospital, Helsinki, Finland
| | - Ilkka Kalliala
- Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.,Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.,Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - A Inkeri Lokki
- Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.,Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Jenni Heikkinen-Eloranta
- Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Pekka Nieminen
- Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.,Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.,HUS Diagnostic Center, Helsinki University Hospital Laboratory, Helsinki University Hospital, Helsinki, Finland
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Monoclonal Gammopathy of Renal Significance with Deposits of Peculiar Morphology and Injuries of Secondary Thrombotic Microangiopathy: A Case Report and Review of the Literature. Case Rep Nephrol 2020; 2020:6679857. [PMID: 33376611 PMCID: PMC7738783 DOI: 10.1155/2020/6679857] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 11/30/2020] [Indexed: 12/02/2022] Open
Abstract
We present the case of an 82-year-old woman diagnosed with monoclonal gammopathy of renal significance (MGRS) with the presence of different and peculiar kidney lesions, who began treatment with bortezomib and dexamethasone, presenting during her evolution a relapse. Although the bone marrow biopsy in this case showed plasma cells as pathologic clone and there was also a reduction after chemotherapeutic treatment, rituximab was proposed as a second line. We suspected that the relapse was possibly due to another precursor as B-cell or lymphoplasmacytic cell clone. We review the literature and suggest that the treatment for MGRS should be patient-tailored, preferably by consulting a multidisciplinary team. Future research is needed to better understand the disease course and establish the efficacy and safety of the therapeutic approach for the relapse of MGRS.
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29
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Meri S, Haapasalo K. Function and Dysfunction of Complement Factor H During Formation of Lipid-Rich Deposits. Front Immunol 2020; 11:611830. [PMID: 33363547 PMCID: PMC7753009 DOI: 10.3389/fimmu.2020.611830] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/09/2020] [Indexed: 01/19/2023] Open
Abstract
Complement-mediated inflammation or dysregulation in lipid metabolism are associated with the pathogenesis of several diseases. These include age-related macular degeneration (AMD), C3 glomerulonephritis (C3GN), dense deposit disease (DDD), atherosclerosis, and Alzheimer's disease (AD). In all these diseases, formation of characteristic lipid-rich deposits is evident. Here, we will discuss molecular mechanisms whereby dysfunction of complement, and especially of its key regulator factor H, could be involved in lipid accumulation and related inflammation. The genetic associations to factor H polymorphisms, the role of factor H in the resolution of inflammation in lipid-rich deposits, modification of macrophage functions, and complement-mediated clearance of apoptotic and damaged cells indicate that the function of factor H is crucial in limiting inflammation in these diseases.
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Affiliation(s)
- Seppo Meri
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
- Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Karita Haapasalo
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
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30
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The Immunopathology of Complement Proteins and Innate Immunity in Autoimmune Disease. Clin Rev Allergy Immunol 2020; 58:229-251. [PMID: 31834594 DOI: 10.1007/s12016-019-08774-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The complement is a powerful cascade of the innate immunity and also acts as a bridge between innate and acquired immune defence. Complement activation can occur via three distinct pathways, the classical, alternative and lectin pathways, each resulting in the common terminal pathway. Complement activation results in the release of a range of biologically active molecules that significantly contribute to immune surveillance and tissue homeostasis. Several soluble and membrane-bound regulatory proteins restrict complement activation in order to prevent complement-mediated autologous damage, consumption and exacerbated inflammation. The crucial role of complement in the host homeostasis is illustrated by association of both complement deficiency and overactivation with severe and life-threatening diseases. Autoantibodies targeting complement components have been described to alter expression and/or function of target protein resulting in a dysregulation of the delicate equilibrium between activation and inhibition of complement. The spectrum of diseases associated with complement autoantibodies depends on which complement protein and activation pathway are targeted, ranging from autoimmune disorders to kidney and vascular diseases. Nevertheless, these autoantibodies have been identified as differential biomarkers for diagnosis or follow-up of disease only in a small number of clinical conditions. For some autoantibodies, a clear relationship with clinical manifestations has been identified, such as anti-C1q, anti-Factor H, anti-C1 Inhibitor antibodies and C3 nephritic factor. For other autoantibodies, the origin and the functional consequences still remain to be elucidated, questioning about the pathophysiological significance of these autoantibodies, such as anti-mannose binding lectin, anti-Factor I, anti-Factor B and anti-C3b antibodies. The detection of autoantibodies targeting complement components is performed in specialized laboratories; however, there is no consensus on detection methods and standardization of the assays is a real challenge. This review summarizes the current panorama of autoantibodies targeting complement recognition proteins of the classical and lectin pathways, associated proteases, convertases, regulators and terminal components, with an emphasis on autoantibodies clearly involved in clinical conditions.
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31
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The Factor H-Binding Site of CspZ as a Protective Target against Multistrain, Tick-Transmitted Lyme Disease. Infect Immun 2020; 88:IAI.00956-19. [PMID: 32122944 DOI: 10.1128/iai.00956-19] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/27/2020] [Indexed: 01/13/2023] Open
Abstract
The spirochete Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD). The spirochetes produce the CspZ protein that binds to a complement regulator, factor H (FH). Such binding downregulates activation of host complement to facilitate spirochete evasion of complement killing. However, vaccination with CspZ does not protect against LD infection. In this study, we demonstrated that immunization with CspZ-YA, a CspZ mutant protein with no FH-binding activity, protected mice from infection by several spirochete genotypes introduced via tick feeding. We found that the sera from CspZ-YA-vaccinated mice more efficiently eliminated spirochetes and blocked CspZ FH-binding activity than sera from CspZ-immunized mice. We also found that vaccination with CspZ, but not CspZ-YA, triggered the production of anti-FH antibodies, justifying CspZ-YA as an LD vaccine candidate. The mechanistic and efficacy information derived from this study provides insights into the development of a CspZ-based LD vaccine.
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32
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Multiple morphological phenotypes of monoclonal immunoglobulin disease on renal biopsy: Significance of treatment. Clin Nephrol Case Stud 2020; 8:17-24. [PMID: 32318322 PMCID: PMC7171697 DOI: 10.5414/cncs110052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/14/2020] [Indexed: 11/18/2022] Open
Abstract
Plasma cell dyscrasias frequently involve the kidney causing renal dysfunction. Multiple morphologic manifestations of κ light chain disease occurring simultaneously in the same kidney biopsy are uncommon and suggest local microenvironment effects in addition to structural properties of the light chain. A 61-year-old female presented with new onset renal failure and proteinuria. Serological workup revealed monoclonal gammopathy with elevated κ : λ ratio of 1,371. Renal biopsy revealed several paraprotein manifestations including κ light chain deposition disease, monoclonal fibrillary glomerulonephritis, cryocrystalglobulenemia and fibrillar/microtubular cast nephropathy. There was also incidental leukocyte chemotactic factor 2 amyloidosis (ALECT 2), negative for κ light chain and confirmed by immunohistochemistry (IHC). Bone marrow biopsy revealed 10 - 20% κ restricted plasma cells. The patient received 10 cycles of CyBorD (cyclophosphamide, bortezomib, and dexamethasone) chemotherapy. Renal function improved with decreased κ : λ ratio. Repeat bone marrow biopsy showed no evidence of abnormal plasma cells by IHC. The renal recovery demonstrates there may be response to chemotherapy irrespective of the morphologic manifestations of light chain-related injury. Additionally, if amyloid is not demonstrated to be of light chain origin, other amyloid types should be considered.
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Ahmad SB, Bomback AS. C3 Glomerulopathy: Pathogenesis and Treatment. Adv Chronic Kidney Dis 2020; 27:104-110. [PMID: 32553242 DOI: 10.1053/j.ackd.2019.12.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 12/13/2019] [Accepted: 12/13/2019] [Indexed: 12/18/2022]
Abstract
C3 glomerulopathy (C3G) is a rare set of kidney diseases with 2 patterns: C3 glomerulonephritis (C3GN) and dense deposit disease. Pathogenesis of both diseases is due to complement dysregulation in the alternative pathway. Acquired or genetic alterations of the regulatory proteins of the complement pathway result in C3G. Although the disease is characterized by low C3 levels in serum and C3-dominant staining by immunofluorescence on biopsy, other disease entities such as infection-related glomerulonephritis and masked monoclonal deposits can present similarly. Both the C3GN and dense deposit disease variants of C3G are progressive and recur in transplanted kidneys. Although no direct treatment is available, complement blockers are either available or in the clinical trial phase. This review will survey the pathogenesis of C3GN and current treatment options.
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Monoclonal immunoglobulin mediates complement activation in monoclonal gammopathy associated-C3 glomerulonephritis. BMC Nephrol 2019; 20:459. [PMID: 31823738 PMCID: PMC6902416 DOI: 10.1186/s12882-019-1640-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 11/22/2019] [Indexed: 12/28/2022] Open
Abstract
Background C3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro. Case presentation A 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient’s plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made. Conclusions This is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.
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Abstract
Glomerulonephritis (GN) refers to a group of renal diseases affecting the glomeruli due to the damage mediated by immunological mechanisms. A large proportion of the disease manifestations are caused by disturbances in the complement system. They can be due to genetic errors, autoimmunity, microbes or abnormal immunoglobulins, like modified IgA or paraproteins. The common denominator in most of the problems is an overactive or misdirected alternative pathway complement activation. An assessment of kidney function, amount of proteinuria and hematuria are crucial elements to evaluate, when glomerulonephritis is suspected. However, the cornerstones of the diagnoses are renal biopsy and careful examination of the complement abnormality. Differential diagnostics between the various forms of GN is not possible based on clinical features, as they may vary greatly. This review describes the known mechanisms of complement dysfunction leading to different forms of primary GN (like IgA glomerulonephritis, dense deposit disease, C3 glomerulonephritis, post-infectious GN, membranous GN) and differences to atypical hemolytic uremic syndrome. It also covers the basic elements of etiology-directed therapy and prognosis of the most common forms of GN. Common principles in the management of GN include treatment of hypertension and reduction of proteinuria, some require immunomodulating treatment. Complement inhibition is an emerging treatment option. A thorough understanding of the basic disease mechanism and a careful follow-up are needed for optimal therapy.
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Affiliation(s)
- Kati Kaartinen
- Department of Nephrology, Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland
| | - Adrian Safa
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Soumya Kotha
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Giorgio Ratti
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Seppo Meri
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
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36
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Nasr SH, Larsen CP, Sirac C, Theis JD, Domenger C, Chauvet S, Javaugue V, Hogan JJ, Said SM, Dasari S, Vrana JA, McPhail ED, Cornell LD, Vilaine E, Massy ZA, Boffa JJ, Buob D, Toussaint S, Guincestre T, Touchard G, D'Agati VD, Leung N, Bridoux F. Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone. Kidney Int 2019; 97:589-601. [PMID: 32001067 DOI: 10.1016/j.kint.2019.10.025] [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] [Received: 07/22/2019] [Revised: 09/25/2019] [Accepted: 10/17/2019] [Indexed: 10/25/2022]
Abstract
IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.
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Affiliation(s)
- Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
| | | | - Christophe Sirac
- Department of Immunology, Joint Research Unit CNRS 7276, INSERM 1262, University of Limoges, French Reference Center for AL Amyloidosis, University Hospital Dupuytren, Limoges, France
| | - Jason D Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Camille Domenger
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France
| | - Sophie Chauvet
- Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Department of Nephrology, Paris, France; INSERM UMRS1138, Research Center Cordeliers, Paris Descartes Sorbonne Paris-Cité University, Paris, France
| | - Vincent Javaugue
- Department of Immunology, Joint Research Unit CNRS 7276, INSERM 1262, University of Limoges, French Reference Center for AL Amyloidosis, University Hospital Dupuytren, Limoges, France; Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France
| | - Jonathan J Hogan
- Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Samar M Said
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Julie A Vrana
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ellen D McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Lynn D Cornell
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Eve Vilaine
- Assistance Publique-Hôpitaux de Paris, Department of Nephrology, Ambroise Paré Hospital, Boulogne-Billancourt, France; Inserm U1018 Team5 UVSQ, University Paris Saclay, Villejuif, France
| | - Ziad A Massy
- Assistance Publique-Hôpitaux de Paris, Department of Nephrology, Ambroise Paré Hospital, Boulogne-Billancourt, France; Inserm U1018 Team5 UVSQ, University Paris Saclay, Villejuif, France
| | - Jean-Jacques Boffa
- Assistance Publique-Hôpitaux de Paris, Department of Nephrology, Hôpital Tenon, Paris Sorbonne University, Paris, France
| | - David Buob
- Assistance Publique-Hôpitaux de Paris, Department of Pathology, Hôpital Tenon, Paris Sorbonne University, Paris, France
| | - Stéphanie Toussaint
- Department of Nephrology, Bourg-en-Bresse General Hospital, Bourg-en-Bresse, France
| | | | - Guy Touchard
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France
| | - Vivette D D'Agati
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Nelson Leung
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Frank Bridoux
- Department of Immunology, Joint Research Unit CNRS 7276, INSERM 1262, University of Limoges, French Reference Center for AL Amyloidosis, University Hospital Dupuytren, Limoges, France; Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France
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Fung AWS, Sugumar V, Ren AH, Kulasingam V. Emerging role of clinical mass spectrometry in pathology. J Clin Pathol 2019; 73:61-69. [PMID: 31690564 DOI: 10.1136/jclinpath-2019-206269] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 10/14/2019] [Indexed: 12/20/2022]
Abstract
Mass spectrometry-based assays have been increasingly implemented in various disciplines in clinical diagnostic laboratories for their combined advantages in multiplexing capacity and high analytical specificity and sensitivity. It is now routinely used in areas including reference methods development, therapeutic drug monitoring, toxicology, endocrinology, paediatrics, immunology and microbiology to identify and quantify biomolecules in a variety of biological specimens. As new ionisation methods, instrumentation and techniques are continuously being improved and developed, novel mass spectrometry-based clinical applications will emerge for areas such as proteomics, metabolomics, haematology and anatomical pathology. This review will summarise the general principles of mass spectrometry and specifically highlight current and future clinical applications in anatomical pathology.
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Affiliation(s)
- Angela W S Fung
- Department of Pathology and Laboratory Medicine, St Paul's Hospital, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Vijithan Sugumar
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Annie He Ren
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Vathany Kulasingam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada .,Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada
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38
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Frangou E, Varnavidou-Nicolaidou A, Petousis P, Soloukides A, Theophanous E, Savva I, Michael N, Toumasi E, Georgiou D, Stylianou G, Mean R, Anastasiadou N, Athanasiou Y, Zavros M, Kyriacou K, Deltas C, Hadjianastassiou V. Clinical course and outcome after kidney transplantation in patients with C3 glomerulonephritis due to CFHR5 nephropathy. Nephrol Dial Transplant 2019; 34:1780-1788. [PMID: 30844074 DOI: 10.1093/ndt/gfz021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 01/17/2019] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Complement factor H-related protein 5 (CFHR5) nephropathy is an inherited renal disease characterized by microscopic and synpharyngitic macroscopic haematuria, C3 glomerulonephritis and renal failure. It is caused by an internal duplication of exons 2-3 within the CFHR5 gene resulting in dysregulation of the alternative complement pathway. The clinical characteristics and outcomes of transplanted patients with this rare familial nephropathy remain unknown. METHODS This is a retrospective case series study of 17 kidney transplant patients with the established founder mutation, followed-up over a span of 30 years. RESULTS The mean (±SD) age of patients at the time of the study and at transplantation was 58.6 ± 9.9 and 46.7 ± 8.8 years, respectively. The 10- and 15-year patient survival rates were 100 and 77.8%, respectively. Proteinuria was present in 33.3% and microscopic haematuria in 58.3% of patients with a functional graft. Serum complement levels were normal in all. 'Confirmed' and 'likely' recurrence of CFHR5 nephropathy were 16.6 and 52.9%, respectively; however, 76.5% of patients had a functional graft after a median of 120 months post-transplantation. Total recurrence was not associated with graft loss (P = 0.171), but was associated with the presence of microscopic haematuria (P = 0.001) and proteinuria (P = 0.018). Graft loss was associated with the presence of proteinuria (P = 0.025). CONCLUSIONS We describe for the first time the clinical characteristics and outcome of patients with CFHR5 nephropathy post-transplantation. Despite the recurrence of CFHR5 nephropathy, we provide evidence for a long-term favourable outcome and support the continued provision of kidney transplantation as a renal replacement option in patients with CFHR5 nephropathy.
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Affiliation(s)
- Eleni Frangou
- Department of Nephrology and Transplantation, Nicosia General Hospital, Nicosia, Cyprus.,Medical School, University of Cyprus, Nicosia, Cyprus.,Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | | | | | - Andreas Soloukides
- Department of Nephrology and Transplantation, Nicosia General Hospital, Nicosia, Cyprus.,Medical School, University of Cyprus, Nicosia, Cyprus
| | - Elena Theophanous
- Department of Histopathology, Nicosia General Hospital, Nicosia, Cyprus
| | - Isavella Savva
- Department of Nephrology and Transplantation, Nicosia General Hospital, Nicosia, Cyprus.,Molecular Medicine Research Center, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
| | - Nicos Michael
- Department of Nephrology and Transplantation, Nicosia General Hospital, Nicosia, Cyprus.,Medical School, University of Nicosia, Nicosia, Cyprus
| | - Elpida Toumasi
- Department of Nephrology and Transplantation, Nicosia General Hospital, Nicosia, Cyprus.,Medical School, University of Cyprus, Nicosia, Cyprus
| | - Dora Georgiou
- Histocompatibility and Immunogenetics Laboratory, Nicosia General Hospital, Nicosia, Cyprus
| | - Galatia Stylianou
- Histocompatibility and Immunogenetics Laboratory, Nicosia General Hospital, Nicosia, Cyprus
| | - Richard Mean
- Histocompatibility and Immunogenetics Laboratory, Nicosia General Hospital, Nicosia, Cyprus
| | | | - Yiannis Athanasiou
- Department of Nephrology and Transplantation, Nicosia General Hospital, Nicosia, Cyprus.,Medical School, University of Cyprus, Nicosia, Cyprus
| | - Michalis Zavros
- Department of Nephrology and Transplantation, Nicosia General Hospital, Nicosia, Cyprus
| | - Kyriacos Kyriacou
- Department of Electron Microscopy, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Constantinos Deltas
- Molecular Medicine Research Center, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
| | - Vassilis Hadjianastassiou
- Department of Nephrology and Transplantation, Nicosia General Hospital, Nicosia, Cyprus.,Medical School, University of Nicosia, Nicosia, Cyprus
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39
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Cassol CA, Williams MP, Caza TN, Rodriguez S. Renal and pulmonary thrombotic microangiopathy triggered by proteasome-inhibitor therapy in patient with smoldering myeloma: A renal biopsy and autopsy case report. Medicine (Baltimore) 2019; 98:e17148. [PMID: 31574818 PMCID: PMC6775360 DOI: 10.1097/md.0000000000017148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
RATIONALE Thrombotic microangiopathy (TMA) is a group of clinical syndromes characterized by excessive platelet activation and endothelial injury that leads to acute or chronic microvascular obliteration by intimal mucoid and fibrous thickening, with or without associated thrombi. It frequently involves the kidney but may involve any organ or system at variable frequencies depending on the underlying etiology. Among its numerous causes, drug toxicities and complement regulation abnormalities stand out as some of the most common. A more recently described association is with monoclonal gammopathy. Lung involvement by TMA is infrequent, but has been described in Cobalamin C deficiency and post stem-cell transplantation TMA. PATIENT CONCERNS This is the case of a patient with smoldering myeloma who received proteasome-inhibitor therapy due to retinopathy and developed acute renal failure within one week of therapy initiation. DIAGNOSES A renal biopsy showed thrombotic microangiopathy. At the time, mild pulmonary hypertension was also noted and presumed to be idiopathic. INTERVENTIONS Given the known association of proteasome-inhibitor therapy with thrombotic microangiopathy, Bortezomib was discontinued and dialysis was initiated. OUTCOMES Drug withdrawal failed to prevent disease progression and development of end-stage renal disease, as well as severe pulmonary hypertension that eventually lead to the patient's death. LESSONS To our knowledge, this is the first reported case of pulmonary involvement by TMA associated with monoclonal gammopathy which appears to have been triggered by proteasome-inhibitor therapy. Clinicians should be aware of this possibility to allow for more prompt recognition of pulmonary hypertension as a potential manifestation of monoclonal gammopathy-associated TMA, especially in patients also receiving proteasome-inhibitors, so that treatment aiming to slow disease progression can be instituted.
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Affiliation(s)
| | | | | | - Sophia Rodriguez
- Queens Office of the Chief Medical Examiner of the City of New York, New York
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40
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Haapasalo K, Meri S. Regulation of the Complement System by Pentraxins. Front Immunol 2019; 10:1750. [PMID: 31428091 PMCID: PMC6688104 DOI: 10.3389/fimmu.2019.01750] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 07/10/2019] [Indexed: 01/09/2023] Open
Abstract
The functions of pentraxins, like C-reactive protein (CRP), serum amyloid protein P (SAP) and pentraxin-3 (PTX3), are to coordinate spatially and temporally targeted clearance of injured tissue components, to protect against infections and to regulate related inflammation together with the complement system. For this, pentraxins have a dual relationship with the complement system. Initially, after a focused binding to their targets, e.g., exposed phospholipids or cholesterol in the injured tissue area, or microbial components, the pentraxins activate complement by binding its first component C1q. However, the emerging inflammation needs to be limited to the target area. Therefore, pentraxins inhibit complement at the C3b stage to prevent excessive damage. The complement inhibitory functions of pentraxins are based on their ability to interact with complement inhibitors C4bp or factor H (FH). C4bp binds to SAP, while FH binds to both CRP and PTX3. FH promotes opsonophagocytosis through inactivation of C3b to iC3b, and inhibits AP activity thus preventing formation of the C5a anaphylatoxin and the complement membrane attack complex (MAC). Monitoring CRP levels gives important clinical information about the extent of tissue damage and severity of infections. CRP is a valuable marker for distinguishing bacterial infections from viral infections. Disturbances in the functions and interactions of pentraxins and complement are also involved in a number of human diseases. This review will summarize what is currently known about the FH family proteins and pentraxins that interact with FH. Furthermore, we will discuss diseases, where interactions between these molecules may play a role.
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Affiliation(s)
- Karita Haapasalo
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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41
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Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy. Pediatr Nephrol 2019; 34:1311-1323. [PMID: 29948306 DOI: 10.1007/s00467-018-3989-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 05/08/2018] [Accepted: 05/25/2018] [Indexed: 02/08/2023]
Abstract
Membranoproliferative glomerulonephritis (MPGN) is a rare chronic kidney disease associated with complement activation. Recent immunofluorescence-based classification distinguishes between immune complex (IC)-mediated MPGN, with glomerular IgG and C3 deposits, and C3 glomerulopathies (C3G), with predominant C3 deposits. Genetic and autoimmune abnormalities causing hyperactivation of the complement alternative pathway have been found as frequently in patients with immune complex-associated MPGN (IC-MPGN) as in those with C3G. In the last decade, there have been great advances in research into the autoimmune causes of IC-MPGN and C3G. The complement-activating autoantibodies called C3-nephritic factors (C3NeFs), which are present in 40-80% of patients, form a heterogeneous group of autoantibodies that stabilise the C3 convertase or the C5 convertase of the alternative pathway or both. A few patients, mainly with IC-MPGN, carry autoantibodies directed against the two components of the alternative pathway C3 convertase, factors B and C3b. Finally, autoantibodies against factor H, the main regulator of the alternative pathway, have been reported in a small proportion of patients with IC-MPGN or C3G. The identification of distinct pathogenetic patterns leading to kidney injury and of targets in the complement cascade may pave the way for tailored therapies for IC-MPGN and C3G, with specific complement inhibitors in the development pipeline.
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42
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Kozlovskaya(Lysenko) LV, Chebotareva NV, Mrykhin NN, Rameev VV, Androsova TV, Roshchupkina SV, Maryina SA, Kogarko IN, Kogarko BS. Modern approaches to the detection of monoclonal gammopathy of undetermined significance (MGUS) in patients with kidney diseases. TERAPEVT ARKH 2019; 91:67-72. [DOI: 10.26442/00403660.2019.06.000281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Indexed: 11/22/2022]
Abstract
Monoclonal gammopathy (MG) is not only the state preceding of hematological neoplasms, but also associated with non - hematological diseases, in particular kidney damage. Aim. To assess the diagnostic value of “Freelite” methods in addition to electrophoresis (EF) and immunofixation (IF) of serum and urine proteins for detecting MG in patients with kidney diseases. Materials and methods. 87 patients with kidney damage, in which MG was established using the method of electrophoresis of serum proteins (EF), immunofixation (IF) and the method of free light chains determination - FLC “Freelite” were selected. The diagnostic value of three - component serum panel was compared with EF and IF. Results and discussion. AL-amyloidosis with kidney involvement was diagnosed in 41% patients, cryoglobulinemic glomerulonephritis (cryo GN) - in 18%, chronic glomerulonephritis (CGN) - in 35%, also there was small number of patients with light chain disease and cast - nephropathy. Determination of MG using EP was possible only in 38 (44%). Adding to the serum electrophoretic methods instead of the “Freelite” method, the urine EF and IF reduced the number of missed patients with monoclonal gammopathy from 24 (27%) to 11 (13%), including in the subgroup of patients with AL-amyloidosis but did not reach the sensitivity of the three - component serum screening panel. In 10 (11.5%) MG was represented only by intact mIg with one type of light chain, either κ or λ. Most often - in 25% of patients, intact monoclonal gammopathy was observed in HCV (+) cryo GN. A combination of intact mIgM, mIgG or mIgA with mFLC, was detected in 37 (42.5%). In almost half (46%) of the patients, only mFLC was detected - an abnormal κ/λ ratio. Conclusion: The serum screening panel EF + IF + “Freelite” spreads the low - grade monoclonal gammopathy recognition (MGUS) and should be included in the algorithm of examining patients with kidney disease.
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43
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Hauer JJ, Shao D, Zhang Y, Nester CM, Smith RJH. Factor B and C4b2a Autoantibodies in C3 Glomerulopathy. Front Immunol 2019; 10:668. [PMID: 31024533 PMCID: PMC6460050 DOI: 10.3389/fimmu.2019.00668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 03/11/2019] [Indexed: 12/04/2022] Open
Abstract
C3 Glomerulopathy (C3G) is a renal disease mediated primarily by dysregulation of the alternative pathway of complement. Complement is the cornerstone of innate immunity. It targets infectious microbes for destruction, clears immune complexes, and apoptotic cells from the circulation, and augments the humoral response. In C3G, this process becomes dysregulated, which leads to the deposition of complement proteins—including complement component C3—in the glomerular basement membrane of the kidney. Events that trigger complement are typically environmental insults like infections. Once triggered, in patients who develop C3G, complement activity is sustained by a variety of factors, including rare or novel genetic variants in complement genes and autoantibodies that alter normal complement protein function and/or regulation. Herein, we review two such autoantibodies, one to Factor B and the other to C4b2a, the C3 convertase of the classical, and lectin pathways. These two types of autoantibodies are identified in a small fraction of C3G patients and contribute marginally to the C3G phenotype.
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Affiliation(s)
- Jill J Hauer
- Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA, United States
| | - Dingwu Shao
- Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA, United States
| | - Yuzhou Zhang
- Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA, United States
| | - Carla M Nester
- Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA, United States
| | - Richard J H Smith
- Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA, United States
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44
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Smith RJH, Appel GB, Blom AM, Cook HT, D'Agati VD, Fakhouri F, Fremeaux-Bacchi V, Józsi M, Kavanagh D, Lambris JD, Noris M, Pickering MC, Remuzzi G, de Córdoba SR, Sethi S, Van der Vlag J, Zipfel PF, Nester CM. C3 glomerulopathy - understanding a rare complement-driven renal disease. Nat Rev Nephrol 2019; 15:129-143. [PMID: 30692664 PMCID: PMC6876298 DOI: 10.1038/s41581-018-0107-2] [Citation(s) in RCA: 232] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients - namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.
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Affiliation(s)
- Richard J H Smith
- Molecular Otolaryngology and Renal Research Laboratories and the Departments of Internal Medicine and Pediatrics (Divisions of Nephrology), Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
| | - Gerald B Appel
- Department of Nephrology, Columbia University, New York, NY, USA
| | - Anna M Blom
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - H Terence Cook
- Centre for Inflammatory Disease, Imperial College London, London, UK
| | - Vivette D D'Agati
- Department of Pathology, Renal Pathology Laboratory, Columbia University Medical Center, New York, NY, USA
| | - Fadi Fakhouri
- Department of Nephrology and Immunology, Centre Hospitalier et Universitaire de Nantes, Nantes, France
| | - Véronique Fremeaux-Bacchi
- Service de Néphrologie-Transplantation Adulte, Hôpital Necker-Enfants Malades, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Mihály Józsi
- Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University and the MTA-SE Research Group of Immunology and Haematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
| | - David Kavanagh
- Newcastle University, Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK
| | - John D Lambris
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marina Noris
- Istituto di Ricerche Farmacologiche (IRCCS) 'Mario Negri', Clinical Research Centre for Rare Diseases 'Aldo e Cele Daccò', Ranica, Bergamo, Italy
| | | | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche (IRCCS) 'Mario Negri', Clinical Research Centre for Rare Diseases 'Aldo e Cele Daccò', Ranica, Bergamo, Italy
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Santiago Rodriguez de Córdoba
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
| | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Johan Van der Vlag
- Department of Nephrology, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Peter F Zipfel
- Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
- Friedrich Schiller University, Jena, Germany
| | - Carla M Nester
- Molecular Otolaryngology and Renal Research Laboratories and the Departments of Internal Medicine and Pediatrics (Divisions of Nephrology), Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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45
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Evolving complexity of complement-related diseases: C3 glomerulopathy and atypical haemolytic uremic syndrome. Curr Opin Nephrol Hypertens 2019. [PMID: 29517501 DOI: 10.1097/mnh.0000000000000412] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW The current review will discuss recent advances in our understanding of the pathology of C3 glomerulopathy and atypical haemolytic uremic syndrome (aHUS). RECENT FINDINGS C3 glomerulopathy and aHUS are associated with abnormalities of control of the alternative pathway of complement. Recent articles have provided new insights into the classification of C3 glomerulopathy and its relationship to idiopathic immune complex-mediated glomerulonephritis. They suggest that there may be considerable overlap in pathogenesis between these entities and have indicated novel ways in which classification may be improved. There is increasing evidence that monoclonal gammopathy may cause C3 glomerulopathy or aHUS in older patients and emerging evidence that treatment of the underlying plasma cell clone may ameliorate the kidney disease. SUMMARY Recent work has provided new insights into the causes of C3 glomerulopathy and aHUS, and the mechanism by which complement is dysregulated. This is of particular importance with the advent of new therapeutic agents which can specifically target different parts of the complement cascade.
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46
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Complement factor H family proteins in their non-canonical role as modulators of cellular functions. Semin Cell Dev Biol 2019; 85:122-131. [DOI: 10.1016/j.semcdb.2017.12.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 11/23/2017] [Accepted: 12/31/2017] [Indexed: 12/17/2022]
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47
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Nissilä E, Hakala P, Leskinen K, Roig A, Syed S, Van Kessel KPM, Metso J, De Haas CJC, Saavalainen P, Meri S, Chroni A, Van Strijp JAG, Öörni K, Jauhiainen M, Jokiranta TS, Haapasalo K. Complement Factor H and Apolipoprotein E Participate in Regulation of Inflammation in THP-1 Macrophages. Front Immunol 2018; 9:2701. [PMID: 30519244 PMCID: PMC6260146 DOI: 10.3389/fimmu.2018.02701] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 11/01/2018] [Indexed: 12/28/2022] Open
Abstract
The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Factor H (FH), the main AP regulator in plasma. Although complement is known to play a role in atherosclerosis, the mechanisms of its contribution are not fully understood. Since FH via its domains 5-7 binds apoliporotein E (apoE) and macrophages produce apoE we examined how FH could be involved in the antiatherogenic effects of apoE. We used blood peripheral monocytes and THP-1 monocyte/macrophage cells which were also loaded with acetylated low-density lipoprotein (LDL) to form foam cells. Binding of FH and apoE on these cells was analyzed by flow cytometry. High-density lipoprotein (HDL)-mediated cholesterol efflux of activated THP-1 cells was measured and transcriptomes of THP-1 cells using mRNA sequencing were determined. We found that binding of FH to human blood monocytes and cholesterol-loaded THP-1 macrophages increased apoE binding to these cells. Preincubation of fluorescent cholesterol labeled THP-1 macrophages in the presence of FH increased cholesterol efflux and cholesterol-loaded macrophages displayed reduced transcription of proinflammatory/proatherogenic factors and increased transcription of anti-inflammatory/anti-atherogenic factors. Further incubation of THP-1 cells with serum reduced C3b/iC3b deposition. Overall, our data indicate that apoE and FH interact with monocytic cells in a concerted action and this interaction reduces complement activation and inflammation in the atherosclerotic lesions. By this way FH may participate in mediating the beneficial effects of apoE in suppressing atherosclerotic lesion progression.
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Affiliation(s)
- Eija Nissilä
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Pipsa Hakala
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Katarzyna Leskinen
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Angela Roig
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Shahan Syed
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | | | - Jari Metso
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Carla J. C. De Haas
- Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Päivi Saavalainen
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Angeliki Chroni
- Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, Athens, Greece
| | | | | | - Matti Jauhiainen
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - T. Sakari Jokiranta
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Karita Haapasalo
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
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Senant M, Bordereau P, Tartour E, Dragon-Durey MA. Analytical validation of an alternative method to quantify specific antibodies in 3 applications. J Immunol Methods 2018; 464:40-46. [PMID: 30342009 DOI: 10.1016/j.jim.2018.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/15/2018] [Accepted: 10/16/2018] [Indexed: 10/28/2022]
Abstract
The detection and the quantification of specific antibodies represent essential tools for the diagnosis and for the biological monitoring of immune humoral response in many clinical situations in particular in autoimmune diseases or in the context of immunotherapy using monoclonal antibodies. This article focuses on the development of a specific antibody measuring method (Patent n°PCT/IB2014/064437). The principle of this method is based on the combined use of a monoclonal antibody as standard and the protein G as immunoglobulins detecting agent. We performed a complete analytical validation of this method for the quantification of antibodies in three different applications: autoantibodies, alloantibodies and therapeutic monoclonal antibody. The results showed good performances compatible with the use of these assays as diagnostic tools. This method allows avoiding the use of products from human origin as reagent that causes ethical and infectious concerns but also storage and long term stock management problems. Moreover, this approach is particularly useful when no commercial reagent is available, especially in the case of rare diseases.
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Affiliation(s)
- Marie Senant
- Paris Descartes University, Paris, France; Hôpital Européen Georges Pompidou, APHP, Service d'Immunologie Biologique, Paris, France
| | - Pauline Bordereau
- Hôpital Européen Georges Pompidou, APHP, Service d'Immunologie Biologique, Paris, France
| | - Eric Tartour
- Paris Descartes University, Paris, France; Hôpital Européen Georges Pompidou, APHP, Service d'Immunologie Biologique, Paris, France
| | - Marie-Agnès Dragon-Durey
- Paris Descartes University, Paris, France; Hôpital Européen Georges Pompidou, APHP, Service d'Immunologie Biologique, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, INSERM UMRS1138, Paris, France.
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Ravindran A, Fervenza FC, Smith RJH, De Vriese AS, Sethi S. C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic. Mayo Clin Proc 2018; 93:991-1008. [PMID: 30077216 PMCID: PMC6312642 DOI: 10.1016/j.mayocp.2018.05.019] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 04/23/2018] [Accepted: 05/14/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To describe the clinicopathological features, complement abnormalities, triggers, treatment, and outcomes of C3 glomerulopathy. PATIENTS AND METHODS A total of 114 patients with C3 glomerulopathy seen at Mayo Clinic from January 1, 2007, through December 31, 2016, were evaluated in this study. RESULTS The mean age at diagnosis for the entire cohort was 40.4±22.3 years, with a median serum creatinine level and proteinuria value of 1.6 mg/dL (range: 0.3-14.7) (to convert to mmol/L, multiply by 0.0259) and 2605 mg/24 h (range: 233-24,165), respectively. Hematuria was present in 100 patients (87.7%). The C3 and C4 levels were low in 50 of 112 (44.6%) and 13 of 110 (11.8%) patients, respectively. A history of infection, positive autoimmune findings, and monoclonal gammopathy (MIg) were present in 33 of 114 (28.9%), 28 of 114 (24.6%), and 36 of 95 (37.9%) patients, respectively. However, 28 of 43 patients 50 years or older (65.1%) had MIg. A genetic variant in complement genes, C3 nephritic factor (C3Nef), and other autoantibodies was present in 26 of 70 (37.1%), 30 of 69 (43.5%), and 9 of 67 (13.4%) patients, respectively. Membranoproliferative and mesangial proliferative glomerulonephritis were the common patterns of injury. Patients without MIg were younger (mean age, 32.3±20.6 years), with a median serum creatinine level and proteinuria value of 1.4 mg/dL (range: 0.3-7.9) and 2450 mg/24 h (range: 250-24, 165) and with low C3 and C4 levels in 38 of 77 (49.4%) and 9 of 75 (12.0%) patients, respectively. Most patients received corticosteroids and other immunosuppressive drugs. In patients without MIg, at a median follow-up of 22.3 months (range: 0.1-201.1), the median serum creatinine level and proteinuria value were 1.4 mg/dL (range: 0.3-3.7) and 825.5 mg/24 h (range: 76-22, 603), and 7 patients (9.2%) had progression to end-stage renal disease. CONCLUSION C3 glomerulopathy is a heterogeneous disease entity with complex triggering events and abnormalities of the alternative pathway of complement. The disease tends to be progressive and exhibits a variable response to immunosuppressive therapy.
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Affiliation(s)
- Aishwarya Ravindran
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | - Richard J H Smith
- Molecular Otolaryngology and Renal Research Laboratories, Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, Iowa City, IA; Department of Pediatrics, Carver College of Medicine, Iowa City, IA
| | - An S De Vriese
- Division of Nephrology, Department of Internal Medicine, AZ Sint-Jan Brugge-Oostende, Brugge, and Ghent University, Ghent, Belgium
| | - Sanjeev Sethi
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
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Sánchez-Corral P, Pouw RB, López-Trascasa M, Józsi M. Self-Damage Caused by Dysregulation of the Complement Alternative Pathway: Relevance of the Factor H Protein Family. Front Immunol 2018; 9:1607. [PMID: 30050540 PMCID: PMC6052053 DOI: 10.3389/fimmu.2018.01607] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 06/28/2018] [Indexed: 12/13/2022] Open
Abstract
The alternative pathway is a continuously active surveillance arm of the complement system, and it can also enhance complement activation initiated by the classical and the lectin pathways. Various membrane-bound and plasma regulatory proteins control the activation of the potentially deleterious complement system. Among the regulators, the plasma glycoprotein factor H (FH) is the main inhibitor of the alternative pathway and its powerful amplification loop. FH belongs to a protein family that also includes FH-like protein 1 and five factor H-related (FHR-1 to FHR-5) proteins. Genetic variants and abnormal rearrangements involving the FH protein family have been linked to numerous systemic and organ-specific diseases, including age-related macular degeneration, and the renal pathologies atypical hemolytic uremic syndrome, C3 glomerulopathies, and IgA nephropathy. This review covers the known and recently emerged ligands and interactions of the human FH family proteins associated with disease and discuss the very recent experimental data that suggest FH-antagonistic and complement-activating functions for the FHR proteins.
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Affiliation(s)
- Pilar Sánchez-Corral
- Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
| | - Richard B Pouw
- Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Margarita López-Trascasa
- Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.,Department of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Mihály Józsi
- Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-SE Research Group of Immunology and Hematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
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