Pathogenesis of autoimmune disease

Nature Reviews Nephrology, Год журнала: 2023, Номер 19(8), С. 509 - 524

Опубликована: Май 10, 2023

Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T reactivity to normal constituents the host. These occur widely affect individuals all ages, especially women. Among these diseases, most prominent immunological manifestation is production autoantibodies, which provide valuable biomarkers for diagnosis, classification disease activity. Although cells have key role in pathogenesis, they technically more difficult assay. In general, autoimmune results from an interplay between genetic predisposition environmental factors. Genetic autoimmunity complex can involve multiple genes that regulate function immune populations. Less frequently, result single-gene mutations regulatory pathways. Infection seems be common trigger disease, although microbiota also influence pathogenesis. As shown seminal studies, patients may express autoantibodies many years before appearance clinical or laboratory signs — period called pre-clinical autoimmunity. Monitoring autoantibody expression at-risk populations therefore enable early detection initiation therapy prevent attenuate tissue damage. Autoimmunity not static, however, remission achieved some treated with current agents. host constituents. This Review provides overview basis focus on given their as markers

Язык: Английский

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Protocadherin 7–Associated Membranous Nephropathy

Journal of the American Society of Nephrology, Год журнала: 2021, Номер 32(5), С. 1249 - 1261

Опубликована: Апрель 8, 2021

Significance Statement Membranous nephropathy (MN) results from antibodies targeting an antigen in the glomerular basement membrane (GBM). The target antigens identified so far include PLA2R, THSD7A, NELL1, SEMA3B, and EXT1/EXT2. Using laser microdissection mass spectrometry analysis, authors a novel protein, protocadherin 7 (PCDH7), that is present GBM of subset patients with MN who are negative for all known associated MN. PCDH7 shows granular staining colocalizes Ig GBM. Furthermore, to were detected both serum kidney biopsy tissue individuals PCDH7-associated but not controls. These findings suggest defines distinct type Background deposition antigen-antibody complexes along SEMA3B account 80%–90% Methods We performed (MS/MS) biopsies 135 PLA2R-negative MN, used immunohistochemistry/immunofluorescence confocal microscopy confirm MS/MS finding, detect additional cases, localize protein. also immunohistochemistry on 116 controls immunofluorescence screen samples two validation cohorts. Western blot elution studies tissue. Results unique glomeruli ten (5.7%) which EXT1/EXT2, SEMA3B. Spectral counts ranged six 24 (average 13.2 [SD 6.6]). did (which included 28 PLA2R-positive cases). In PCDH7-positive showed bright GBM, was absent remaining cases control cases. Four 69 (5.8%) cohorts (all EXT1, SEMA3B) Kidney minimal complement 12 14 Confocal colocalization IgG analysis using sera nonreduced PCDH7. Elution frozen reactivity against Conclusions appears be distinct, previously unidentified

Язык: Английский

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Mechanisms of Primary Membranous Nephropathy

Biomolecules, Год журнала: 2021, Номер 11(4), С. 513 - 513

Опубликована: Март 30, 2021

Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one leading causes nephrotic syndrome. The exhibits heterogenous outcomes with approximately 30% cases progressing to end-stage renal disease. clinical management MN has steadily advanced owing identification autoantibodies phospholipase A2 receptor (PLA2R) in 2009 thrombospondin domain-containing 7A (THSD7A) 2014 on podocyte surface. Approximately 50–80% 3–5% primary (PMN) are associated either anti-PLA2R or anti-THSD7A antibodies, respectively. presence these used for diagnosis; antibody levels correlate severity possess significant biomarker values monitoring progression treatment response. Importantly, both causative MN. Additionally, evidence emerging that NELL-1 5–10% PMN PLA2R- THSD7A-negative, which moves us step closer mapping out full spectrum antigens. Recent developments suggest exostosin 1 (EXT1), EXT2, NELL-1, contactin (CNTN1) Genetic factors other mechanisms place regulate may contribute pathogenesis. This review will discuss recent over past 5 years.

Язык: Английский

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Advances in the Management of Primary Membranous Nephropathy and Rituximab-Refractory Membranous Nephropathy

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Май 4, 2022

Primary membranous nephropathy (pMN) is an auto-immune disease characterized by auto-antibodies targeting podocyte antigens resulting in activation of complement and damage to the glomerular basement membrane. pMN most common cause nephrotic syndrome adults without diabetes. Despite a very heterogeneous course disease, treatment has for many years been based on uniform management all patients regardless severity disease. The identification prognostic markers radically changed vision allowed KDIGO guidelines evolve 2021 towards more personalized assessment risk progressive loss kidney function. recognition as antibody-mediated autoimmune rationalized use immunosuppressive drugs such rituximab. Rituximab now first line therapy with proven safety efficacy achieving remission 60-80% patients. For remaining 20-40% patients, several mechanisms may explain rituximab resistance: (i) decreased bioavailability; (ii) immunization against rituximab; (iii) chronic damage. rituximab-refractory remains controversial challenging. In this review, we provide overview recent advances (according guidelines), understanding pathophysiology resistance, pMN. We propose decision aid immunomonitoring identify failures related underdosing or overcome resistance.

Язык: Английский

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COVID-19 and Glomerular Diseases

Kidney International Reports, Год журнала: 2023, Номер 8(6), С. 1137 - 1150

Опубликована: Март 27, 2023

Язык: Английский

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A Target Antigen–Based Approach to the Classification of Membranous Nephropathy

Mayo Clinic Proceedings, Год журнала: 2021, Номер 96(3), С. 577 - 591

Опубликована: Март 1, 2021

ObjectiveTo describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipase–A2-receptor (PLA2R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1), protocadherin 7 (PCDH7), exostosin 1/exostosin 2 (EXT1/EXT2) neural cell adhesion molecule 1 (NCAM-1) as target antigens.MethodsA retrospective cohort 270 adult patients biopsy-proven MN diagnosed between January 2015 April 2020 was classified PLA2R-, THSD7A-, SEMA3B-, NELL-1–, PCDH7-, EXT1/EXT2-, NCAM-1–associated or septuple-negative using serologic tests, immunostaining, and/or mass spectrometry. Clinical, biochemical, pathologic, follow-up data were systematically abstracted from medical records, including disease activity conditions traditionally occurring within 5 years diagnosis.ResultsPatients PLA2R-associated predominantly middle-aged white men without disease. The presence did not affect pathologic characteristics MN, suggesting that they coincidental rather than causally linked. rare SEMA3B-associated discovered in our cohort. EXT1/EXT2-associated primarily younger women active systemic autoimmunity. A significant proportion had malignancy autoimmunity.ConclusionThe widely used distinction primary secondary has limitations. We propose a refined terminology combines antigen to better classify guide decision making.

Язык: Английский

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Advances in Lupus Nephritis Pathogenesis: From Bench to Bedside

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(7), С. 3766 - 3766

Опубликована: Апрель 5, 2021

Systemic lupus erythematosus (SLE) is the prototype of autoimmune disorders caused by a loss tolerance to endogenous nuclear antigens triggering an aberrant response targeting various tissues. Lupus nephritis (LN), major cause morbidity and mortality in patients with SLE, affects up 60% patients. The recent insights into genetic molecular basis SLE LN paved way for newer therapies be developed these Apart from traditional B-cell-centered view this disease pathogenesis, acknowledging that multiple extrarenal intrarenal pathways contribute kidney-specific autoimmunity injury may help refine individual therapeutic prognostic characterization such Accordingly, formerly induction-maintenance treatment strategy was recently challenged exciting results obtained trials evaluated add-on therapy voclosporin, belimumab, or Obinutuzumab. scope review provide insight current knowledge pathogenesis future strategies.

Язык: Английский

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Transforming Growth Factor Beta Receptor 3 (TGFBR3)–Associated Membranous Nephropathy

Kidney360, Год журнала: 2021, Номер 2(8), С. 1275 - 1286

Опубликована: Июнь 11, 2021

Membranous lupus nephritis (MLN) comprises 10%-15% of and increases morbidity mortality patients with SLE through complications nephrotic syndrome chronic kidney failure. Identification the target antigens in MLN may enable noninvasive monitoring disease activity, inform treatment decisions, aid prognostication, as is now possible for idiopathic MN caused by antibodies against phospholipase A2 receptor. Here, we show evidence type III TGF-β receptor (TGFBR3) a novel biomarker expressed subset MLN.Mass spectrometry was used protein discovery enrichment glomerular proteins laser capture microdissection elution immune complexes within biopsy specimens. Colocalization IgG deposits from controls evaluated confocal microscopy. Immunostaining consecutive case series to determine overall frequency MLN.TGFBR3 found be enriched glomeruli coimmunoprecipitated specimens mass spectrometry. Staining cases without clinical did not TGFBR3 expression (zero 104), but showed 6% prevalence (11 199 cases). colocalized along basement membranes TGFBR3-associated MN, controls.Positive staining represents distinct form substantially MLN. A diagnosis can alert clinician search an underlying autoimmune disease.

Язык: Английский

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Recurrent Glomerular Disease after Kidney Transplantation

Clinical Journal of the American Society of Nephrology, Год журнала: 2021, Номер 16(11), С. 1730 - 1742

Опубликована: Окт. 22, 2021

Recurrent glomerular disease after kidney transplant remains an important cause of allograft failure. Many the different entities post-transplant still suffer from incomplete knowledge on pathophysiology, and therefore lack targeted effective therapies. In this review, we focus specific clinical dilemmas encountered by physicians in managing recurrent highlighting new insights into understanding treatment focal segmental glomerulosclerosis, membranous nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, amyloid light-chain (AL) amyloidosis, IgA nephropathy.

Язык: Английский

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Proteomics: Progress and Promise of High-Throughput Proteomics in Chronic Kidney Disease

Molecular & Cellular Proteomics, Год журнала: 2023, Номер 22(6), С. 100550 - 100550

Опубликована: Апрель 17, 2023

Current proteomic tools permit the high-throughput analysis of blood proteome in large cohorts, including those enriched for chronic kidney disease (CKD) or its risk factors. To date, these studies have identified numerous proteins associated with cross-sectional measures function, as well longitudinal CKD progression. Representative signals that emerged from literature include an association between levels testican-2 and favorable prognosis TNFRSF1A TNFRSF1B worse prognosis. For other associations, however, understanding whether play a causal role pathogenesis remains fundamental challenge, especially given strong impact function can on protein levels. Prior to investing dedicated animal models randomized trials, methods leverage availability genotyping epidemiologic cohorts-including Mendelian randomization, colocalization analyses, proteome-wide studies-can add evidence inference proteomics research. In addition, integration large-scale analyses urine tissue proteomics, improved assessment posttranslational modifications (e.g., carbamylation), represent important future directions. Taken together, approaches seek translate progress profiling into promise diagnostic therapeutic target identification disease.

Язык: Английский

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