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Science Advances Mar 2023Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition...
Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including βII-spectrin. Most patients with IgAN also have serum anti-βII-spectrin IgA. As in patients with IgAN, IgA plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to βII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous βII-spectrin exposed on the surface of embryonic kidney-derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.
Topics: Mice; Animals; Glomerulonephritis, IGA; Mesangial Cells; Spectrin; Immunoglobulin A; Autoantibodies
PubMed: 36947618
DOI: 10.1126/sciadv.add6734 -
Internal Medicine (Tokyo, Japan) Mar 2021Collagenofibrotic glomerulopathy or LMX1B-associated nephropathy is a rare disease in which type III collagen accumulates in the glomeruli. We herein report a...
Collagenofibrotic glomerulopathy or LMX1B-associated nephropathy is a rare disease in which type III collagen accumulates in the glomeruli. We herein report a 64-year-old Japanese woman with an elevated serum creatinine level and persistent proteinuria for 7 years. An electron microscopic study using tannic acid showed curved and frayed collagen fibers within mesangial and subendothelial regions compatible with type III collagen depositions. The distribution of type IV collagen α1-6 chains was normal. Since no pathogenic mutations were identified in the LMX1B gene, she was diagnosed with collagenofibrotic glomerulopathy and treated with angiotensin II receptor blocker and calcium antagonist to control her blood pressure.
Topics: Collagen Type III; Female; Glomerular Mesangium; Humans; Kidney Diseases; Kidney Glomerulus; Middle Aged; Proteinuria
PubMed: 33055489
DOI: 10.2169/internalmedicine.6090-20 -
Journal of the American Society of... May 2022IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered...
BACKGROUND
IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered O-glycans (Gd-IgA1) and anti-glycan antibodies in the kidney mesangium. The mesangial IgA deposits and serum IgA1 contain predominantly light (L) chains, but the nature and origin of such IgA remains enigmatic.
METHODS
We analyzed L chain expression in peripheral blood B cells of 30 IgAN patients, 30 healthy controls (HCs), and 18 membranous nephropathy patients selected as disease controls (non-IgAN).
RESULTS
In comparison to HCs and non-IgAN patients, peripheral blood surface/membrane bound (mb)-Gd-IgA1 cells from IgAN patients express predominantly L chains. In contrast, total mb-IgA, mb-IgG, and mb-IgM cells were preferentially positive for kappa () L chains, in all analyzed groups. Although minor in comparison to L chains, L chain subsets of mb-IgG, mb-IgM, and mb-IgA cells were significantly enriched in IgAN patients in comparison to non-IgAN patients and/or HCs. In contrast to HCs, the peripheral blood of IgAN patients was enriched with mb-Gd-IgA1, CCR10, and CCR9 cells, which preferentially home to the upper respiratory and digestive tracts. Furthermore, we observed that mb-Gd-IgA1 cell populations comprise more CD138 cells and plasmablasts (CD38) in comparison to total mb-IgA cells.
CONCLUSIONS
Peripheral blood of IgAN patients is enriched with migratory mb-Gd-IgA1 B cells, with the potential to home to mucosal sites where Gd-IgA1 could be produced during local respiratory or digestive tract infections.
Topics: Female; Galactose; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Male
PubMed: 35115327
DOI: 10.1681/ASN.2021081086 -
Kidney360 Sep 2022Immunoglobulin A nephropathy(IgAN) is the most common primary glomerulonephritis worldwide. The working model for the pathogenesis of IgAN involves a multistep process... (Review)
Review
Immunoglobulin A nephropathy(IgAN) is the most common primary glomerulonephritis worldwide. The working model for the pathogenesis of IgAN involves a multistep process starting from the production of galactose-deficient and polymeric immunoglobulin A-1 (gd-IgA1) that enters systemic circulation from gut-associated lymphoid tissue (GALT). Galactose-deficient IgA are targeted by endogenous IgG, leading to the formation of circulating immune complexes that deposit in the mesangium and resulting in glomerular inflammation. Disease onset and relapses are often associated with gut infections, supporting the hypothesis that the gut plays an important pathogenic role. In the presence of microbial pathogens or food antigens, activated dendritic cells in the gut mucosa induce T cell dependent and independent B cell differentiation into IgA secreting plasma cells. In IgAN patients, this promotes the systemic release of mucosal gd-IgA1. Not all bacterial strains have the same capacity to elicit IgA production, and little is known about the antigen specificity of the pathogenic gd-IgA1. However, efficacy of treatments targeting gut inflammation support a pathogenic link between the bowel immune system and IgAN. Herein, we review the evidence supporting the role of gut inflammation in IgAN pathogenesis.
Topics: Antigen-Antibody Complex; Galactose; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Immunoglobulin G; Inflammation; Kidney
PubMed: 36245664
DOI: 10.34067/KID.0002382022 -
Frontiers in Medicine 2023Immune complex (IC) vasculitides present inflammations of vessel walls associated with perivascular deposition of immunoglobulins (Igs), mostly ICs. They encompass... (Review)
Review
Immune complex (IC) vasculitides present inflammations of vessel walls associated with perivascular deposition of immunoglobulins (Igs), mostly ICs. They encompass systemic and skin-limited variants of IgA vasculitis (IgAV), cryoglobulinemic vasculitis (CV), rheumatoid, lupus, and hypocomplementemic vasculitides, serum sickness cutaneous IgM/IgG (non-IgA) vasculitis, and recurrent macular (hypergammaglobulinemic or exertion-induced) vasculitis. Serum sickness and CV fulfill the criteria of a type III hypersensitivity immune reaction as large lattices of the IC precipitate at vessel walls and activate polymorphonuclear neutrophils (PMNs). Immunoglobulin-A vasculitis differs with regard to the causes of perivascular deposition of ICs since here many IgA1 molecules are hypoglycosylated (Gd-IgA1), which appears to facilitate their perivascular deposition in skin and mesangium (via e.g. CD71). The reasons for increased generation of immunoglobulins or formation of IC and their perivascular deposition in either skin or systemic organs are different and not fully explored. A common denominator of OC vasculitides is the activation of PMNs near the vessel wall Fcy or Fcα receptors. Acute episodes of IgAV additionally require PMNs to become preactivated by IgA1 or by IC already in circulation. This intravascular priming results in increased adherence and subsequently vessel-destructive NETosis when they encounter IgA deposited at the vessel walls. Binding of IgA1 to PMNs in blood stream is associated with increased serum levels of hypogalactosidated IgA1. The characteristic clinical picture of IgAV (and also of so-called IgG/IgM vasculitis) comprises palpable or retiform purpura with a clear predilection for lower legs, probably due to stasis-related reduction in blood velocity, while in other IC vasculitides, additional factors influence the sites of vasculitides. Our knowledge of distinct forms and different pathophysiological pathways of IC vasculitides may lead to in efficacious or targeted therapies. Antibodies to complement components or intestinal budesonide for IgAV are promising agents (the latter suppresses the pathophysiologically related IgA nephropathy by reducing the generation of mucosal IgA.
PubMed: 36936215
DOI: 10.3389/fmed.2023.1103065 -
Kidney360 May 2023
Topics: Kidney Glomerulus; Glomerular Mesangium; Microvessels; Machine Learning
PubMed: 37229727
DOI: 10.34067/KID.0000000000000111 -
Journal of the American Society of... Jul 2019
Topics: Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Proteinuria
PubMed: 31227635
DOI: 10.1681/ASN.2019040373 -
Frontiers in Immunology 2022Lupus nephritis (LN) is a severe renal disease caused by the massive deposition of the immune complexes (ICs) in renal tissue, acting as one of the significant organ... (Review)
Review
Lupus nephritis (LN) is a severe renal disease caused by the massive deposition of the immune complexes (ICs) in renal tissue, acting as one of the significant organ manifestations of systemic lupus erythematosus (SLE) and a substantial cause of death in clinical patients. As mesangium is one of the primary sites for IC deposition, mesangial cells (MCs) constantly undergo severe damage, resulting in excessive proliferation and increased extracellular matrix (ECM) production. In addition to playing a role in organizational structure, MCs are closely related to immunomodulation by phagocytosis, antigen-presenting function, and inflammatory effects, aberrantly participating in the tissue-resident immune responses and leading to immune-mediated renal lesions. Notably, such renal-resident immune responses drive a second wave of MC damage, accelerating the development of LN. This review summarized the damage mechanisms and the immune regulation of MCs in LN, facilitating the current drug research for exploring clinical treatment strategies.
Topics: Humans; Lupus Nephritis; Mesangial Cells; Lupus Erythematosus, Systemic; Kidney; Glomerular Mesangium
PubMed: 36591251
DOI: 10.3389/fimmu.2022.1063497 -
Journal of Clinical Medicine Jul 2021IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of... (Review)
Review
IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of intercapillary deposits of IgA. Despite this simple description, patients with IgAN may present very broad clinical features ranging from the isolated presence of IgA in the mesangium without clinical or biological manifestations to rapidly progressive kidney failure. These features are associated with a variety of histological lesions, from the discrete thickening of the mesangial matrix to diffuse cell proliferation. Immunofluorescence on IgAN kidney specimens shows the isolated presence of IgA or its inconsistent association with IgG and complement components. This clinical heterogeneity of IgAN clearly echoes its complex and multifactorial pathophysiology in humans, inviting further analyses of its various aspects through the use of experimental models. Small-animal models of IgAN provide the most pertinent strategies for studying the multifactorial aspects of IgAN pathogenesis and progression. Although only primates have the IgA1 subclass, several murine models have been developed in which various aspects of immune responses are deregulated and which are useful in the understanding of IgAN physiopathology as well as in the assessment of IgAN therapeutic approaches. In this manuscript, we review all murine IgAN models developed since 1968 and discuss their remarkable contribution to understanding the disease.
PubMed: 34300307
DOI: 10.3390/jcm10143142