IgA nephropathy pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Ali Poyan Mehr, M.D. [2]; Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3]
Overview
IgA nephropathy is characterized by the presence of aberrant IgA1 immunoglobulins deposited on the glomerular mesangium. IgG and IgM may also be present to a much lower extent. On the other hand, serum IgA1 levels are elevated in patients with IgA nephropathy in 30-50% of cases. IgA1 subtypes contain galactose-deficient 3-6 O-glycans that may act as binding sites for anti-N-acetyl-galactosamine antibodies. These antibodies have been shown to be expressed following antigenic exposure to certain infectious agents. Currently, IgA nephropathy is believed to be a 4-hit process that eventually leads to IgA deposition on glomerular mesangium. Although mesangial deposition is most commonly seen in patients with IgA nephropathy, other pathological features might still be present.
Pathophysiology
To understand the pathology behind IgAN, there must be an understanding of the physiology of IgA.
- Humans produce two isotype subclasses of IgA —IgA1 and IgA2. Both IgA1 and IgA2 are produced by the plasma cells found within the gastrointestinal and respiratory tracts.
- However, the plasma cells in the bone marrow, lymph nodes, and spleen produce predominantly IgA1. [1]
- The IgA deposited in IgA nephropathy is predominantly of the IgA1 subclass. [2]
- IgA nephropathy is characterized by the presence of IgA1 deposits along the glomerular mesangium, in addition to complement C3, and properidine that are concomitantly present in almost all cases of IgA nephropathy.
Genetics
Serum IgA1 levels are increased in 30-50% of patients with IgA nephropathy. The elevated serum levels of IgA1 in such patients is currently believed to be genetically determined. Nonetheless, genetic predisposition and aberrant glycosylation do not seem to sufficiently cause IgA nephropathy alone.
Pathogenesis
- The presence of increased IgA1 in IgA nephropathy has clear pathological implications due to the characteristic morphology of the IgA1 subclass.
- IgA1 contains a unique hinge region at a location of the immunoglobulin heavy chain between the first and second constant region domains.[3]
- The location is described to be rich in serine and threonine; the abundance of these amino acids at the specific site is likely to facilitate the attachment of 3-6 O-glycans, deficient in galactose, to the IgA. J chain-containing IgA, IgM, and IgG antibodies against the galactose-deficient IgA1 are needed for the pathogenesis of IgA nephropathy.[3][4][5][6] [3][7]
- These antibodies bind specifically to the N-acetylgalactosamine (GalNAc) residues of the IgA1 antibodies at the O-linked glycans of the hinge region in the heavy chain.
- This process is then followed by the accumulation of the formed immune complexes in the mesangial cells.[3]
- Finally, activated mesangial cells induce renal injury by the production and secretion of extracellular matrix, and pro-inflammatory cytokines and chemokines.[3]
- Several organisms and viruses may produce GalNAc on their surface, which may be the underlying etiology to the development of anti-GalNAc antibodies.[7]
- Respiratory syncytial virus (RSV), Epstein-Barr virus (EBV), Herpes virus, and several strains of streptococci are all examples of infectious agents that express GalNAc epitopes.
- Induced antibodies released during an active infection most likely recognizes and reacts with GalNac terminals found at O-linked glycans of IgA1 antibodies in the galactose-deficient hinge region.[7]
- IgG and/or IgM deposits has been observed to be frequently present, whereas complement C4, C4d, mannose-binding lectin, and C5b-C9 have also been detected to a lesser extent.[8][9][10][11]
- The pathogenesis of IgA nephropathy is thus described by Suzuki and colleagues[3] as a 4-hit hypothesis that is summarized in the image below:
(Adapted from Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011; 22(10):1795-803)
Microscopic Pathology
Light Microscopy Findings
- Ultimately, IgA nephropathy may have any of the following 6 findings on light microscopy (in increasing order of severity):
- Normal appearing biopsy
- Focal mesangial hypercellularity
- Diffuse mesangial hypercellularity
- Focal proliferative glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Chronic sclerosing glomerulonephritis
Electron Microscopy Findings
- On electron microscopy, mesangial deposits are most commonly seen. However, depositions on capillary walls are possible; they herald worse prognosis.
- The following variations may also be found but they are not specific to IgA nephropathy[12]:
- Segmental endocapillary proliferation
- egmental Glomerulosclerosis and adhesions
- Tubular atrophy and interstitial fibrosis
- Glomerular crescent surrounding the glomerular tuft
Associated Conditions
- The following conditions are frequently found in conjunction with IgA nephropathy:
- Dermatitis herpetiformis[13]
- Seronegative arthritis, especially as ankylosing spondylitis[13]
- Small-cell carcinoma[13]
- Hodgkin’s lymphoma[13]
- T-cell lymphoma, such as mycosis fungoides[13]
- Disseminated tuberculosis[13]
- Bronchiolitis obliterans[13]
- Inflammatory bowel disease(Crohn’s disease and ulcerative colitis)[13]
References
- ↑ Donadio JV, Grande JP (2002). "IgA nephropathy". N Engl J Med. 347 (10): 738–48. doi:10.1056/NEJMra020109. PMID 12213946.
- ↑ Lomax-Smith JD, Zabrowarny LA, Howarth GS, Seymour AE, Woodroffe AJ (1983). "The immunochemical characterization of mesangial IgA deposits". Am J Pathol. 113 (3): 359–64. PMC 1916361. PMID 6359892.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB; et al. (2011). "The pathophysiology of IgA nephropathy". J Am Soc Nephrol. 22 (10): 1795–803. doi:10.1681/ASN.2011050464. PMID 21949093.
- ↑ Allen AC, Harper SJ, Feehally J (1995). "Galactosylation of N- and O-linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy". Clin Exp Immunol. 100 (3): 470–4. PMC 1534466. PMID 7774058.
- ↑ Odani H, Yamamoto K, Iwayama S, Iwase H, Takasaki A, Takahashi K; et al. (2010). "Evaluation of the specific structures of IgA1 hinge glycopeptide in 30 IgA nephropathy patients by mass spectrometry". J Nephrol. 23 (1): 70–6. PMID 20091489.
- ↑ Novak J, Julian BA, Mestecky J, Renfrow MB (2012). "Glycosylation of IgA1 and pathogenesis of IgA nephropathy". Semin Immunopathol. 34 (3): 365–82. doi:10.1007/s00281-012-0306-z. PMID 22434325.
- ↑ 7.0 7.1 7.2 Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J (1999). "Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies". J Clin Invest. 104 (1): 73–81. doi:10.1172/JCI5535. PMC 408399. PMID 10393701.
- ↑ Berthoux F, Suzuki H, Thibaudin L, Yanagawa H, Maillard N, Mariat C; et al. (2012). "Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy". J Am Soc Nephrol. 23 (9): 1579–87. doi:10.1681/ASN.2012010053. PMC 3431415. PMID 22904352.
- ↑ Espinosa M, Ortega R, Gómez-Carrasco JM, López-Rubio F, López-Andreu M, López-Oliva MO; et al. (2009). "Mesangial C4d deposition: a new prognostic factor in IgA nephropathy". Nephrol Dial Transplant. 24 (3): 886–91. doi:10.1093/ndt/gfn563. PMID 18842673.
- ↑ Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ; et al. (2006). "Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease". J Am Soc Nephrol. 17 (6): 1724–34. doi:10.1681/ASN.2005090923. PMID 16687629.
- ↑ Miyamoto H, Yoshioka K, Takemura T, Akano N, Maki S (1988). "Immunohistochemical study of the membrane attack complex of complement in IgA nephropathy". Virchows Arch A Pathol Anat Histopathol. 413 (1): 77–86. PMID 3131958.
- ↑ Wyatt RJ, Julian BA (2013). "IgA nephropathy". N Engl J Med. 368 (25): 2402–14. doi:10.1056/NEJMra1206793. PMID 23782179.
- ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 Radhakrishnan J, Cattran DC (2012). "The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines--application to the individual patient". Kidney Int. 82 (8): 840–56. doi:10.1038/ki.2012.280. PMID 22895519.