IgA nephropathy pathophysiology
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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.
- 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. 
- The IgA deposited in IgA nephropathy is predominantly of the IgA1 subclass. 
- 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.
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.
- 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.
- 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. 
- 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.
- Finally, activated mesangial cells induce renal injury by the production and secretion of extracellular matrix, and pro-inflammatory cytokines and chemokines.
- Several organisms and viruses may produce GalNAc on their surface, which may be the underlying etiology to the development of anti-GalNAc antibodies.
- 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.
- 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.
- The pathogenesis of IgA nephropathy is thus described by Suzuki and colleagues as a 4-hit hypothesis that is summarized in the image below:
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:
- Segmental endocapillary proliferation
- egmental Glomerulosclerosis and adhesions
- Tubular atrophy and interstitial fibrosis
- Glomerular crescent surrounding the glomerular tuft
- The following conditions are frequently found in conjunction with IgA nephropathy:
- Dermatitis herpetiformis
- Seronegative arthritis, especially as ankylosing spondylitis
- Small-cell carcinoma
- Hodgkin’s lymphoma
- T-cell lymphoma, such as mycosis fungoides
- Disseminated tuberculosis
- Bronchiolitis obliterans
- Inflammatory bowel disease(Crohn’s disease and ulcerative colitis)
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