The Pathophysiology of IgA Nephropathy

Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

“…This finding is consistent with a multi-hit hypothesis for the disease mechanism of IgAN, wherein an increased serum level of autoantigen alone is not sufficient to induce renal injury [25][26][27] ; it must combine with autoantibodies either in the circulation to form immune complexes that deposit in the glomerular mesangium or in situ with Gd-IgA1 already in the mesangium. Based on the physical and biologic characteristics of the immune complexes, such as composition and size, 17,28 mesangial cells may be activated to proliferate and overproduce components of mesangial matrix, chemokines, and cytokines.…”

IgA1 Glycosylation Is Heritable in Healthy Twins

“…In the proposed four-hit hypothesis of IgAN pathogenesis, an increase in gdIgA1 triggers the production of antiglycan autoantibodies. 8,19,20 This leads to the formation of immune complexes that, under this hypothesis, may deposit in the kidney and cause kidney injury. 21,22 Levels of gd-IgA1 are elevated in IgAN patients, regardless of ethnicity or age.…”

“…[25][26][27] An increased level of gd-IgA1 is associated with IgAN and is considered to be the 'first hit' in the proposed disease pathogenesis model. 8,20 Notably, asymptomatic first-degree relatives of IgAN patients have high gd-IgA1 levels, suggesting that additional factors ('hits') are required for IgAN to develop. Consistent with previous studies, serum IgA levels showed low heritability (46.3%) in our cohort.…”

C4d deposits in IgA nephropathy: where does complement activation come from?

“…The pathogenesis of IgAN is thought to be due to several factors (Bhits^) [2] which play a permissive role in the development of IgA deposits that have an inflammatory potential, leading to glomerular damage. The production of galactose-deficient IgA1 (GdIgA1) as a result of defective galactosylation of O-linked glycans typical of the IgA1 molecule is increased in patients with IgAN, but also in healthy relatives, suggesting the need of additional hits.…”

“…Gd-IgA1 binds to soluble CD89 (Fc alphaRI, myeloid IgA Fc receptor) and forms IgA1-CD89 complexes which interact with transferrin receptors (CD71/TfR1) and transglutaminase 2 (TGase2) in mesangial cells, thereby activating mediators and matrix production [3]. Moreover, GdIgA1 induces antiglycan autoantibody synthesis, leading to macromolecular Gd-IgA1(CD89)/IgG or IgA anti-Gd-IgA1 immune complex formation and renal deposition [2]. However, renal damage and progression towards sclerosis is highly variable, hence the presence of a crucial additional hit is envisaged.…”