IgA nephropathy is the most common cause of glomerulonephritis in countries where renal biopsies are commonly performed. See a previous post on the wide variety of presentations with this syndrome and this review. But what do we know of the actual pathogenesis of this condition?
IgA has two subclasses – IgA1 and IgA2, the latter lacks a specific amino acid sequence comprising the hinge region. The absence of this region confers more resistance to bacterial degradation. The majority of IgA in humans (95%) is monomeric, produced by plasma cells and freely circulates in the bloodstream. The remainder is produced by mucosal lymphoid cells and secreted in a dimeric form. The half-life is usually 4-5 days, with IgA molecules undergoing rapid hepatic metabolism.
IgA renal lesions characteristically involve IgA1 deposition in the mesangium. Therefore, research has focused on identifying abnormalities in the hinge region, unique to this sub-class. In normal circumstances the hinge region undergoes glycosylation of serine and threonine molecules, followed by the incorporation of galactose and sialic acid.
However, abnormalities that result in reduced glycosylation can predispose to self-aggregation of IgA1 molecules to form large complexes. These complexes can bind to Fc receptors on immune cells, causing cleavage of the receptor from the cell and formation of a larger complex. Hypo-glycosylation may also lead to exposure of certain residues in the hinge region that are immunogenic in themselves.
Circulating polymeric IgA can also bind IgG, forming circulating immune complexes. The resultant molecules can then deposit in the mesangium, with subsequent stimulation of complement and immune/inflammatory pathways. Polymeric IgA1 predominantly activates the alternative complement pathway.
Some enzyme deficiencies are hereditary, but these defects alone are not sufficient to give rise to clinical IgA nephropathy. Furthermore, around 20% of patients do not have detectable hypo-glycosylation – so other patho-physiological pathways must also exist.