Studies of the pathogenesis of IgA nephropathy and Henoch-Schönlein purpura, with special reference to Streptococcus pyogenes infections and complement

Sammanfattning: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and Henoch-Schönlein purpura (HSP) the most common form of vasculitis in childhood. HSP may affect kidneys, a complication termed Henoch-Schönlein nephropathy (HSN). Renal pathology in HSN resembles that seen in IgAN. The pathogenesis of IgAN and HSP is so far unclear. Both are characterized by tissue deposits of underglycosylated polymeric IgA1 and the debut or exacerbations are regularly preceded by infections usually affecting the respiratory tract and often caused by group A streptococci (GAS). GAS express the surface bound M protein, which varies in sequence between strains and in certain serotypes includes an IgA-binding region (IgA-BR). The complement system, an important part of the innate immune system, is activated during IgAN and HSN reflected by the common finding of mesangial depositions of C3.
Paper I-III investigated whether IgA-binding M proteins are involved in the pathogenesis of IgAN and HSP. In the first study we examined tissue samples from pediatric patients with IgAN and HSP and detected IgA-BR co-localizing in the mesangial region with IgA in most of the kidney samples from patients with IgAN and HSN and skin samples from patients with HSP. In the second study we showed that pediatric patients with IgAN had higher antibody levels to IgA-BR than age-matched controls. The third study showed that the IgA-binding M protein from GAS serotype 4 (M4) had a significantly higher binding affinity for underglycosylated polymeric IgA1 than for other forms of IgA1. Mesangial cells stimulated with M4 exhibited increased synthesis and secretion of IL-6. Co-stimulation with both M4 and IgA1 induced excessive IL-6 secretion. IgA1 also induced C3 secretion from mesangial cells, which was enhanced when the cells were co-stimulated with M4.
Paper IV identified a novel mutation heterozygous mutation in exon 2 of the factor H gene (CFH) in a child with IgAN complicated by thrombotic microangiopathy (TMA) most probably triggered by malignant hypertension. In addition, three heterozygous CFH polymorphisms were identified, known to increase the risk for TMA. This genotype may thus have contributed to the combined phenotype of IgAN and TMA.
This thesis provides evidence for the involvement of GAS expressing IgA-binding M proteins in the etiology and pathogenesis of IgAN and HSP. An N terminal mutation in CFH may have influenced the course and pathological findings in IgAN and particularly conferred susceptibility for TMA.