The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis.

Abstract

Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including <i>Akkermansia muciniphila</i>. IgA1 was deglycosylated by <i>A. muciniphila</i> both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1^KI-CD89^tg) that underwent intestinal colonization by <i>A. muciniphila</i> developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by <i>A. muciniphila</i> in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins-a risk locus for IgA nephropathy-inhibited growth of <i>A. muciniphila in</i> vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of <i>A. muciniphila</i> in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.