Inter-molecular epitope spreading does not lead to extension of autoimmunity beyond target tissue in autoimmune glomerulonephritis

Abstract

Inter-molecular epitope spreading during autoimmune pathogenesis leads to generation of new pathogenic epitopes on other autoantigens beyond the original one. It raises an important question as whether autoimmunity extends beyond the target tissues if new epitopes are on the molecules shared with other tissues. This study is aimed addressing this question in a rat anti-glomerular basement membrane (GBM) glomerulonephritis model induced by a T cell epitope of glomerulus-specific collagen4α3. We have demonstrated inter-molecular B cell epitope spreading. Four novel epitopes were first identified by screening a phage display random peptide library against autoantibodies isolated from the GBM of immunized rats. All four epitopes were derived from GBM proteins with three from laminins and one from collagen4α4. Three out of four synthetic peptides were nephritogenic. Importantly, two peptides from lamininα1 and lamininβ1, respectively, induced severe inflammation in glomeruli but not in the interstitial tissues, despite the presence of more abundant laminins in the tubular basement membranes. Our study suggests that surrounding tissues may display a lower or altered susceptibility to autoimmune inflammation. Thus, preventing extension of autoimmune inflammation beyond the original target tissue.

Laminin-521 is a Novel Target of Autoantibodies Associated with Lung Hemorrhage in Anti-GBM Disease

“…This seems to occur in rats immunized with a nephritogenic a3NC1-derived peptide, which exhibit epitope spreading to peptides from laminins a1 and b1. 20 In a minority of patients, anti-LM521 autoAbs may be the primary cause of disease, eventually followed by epitope spreading to a3(IV) collagen. This may occur in rare cases of patients initially presenting with seronegative hemoptysis and normal kidney function, who later develop GN and become seropositive for anti-GBM autoAbs.…”

“…18 In addition, rats develop GN mediated by GBMbound antilaminin antibodies 19 or induced by immunization with peptides derived from laminin a1, a5, and b1 chains. 20 Whether true antilaminin autoAbs occur in human glomerulonephritides is controversial. Although antibodies binding to mouse laminin-111 have been described in patients with GP disease, poststreptococcal GN, IgA nephropathy, SLE, or ANCA-associated vasculitis, proof of their binding to human laminins is lacking.…”

“…18 In addition, rats develop GN mediated by GBM-bound antilaminin antibodies 19 or induced by immunization with peptides derived from laminin α1, α5, and β1 chains. 20…”