The HLA complex in Goodpasture's disease: A model for analyzing susceptibility to autoimmunity

Abstract

Human lymphocyte antigen (HLA) associations are recognized for many autoimmune diseases, but the mechanisms are not clear. Goodpasture's disease provides a unique opportunity to investigate possible mechanisms because strong HLA associations are known, the autoantigen is well defined, and major antigen-derived peptides presented bound to HLA molecules have been identified. Therefore, it may be possible to directly analyze interactions between the antigen and HLA molecules associated with the disease, and to examine influences on antigen presentation to T cells. Towards this goal, we present a detailed analysis of HLA associations with the disease and examine molecular mechanisms that could account for them.

The HLA-DRB1*15

“…11 DRB1*15:01 Tg mice were immunized with a1(IV)NC1, a3(IV)NC1, or the E A chimera (containing ha3 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] or the E B chimera (containing ha3 127-141 overlapping the restricted T cell epitope), and lymphocytes were then re-stimulated with either murine a3 9-28 or a3 129-148 . Mice immunized with a1(IV)NC1 or the E A chimera responded to neither peptide ( Figure 4A), whereas mice immunized with the E B chimera or full-length a3(IV)NC1 responded to a3 129-148 but not a3 [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] . Further groups of mice were immunized with a3(IV)NC1, the E A chimera, or the E B chimera and re-stimulated with chimeric and whole proteins.…”

“…10 By using mice expressing this risk allele or the protective HLA-DRB1*01:01 allele (but no mouse MHC II), 19 we have defined an immunodominant CD4 + T cell epitope in a3 (IV)NC1 (a3 [136][137][138][139][140][141][142][143][144][145][146] ) that also triggers autoantibody production. Importantly, a3 136-146 -specific CD4 + cells induce GN in naïve DRB1*15:01 mice and when additional FcgR-related susceptibility elements are introduced, active autoimmunity and disease is markedly enhanced.…”

Mammalian collagen IV

“…In this regard, the immunospecificity of antibodies to α3(IV) NC1 domain is puzzling, since antibodies to NC1 domains of other chains, such as α1(IV) and α2(IV), do not cause anti-GBM nephritis (Bolton et al, 1995;Kalluri et al, 1996;. Genetic factors have been reported indicating that patients with certain allelic variations (HLA-DRB1*1501 and DRB1*1502) have increased susceptibility to develop the disease, whereas other alleles (HLA-DR7 and DR1) are protective (Phelps and Rees, 1999). The role of autoreactive CD4+ Tcells in mediating the disease has been reported, clearly indicating the importance of cell-mediated autoimmunity in the pathogenesis (Salama et al, 2001;Wong et al, 2001).…”

T cell infiltration is associated with kidney injury in patients with anti-glomerular basement membrane disease

“…While the autoantibody titers are lower in these mice, cellular reactivity is reduced and renal injury is less severe than that in non-IL-23-deficient mice (Ooi et al, 2009). In human anti-GBM disease, T cell involvement can be implied from strong human leukocyte antigen (HLA) associations (Phelps and Rees, 1999). CD4 + and CD8 + T cell infiltration has been observed in the affected glomeruli (Bolton et al, 1987).…”