Targeting the antigen-binding site of HLA-restricting alleles in treatment of autoimmune disease

Critical Reviews in Immunology
Minako OshimaM Zouhair Atassi

Abstract

In autoimmune disease, production of disease-causing auto-antibodies (Abs) depends on autoreactive T cells that recognize the epitopes of the pathogenic antigen in the context of MHC class II molecules. It is possible that selective inhibition of an antigen-presenting function of disease-associated MHC alleles could lead to suppression of the disease. Myasthenia gravis (MG) is a disabling neuromuscular disease in which autoimmune responses against acetylcholine receptor (AChR), especially against the alpha chain of AChR, cause a postsynaptic defect. HLA linkage of MG has been thus far best detailed for DQB1. Recently, we have shown that certain DQ haplotypes are associated with presentation of AChR alpha-chain peptides in MG. In a mouse model for MG, which can be induced in disease-susceptible C57BL/6 (B6, H-2b) mice by injection with Torpedo AChR, region 62-76 of I-Ab beta chain is involved in the disease mechanism. Monoclonal Abs (mAbs) against synthetic peptide I-Abetab62-76, which localizes at the rim of the antigen-binding site of I-Ab, inhibited in vitro proliferation of disease-associated T cells. Passive transfer of these mAbs as well as vaccination with this peptide strongly suppressed occurrence of clinical MG in B6 m...Continue Reading

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