Targeting the antigen-binding site of HLA-restricting alleles in treatment of autoimmune disease.
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 mice. In both cases, Ab and T-cell responses against AChR, especially those related to disease pathogenesis, also decreased. mAbs against peptides from the ridge of the antigen-binding region of the correlate DQB1 sequences inhibited in vitro the proliferation of AChR-specific T cells from MG patients. The results indicated that the function of disease-associated MHC alleles may be blocked by directly and selectively targeting the antigen-presenting region on these MHC molecules. The strategy could provide an effective means for immunointervention in other autoimmune and allergic responses.
Oshima
Minako
M
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA. moshima@bcm.tmc.edu
Deitiker
Philip
P
Atassi
M Zouhair
MZ
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D051379:Mice; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology / Q000628:therapy*; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D011950:Receptors, Cholinergic