On the initial trigger of myasthenia gravis and suppression of the diseaseby antibodies against the MHC peptide region involved in the presentation of a pathogenic T-cell epitope

Myasthenia gravis (MG) is a disabling autoimmune disease caused by autoanti bodies (auto-Abs) against the self-acetylcholine receptor (AChR). Although a great deal of information is known about the molecular and cellular param eters of the disease, its initial trigger, however, is not known. To study the possibility of the involvement of microbial antigens that mimic AChR in triggering MG, we have searched the microbial proteins in the data bank fo r regions that are similar in structure to the regions of human (h) AChR al pha chain recognized by auto-Abs in MG patients. Hundreds of candidate stru ctures on a large number of bacterial and viral proteins were identified. T o test the feasibility of the idea, we synthesized four microbial regions s imilar to each of the major autodeterminants of hAChR (alpha 12-27, alpha 1 11-126, alpha 122-138, alpha 182-198) and investigated their ability to bin d auto-Abs in MG and normal sera controls. It was found that MG sera potent ially recognized a significant number of these microbial regions. The resul ts indicate that in some MG cases, immune responses to microbial antigens m ay cross-react with self-antigen (in this case hAChR) and could constitute initial triggers of the disease. Although anti-AChR Abs directly contribute to the degradation of AChR at th e neuromuscular junctions, autoreactive T cells provide help to B cells tha t synthesize anti-AChR auto-Abs. To cause MG, T cells must recognize the pa thogenic epitopes in the context of MHC class II molecules related to MG. T he ability to regulate AChR presentation (hence AChR-reactive T-cell activa tion) could form the basis of an effective strategy for the control of auto immunity in MG by selectively inhibiting the function of the Ir gene loci l inked to disease susceptibility. An animal model of MG (experimental autoim mune MG, EAMG) can be induced in C57BL6 (B6, H-2(b)) mice by immunization w ith Torpedo californica (t) AChR. A mutant mouse of B6, B6.C-H-2(bm12) (bm1 2), which has three amino acid changes (at residues 67, 70, and 71) in the I-A beta (b) subunit, is resistant to EAMG development. Recently, we showed that region 62-76 of I-A beta (b), which contains the above residues, is i nvolved in the binding to a pathogenic T-cell epitope within peptide t alph a 146-162. We have prepared several monoclonal antibodies (mAbs) against pe ptide I-A beta (b)62-76, which are highly cross-reactive with I-A(b) molecu les. These mAbs inhibited in vitro the proliferation of disease-related T c ells of B6 specific to tAChR peptide t alpha 146-162. Passive transfer of t hese mAbs suppressed the occurrence of clinical EAMG, which was accompanied by lower T-cell and Ab responses to tAChR. The results indicated that bloc king disease-related MHC by targeting a disease-associated region on MHC mo lecules could be an effective, straightforward, and feasible strategy for i mmunointervention in MG.