T helper cell recognition of muscle acetylcholine receptor in myasthenia gravis. Epitopes on the gamma and delta subunits.

Abstract

We tested the response of CD4' cells and/or total lymphocytes from the blood of 22 myasthenic patients and 10 healthy controls to overlapping synthetic peptides, 20 residues long, to screen the sequence of the y and 5 subunits of human muscle acetylcholine receptor (AChR). The oy subunit is part of the AChR expressed in embryonic muscle and is substituted in the AChRs of most adult muscles by an e subunit. The 5 subunit is present in both embryonic and adult AChRs. Adult extrinsic ocular muscles, which are preferentially and sometimes uniquely affected by myasthenic symptoms, and thymus, which has a still obscure but important role in the pathogenesis of myasthenia gravis, express the embryonic 'y subunit. AntiAChR CD4+ responses were more easily detected after CD8+ depletion. All responders recognized epitopes on both the y and a subunits and had severe symptoms. In four patients the CD4 + cell response was tested twice, when the symptoms were severe and during a period of remission. Consistently, the response was only detectable, or larger, when the patients were severely affected. (J. Clin. Invest. 1993. 92:1055-1067

Epitopes on the beta subunit of human muscle acetylcholine receptor recognized by CD4+ cells of myasthenia gravis patients and healthy subjects.

“…Testing of unselected, CD4+-enriched PBMC did not yield measurable responses to the (3 pool, or to individual ( subunit peptides, or to the a, y, and 6 peptide pools. Since the patients we studied suffered from mild or moderate symptoms, the negative results agree with those we obtained previously in studies investigating the Th response to the a, y, and 6 subunits, which indicated that a response to AChR epitopes of unselected blood CD4+ cells could be detected only in patients suffering from severe symptoms ( 13,18,28).…”

“…Given the absence of cytotoxic phenomena in MG (1)(2)(3)(4)(5), it is unlikely that the cells described here are anti-AChR cytolitic Th (10,11,13,28). A polyclonal T cell response focused on a relatively small number of immunodominant sequence regions also occurs in normal human Th responses to exogenous antigens (40,41, and Diethelm, B., R. Raju, and B. M. ContiTronconi, manuscript in preparation).…”

Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes.

“…The most characterized T-lymphocyte reactive determinants analyzed to date in human autoimmune disease include the acetylcholine receptor and myelin basic protein, which respectively serve as target autoantigens in myasthenia gravis and multiple sclerosis (23)(24)(25). Our observations in IDD are consistent with these studies in that synthetic peptides could be used to identify autoreactive determinants, responses to autoantigenic peptides were observed in autoimmune as well as in healthy control subjects, specific peptide recognition was in some but not all cases HLA-DR-restricted, and many T-lymphocyte reactive determinants were observed within a single antigen (23)(24)(25). The absence of a uniform PBMC reactive determinant in IDD subjects was predictable, given the known differences in an individual's MHC, as well as through our studies of immune responses to GAD in NOD mice (14), where an intramolecular spreading of cellular determinants was observed in the natural history of the disease in these animals.…”

Mapping myasthenia gravis–associated T cell epitopes on human acetylcholine receptors in HLA transgenic mice

“…Previous studies used panels of overlapping synthetic peptides spanning the sequence of the different H-AChR subunits, to examine the CD4 + T cell response of PBMCs from MG patients, or H-AChR-specific CD4 + T cell lines derived from MG patients, to identify H-AChR T cell epitopes (29)(30)(31)(32)(33)(35)(36)(37)(38)(39)(40)(41)(42)(43). Those studies identified a number of sequence regions recognized by CD4 + cells of MG patients, including a few immunodominant epitopes, which were recognized by the majority of MG patients on each human AChR subunit; several of those epitopes were within the H-AChR α subunit.…”