Abstract
In myasthenia gravis (MG) an autoimmune response against muscle acetylcholine
receptor (AChR) occurs. Embryonic muscle AChR contains a gamma subunit,
substituted in adult muscle by a homologous epsilon subunit. Antibodies
and CD4+ cells specific for embryonic AChR have been demonstrated
in MG patients. We identified sequence segments of the human gamma
subunit forming epitopes recognized by four embryonic AChR-specific
CD4+ T cell lines, propagated from MG patients' blood by stimulation
with synthetic peptides corresponding to the human gamma subunit
sequence. Each line had an individual epitope repertoire, but two
20-residue sequence regions were recognized by three lines of different
HLA haplotype. Most T epitope sequences were highly diverged between
the gamma and the other AChR subunits, confirming the specificity
of the T cells for embryonic AChR. These T cells may have been sensitized
against AChR expressed by a tissue other than innervated skeletal
muscle, possibly the thymus, which expresses an embryonic muscle
AChR-like protein, containing a gamma subunit. Several sequence segments
forming T epitopes are similar to regions of microbial and/or mammalian
proteins unrelated to the AChR. These findings are consistent with
the possibility that T cell cross-reactivity between unrelated proteins
("molecular mimicry"), proposed as a cause of autoimmune responses,
is not a rare event.
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