Myasthenia gravis. CD4+ T epitopes on the embryonic gamma subunit of human muscle acetylcholine receptor.

Abstract

In myasthenia gravis (MG) an autoimmune response against muscle acetylcholine receptor (AChR) occurs. Embryonic muscle AChR contains a y subunit, substituted in adult muscle by a homologous e subunit. Antibodies and CD4 + cells specific for embryonic AChR have been demonstrated in MG patients.We identified sequence segments of the human y 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 -y 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 y 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 y 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. (J. Clin. Invest. 1992Invest. . 90:1558Invest. -1567

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

“…The responders included two patients with high antibody titer ( 12 and 13, with 47 and 48 nmol, respectively), but the patients with the highest titers of antibody to the AChR (9 and 17) did not respond to y and 6 subunit epitopes at the T cell level. Several patients with little or no detectable anti-AChR antibody (7, 14, ,y381 400 - For 44 sequence regions of the human AChR a, y and 6 subunits identified in this or in previous studies (14,15,31) the involvement of the different AChR subunits in the antiAChR antibody response, it is impossible to reach any conclusions on the complex relationships between the extent ofT cell sensitization, antibody synthesis by the AChR specific B cells, and severity of the symptoms. The finding that the two antibody-negative patients (7 and 14) had T cell sensitization to the AChR suggests that at least in some cases ofantibody-negative MG an immune anti-AChR response occurs.…”

“…It is conceivable that, even in the absence of a CD4+ response to epitopes on a given AChR subunit, the anti-AChR antibodies of that patient may still recognize epitopes formed by residues within that subunit: this is particularly likely for the a subunit, whose corresponding a pool was not recognized by patient 14, since the a subunit contains the MIR, the set of largely overlapping epitopes which dominates the antibody response in MG (21)(22)(23). However, given the conformation dependence of most (1,3,4,6,8,11,12,14,16,17,18, and 20) as described in reference 78 or by RFLP and oligonucleotide hybridization (7,10,13,15,19,21, and 22) as described in reference 79. t Classified as described in reference 80. § The anti-AChR antibody titers, measured as described in reference 81, were usually evaluated on serum collected the day of the experiment.…”

“…AChR-specific long-term Th cell lines can be propagated from the blood of MG patients by stimulation with pools of synthetic peptides corresponding to the sequences of the human AChR a, f3, -y, and 5 subunits (13)(14)(15)30, and Moiola, L., and B. M. Conti-Tronconi, unpublished observations). However, long-term Th lines are not ideal to study the Th epitope repertoire in MG, since during their propagation in vitro selective clonal loss or enrichment may occur, resulting in a biased repertoire of the anti-AChR Th lines.…”

“…Long-term Th lines specific for the AChR a subunit recognize only epitopes within four immunodominant sequence regions (14), while direct testing of unselected CD4+ cells from MG patients' blood reveals several other epitopes (41 ). Furthermore, propagation of Th lines is time consuming and labor intensive, and very few patients can be studied by this approach ( 14,15,30).…”

Association of the gene encoding the δ-subunit of the muscle acetylcholine receptor (CHRND) with acquired autoimmune myasthenia gravis

“…The d-subunit displays immunogenic epitopes for both B and T cells. [10][11][12] It interacts with the a-subunit to form a heterodimer in the first step of AChR assembly in muscle cells. 13 In contrast, it is expressed at a very low level in the thymus and it seems to be excluded from the AChR complexes that are formed in this organ, which plays an essential role in tolerance induction and in MG pathogenesis.…”