Myasthenia gravis

Abstract

We studied autoreactive acetylcholine receptor (AChR)-specific T cell lines from two patients with myasthenia gravis. Anti-AChR autoantibody production by peripheral blood mononuclear cells (PBM) from the donors of the T cell lines was measured with an enzyme-linked immunoadsorbent assay, using purified human AChR as antigen. Freshly isolated PBM produced barely detectable amounts of anti-AChR autoantibodies. If, however, autologous AChR-specific T cells were added to the cultures, the production of anti-AChR autoantibodies, and of total IgM and IgG, was markedly stimulated, depending on the number of T line cells and on the amount of AChR present in the cultures. AChR-specific functional helper T-lymphocytes may have a role in the immunoregulation of myasthenia gravis.

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

“…For the sequence regions found to contain T epitopes, we searched for similarities with unrelated proteins to determine if the results reported here are compatible with the proposed origin of autoimmune responses from mechanisms of molecular mimicry between self components and microbial proteins (27). Mg of each peptide/ml), PHA (10 Ag/ml; Wellcome Reagent Ltd., Beckenham, UK), FBAChR (5, 2.5, and 1.25,ug/ ml), or each individual synthetic peptide (10 ug/ml). Triplicate wells with blasts alone were seeded as controls.…”

“…Several peptides recognized by the CD4+ lines had strong similarities with sequence regions from unrelated proteins, as summarized in Table III, where the y subunit peptide epitopes are aligned on the unrelated, similar sequences. Residues that are identical or conser- 10 ,tg/ml of the unrelated peptide E73 (****P < 0.001, ***P < 0.005, **P < 0.01, *P < 0.025). See text for experimental details.…”

“…They stimulate the production ofanti-AChR antibodies in vitro (10) and recognize the AChR in association with HLA-DR molecules (I I). Because Th cells recognize denatured AChR (6), they can be propagated in vitro using synthetic sequences ofthe AChR to yield polyclonal CD4+ T cell lines enriched in AChRspecific T cells (7,12,13).…”

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

“…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.…”

“…Native, membrane-bound Torpedo AChR (TAChR) was prepared from Torpedo californica electric tissue and characterized as described in reference 12. The specific activity of TAChR preparations (expressed as nanomoles ofa-bungarotoxin binding sites per milligram of protein) was [4][5][6][7] nmol/mg of protein (pure TAChR: 7.2 nmol/mg). CD8' T cell depletion.…”