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T-cell recognition of muscle acetylcholine receptor subunits in generalized and ocular myasthenia gravis

From the Departments of Biochemistry and Pharmacology (Drs. Wang, Okita, and Conti-Fine), University of Minnesota, Twin Cities Campus, MN; and Department of Neurology (Dr. Howard), University of North Carolina at Chapel Hill, NC. *Previously known as Bianca M. Conti-Tronconi.

Address correspondence and reprint requests to Dr. Bianca Conti-Fine, University of Minnesota, Department of Biochemistry, 1479 Gortner Ave., St. Paul, MN 55108.

Objectives: Our purpose was to identify the muscle acetylcholine receptor (AChR) subunits recognized by autoimmune CD4⁺ T cells in myasthenia gravis(MG) and determine whether they differ in generalized (gMG) and ocular MG(oMG), and as gMG progresses.

Methods: We tested the proliferative response of blood CD4⁺ cells from 25 patients with gMG and four patients with oMG to synthetic peptides spanning the sequence of each subunit of human muscle AChR. We also investigated the antisubunit response of Th1 cells (a CD4⁺ subset frequently involved in autoimmune phenomena) using an enzyme-linked immunospot (ELISPOT) assay of antigen-induced secretion of interferon- by individual CD4⁺ cells.

Results: In gMG patients both the total CD4⁺ population and the Th1 subset recognized all AChR subunits to comparable extents. oMG patients recognized the AChR subunit minimally, and other subunits consistently and more strongly. gMG patients whose disease had lasted less than 5 years had lower antisubunit responses, and several of them did not recognize some AChR subunits; patients whose disease had lasted for 5 or more years had higher antisubunit responses and always responded to all AChR subunits.

Conclusions: CD4⁺ and Th1 responses in MG involve the entire AChR molecule. This likely results from spreading of the CD4⁺ sensitization to increasingly larger parts of the AChR as the disease progresses. The differential recognition of AChR subunits in oMG might be related to the preferential involvement of extrinsic ocular muscles, which express AChR containing the subunit.

Supported by NINCDS Grant NS23919 and by a Research Grant from the Muscular Dystrophy Association (to B.M.C.-F.). Dr. Wang was a recipient of a Neuromuscular Disease Research Fellowship from the Muscular Dystrophy Association.

Received May 8, 1997. Accepted in final form October 7, 1997.

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