Suppression of Experimental Autoimmune Myasthenia Gravis by Epitope-Specific Neonatal Tolerance to Synthetic Region α146-162 of Acetylcholine Receptor

Mohan Shenoy, Minako Oshima, M. Zouhair Atassi, Premkumar Christadoss

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70 Citations (Scopus)

Abstract

A gene conversion event between Ebb and Abb in the B6.C-H-2bm12 (bm12) strain, which alters three amino acids in the C-terminal half of the first domain of Abb (Ile-67 → Phe; Arg-70 → Gln; Thr-71 → Lys) resulted in resistance to experimental autoimmune myasthenia gravis (EAMG) pathogenesis. To study the effect of bm12 mutation on the T-cell responses to epitopes of acetylcholine receptor (AChR)-α subunit, C57BL6 (B6) and bm12 mice were primed with Torpedo californica AChR, and the profiles of T-lymphocyte proliferation were determined with 18 synthetic overlapping peptides encompassing the entire extracellular portion of the AChR-α subunit. The proliferative responses of AChR-primed bm12 lymphocytes were markedly reduced to two (α146-162 and α182-198) of the three AChR peptides (α111-126, α146-162, and α182-198) that are immunodominant in B6 mice. Thus, the Ab residues encompassing the region 67-71 determine the immunogenicity of two of the AChR-α subunit T-cell epitopes. To test the involvement of AChR-α chain epitopes within peptide α146-162 in EAMG pathogenesis, B6 mice were neonatally tolerized with soluble peptide α146-162, and subsequently immunized with AChR in complete Freund's adjuvant. Neonatal tolerance to AChR or to peptide α146-162 reduced the incidence of clinical myasthenia gravis and suppressed serum anti-AChR antibodies. This indicates the involvement of T-cell epitopes within AChR-α subunit region α146-162 in EAMG pathogenesis. Neonatal tolerance to peptide α146-162 could have caused specific clonal deletion, and/or clonal anergy, and/or recruited suppressor cells to prevent clinical EAMG. Presumably, epitope(s) with AChR α146-162, in the context of Ab encompassing region 67-71, stimulate specific T helper cells which interact with specific B cells to produce pathogenic antibodies, the primary culprit causing the end plate lesion in patients with myasthenia gravis.

Original languageEnglish
Pages (from-to)230-238
Number of pages9
JournalClinical Immunology and Immunopathology
Volume66
Issue number3
DOIs
StatePublished - Mar 1993
Externally publishedYes

Fingerprint

Autoimmune Experimental Myasthenia Gravis
Cholinergic Receptors
Epitopes
Peptides
T-Lymphocyte Epitopes
Myasthenia Gravis
Clonal Anergy
Clonal Deletion
T-Lymphocytes
Torpedo
Gene Conversion
Freund's Adjuvant
Antibodies
Helper-Inducer T-Lymphocytes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Immunology and Allergy
  • Immunology

Cite this

Suppression of Experimental Autoimmune Myasthenia Gravis by Epitope-Specific Neonatal Tolerance to Synthetic Region α146-162 of Acetylcholine Receptor. / Shenoy, Mohan; Oshima, Minako; Atassi, M. Zouhair; Christadoss, Premkumar.

In: Clinical Immunology and Immunopathology, Vol. 66, No. 3, 03.1993, p. 230-238.

Research output: Contribution to journalArticle

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abstract = "A gene conversion event between Ebb and Abb in the B6.C-H-2bm12 (bm12) strain, which alters three amino acids in the C-terminal half of the first domain of Abb (Ile-67 → Phe; Arg-70 → Gln; Thr-71 → Lys) resulted in resistance to experimental autoimmune myasthenia gravis (EAMG) pathogenesis. To study the effect of bm12 mutation on the T-cell responses to epitopes of acetylcholine receptor (AChR)-α subunit, C57BL6 (B6) and bm12 mice were primed with Torpedo californica AChR, and the profiles of T-lymphocyte proliferation were determined with 18 synthetic overlapping peptides encompassing the entire extracellular portion of the AChR-α subunit. The proliferative responses of AChR-primed bm12 lymphocytes were markedly reduced to two (α146-162 and α182-198) of the three AChR peptides (α111-126, α146-162, and α182-198) that are immunodominant in B6 mice. Thus, the Ab residues encompassing the region 67-71 determine the immunogenicity of two of the AChR-α subunit T-cell epitopes. To test the involvement of AChR-α chain epitopes within peptide α146-162 in EAMG pathogenesis, B6 mice were neonatally tolerized with soluble peptide α146-162, and subsequently immunized with AChR in complete Freund's adjuvant. Neonatal tolerance to AChR or to peptide α146-162 reduced the incidence of clinical myasthenia gravis and suppressed serum anti-AChR antibodies. This indicates the involvement of T-cell epitopes within AChR-α subunit region α146-162 in EAMG pathogenesis. Neonatal tolerance to peptide α146-162 could have caused specific clonal deletion, and/or clonal anergy, and/or recruited suppressor cells to prevent clinical EAMG. Presumably, epitope(s) with AChR α146-162, in the context of Ab encompassing region 67-71, stimulate specific T helper cells which interact with specific B cells to produce pathogenic antibodies, the primary culprit causing the end plate lesion in patients with myasthenia gravis.",
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