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Cryptic epitopes on the nicotinic acetylcholine receptor are recognized by autoreactive CD4+ cells
M Bellone1, N Ostlie, P Karachunski
1Department of Biochemistry, College of Biological Sciences, University of Minnesota, St. Paul 55108.
Journal of Immunology (Baltimore, Md. : 1950)
|July 15, 1993
Summary
This study identifies cryptic CD4+ epitopes on the Torpedo nicotinic acetylcholine receptor (TAChR) involved in experimental autoimmune myasthenia gravis. These findings reveal new targets for understanding autoimmune responses to TAChR.
Area of Science:
- Immunology
- Neuroimmunology
- Autoimmunity
Background:
- Experimental autoimmune myasthenia gravis (EAMG) is an animal model for myasthenia gravis, often induced by Torpedo nicotinic acetylcholine receptor (TAChR).
- Understanding the specific epitopes of TAChR that trigger autoimmune responses is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the presence and characteristics of cryptic CD4+ T-cell epitopes on the TAChR molecule.
- To explore the relationship between these cryptic epitopes and autoreactive CD4+ T-cells in the context of EAMG.
Main Methods:
- C57BL/6 mice were immunized with native or denatured TAChR, or synthetic peptides representing TAChR subunits.
- CD4+ T-cells were isolated and challenged in vitro with overlapping synthetic peptides to identify recognized epitopes.
- Dose-dependent sensitization of CD4+ T-cells in vivo was assessed using varying peptide concentrations.
Main Results:
- Initially, only three epitopes on the TAChR alpha subunit were consistently recognized, with T alpha 150-169 being immunodominant.
- Immunization with peptide pools revealed additional cryptic epitopes on TAChR alpha, gamma, and delta subunits that elicited cross-reactivity with mammalian sequences.
- Sensitization to specific cryptic epitopes (T gamma 120-139, T delta 301-320, T delta 121-140) led to cross-reactivity with autologous sequences, and in vitro TAChR processing generated only two cryptic epitopes.
Conclusions:
- Cryptic epitopes on TAChR, particularly on gamma and delta subunits, can be recognized by CD4+ T-cells and contribute to autoimmune responses in EAMG.
- The dose of peptide immunization affects CD4+ T-cell sensitization, with comparable responses observed for both immunodominant and cryptic epitopes.
- These findings highlight the importance of cryptic epitopes in the pathogenesis of autoimmune diseases targeting the nicotinic acetylcholine receptor.