B-CELL ACTIVATION IN-VITRO BY HELPER T-CELLS SPECIFIC TO REGION ALPHA-146-162 OF TORPEDO-CALIFORNICA NICOTINIC ACETYLCHOLINE-RECEPTOR

We have previously mapped the T and B cell epitopes on the alpha-subun it of acetylcholine receptor (AChR) in human myasthenia gravis (MG) an d in experimental autoimmune MG-susceptible (C57BL/6 (86)) and nonsusc eptible mouse strains, In addition to regions recognized by both T and B cells, the AChR alpha-subunit has regions that are recognized solel y by T cells, An exclusive T cell epitope within residues alpha 146-16 2 of Torpedo californica (t), tAChR, plays an important role in experi mental autoimmune MC pathogenesis in 86 mice, To study its function, w e established, from tAChR-primed 86 mice, two t alpha 146-162-specific T cell lines (P14Th) which comprised Th2-type cells because they secr eted IL-4 but not IL-2, P14Th did not recognize the corresponding regi on on mouse (m) AChR (m alpha 146-162), They caused in vitro different iation of tAChR-primed 8 cells into plasma cells that secreted anti-AC hR Abs directed, in decreasing order, against the following tAChR alph a regions: t alpha 122-138 > t alpha 134-150 > t alpha 45-60 > t alpha 170-186 > t alpha 56-71, Little or no Ab response could be detected a gainst peptides t alpha 182-198 or t alpha 146-162 itself, The major e nhancement was in the Abs against region t alpha 122-150 (spanning the t alpha 122-138/t alpha 134-150 overlap) that is involved in ACh bind ing, These Abs cross-reacted completely with m alpha 122-150, the corr esponding region on mAChR, Therefore, t alpha 136-162-specific T cells , although unable to recognize m alpha 146-162, are nevertheless patho genic because they help B cells responding to a tAChR region that is c onserved in mAChR and involved in ACh binding, These Abs cross-react w ith the corresponding effector-binding region of mAChR, thereby disrup ting the normal physiologic function of the mouse receptor.