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-subunit of acetylcholine receptor (AChR) in human myasthenia gravis (MG) and in experimental autoimmune MG-susceptible (C57BL/6 (B6)) and nonsusceptible mouse strains. In addition to regions recognized by both T and B cells, the AChR alpha-subunit has regions that are recognized solely by T cells. An exclusive T cell epitope within residues alpha 146-162 of Torpedo californica (t), tAChR, plays an important role in experimental autoimmune MG pathogenesis in B6 mice. To study its function, we established, from tAChR-primed B6 mice, two t alpha 146-162-specific T cell lines (P14Th) which comprised Th2-type cells because they secreted IL-4 but not IL-2. P14Th did not recognize the corresponding region on mouse (m) AChR (m alpha 146-162). They caused in vitro differentiation of tAChR-primed B cells into plasma cells that secreted anti-AChR Abs directed, in decreasing order, against the following tAChR alpha 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 against peptides t alpha 182-198 or t alpha 146-162 itself. The major enhancement 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 binding. These Abs cross-reacted completely with m alpha 122-150, the corresponding region on mAChR. Therefore, t alpha 146-162-specific T cells, although unable to recognize m alpha 146-162, are nevertheless pathogenic because they help B cells responding to a tAChR region that is conserved in mAChR and involved in ACh binding. These Abs cross-react with the corresponding effector-binding region of mAChR, thereby disrupting the normal physiologic function of the mouse receptor.
Rosenberg
J S
JS
Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.
Oshima
M
M
Atassi
M Z
MZ
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D000918:Antibody Specificity; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D018920:Coculture Techniques; D003429:Cross Reactions; D017077:Culture Media, Conditioned; D000939:Epitopes / Q000276:immunology*; D005260:Female; D007114:Immunization; D007376:Interleukin-2 / Q000032:analysis; D015847:Interleukin-4 / Q000378:metabolism; D008211:Lymphocyte Cooperation; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D010950:Plasma Cells / Q000276:immunology; D011978:Receptors, Nicotinic / Q000276:immunology*; D016415:Sequence Alignment; D013045:Species Specificity; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014101:Torpedo / Q000276:immunology
D017077:Culture Media, Conditioned; D000939:Epitopes; D007376:Interleukin-2; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D015847:Interleukin-4