Antibodies to acetylcholine receptor in parous women with myasthenia: evidence for immunization by fetal antigen. Export

@article{citeulike:956130, abstract = {The weakness in myasthenia gravis (MG) is mediated by autoantibodies against adult muscle acetylcholine receptors (AChR) at the neuromuscular junction; most of these antibodies also bind to fetal AChR, which is present in the thymus. In rare cases, babies of mothers with MG, or even of asymptomatic mothers, develop a severe developmental condition, arthrogryposis multiplex congenita, caused by antibodies that inhibit the ion channel function of the fetal AChR while not affecting the adult AChR. Here we show that these fetal AChR inhibitory antibodies are significantly more common in females sampled after pregnancy than in those who present before pregnancy, suggesting that they may be induced by the fetus. Moreover, we were able to clone high-affinity combinatorial Fab antibodies from thymic cells of two mothers with MG who had babies with arthrogryposis multiplex congenita. These Fabs were highly specific for fetal AChR and did not bind the main immunogenic region that is common to fetal and adult AChR. The Fabs show strong biases to VH3 heavy chains and to a single Vkappa1 light chain in one mother. Nevertheless, they each show extensive intraclonal diversification from a highly mutated consensus sequence, consistent with antigen-driven selection in successive steps. Collectively, our results suggest that, in some cases of MG, initial immunization against fetal AChR is followed by diversification and expansion of B cells in the thymus; maternal autoimmunity will result if the immune response spreads to the main immunogenic region and other epitopes common to fetal and adult AChR.}, address = {Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.}, author = {Matthews, I. and Sims, G. and Ledwidge, S. and Stott, D. and Beeson, D. and Willcox, N. and Vincent, A.}, citeulike-article-id = {956130}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/12379775}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=12379775}, issn = {0023-6837}, journal = {Lab Invest}, keywords = {anti-acetylcholine, autoantibody, myasthenia, receptor}, month = {October}, number = {10}, pages = {1407--1417}, posted-at = {2006-11-21 22:09:40}, priority = {2}, title = {Antibodies to acetylcholine receptor in parous women with myasthenia: evidence for immunization by fetal antigen.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/12379775}, volume = {82}, year = {2002} }

TY - JOUR ID - citeulike:956130 L3 - citeulike-article-id:956130 N2 - The weakness in myasthenia gravis (MG) is mediated by autoantibodies against adult muscle acetylcholine receptors (AChR) at the neuromuscular junction; most of these antibodies also bind to fetal AChR, which is present in the thymus. In rare cases, babies of mothers with MG, or even of asymptomatic mothers, develop a severe developmental condition, arthrogryposis multiplex congenita, caused by antibodies that inhibit the ion channel function of the fetal AChR while not affecting the adult AChR. Here we show that these fetal AChR inhibitory antibodies are significantly more common in females sampled after pregnancy than in those who present before pregnancy, suggesting that they may be induced by the fetus. Moreover, we were able to clone high-affinity combinatorial Fab antibodies from thymic cells of two mothers with MG who had babies with arthrogryposis multiplex congenita. These Fabs were highly specific for fetal AChR and did not bind the main immunogenic region that is common to fetal and adult AChR. The Fabs show strong biases to VH3 heavy chains and to a single Vkappa1 light chain in one mother. Nevertheless, they each show extensive intraclonal diversification from a highly mutated consensus sequence, consistent with antigen-driven selection in successive steps. Collectively, our results suggest that, in some cases of MG, initial immunization against fetal AChR is followed by diversification and expansion of B cells in the thymus; maternal autoimmunity will result if the immune response spreads to the main immunogenic region and other epitopes common to fetal and adult AChR. IS - 10 JF - Lab Invest SN - 0023-6837 AD - Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom. EP - 1417 TI - Antibodies to acetylcholine receptor in parous women with myasthenia: evidence for immunization by fetal antigen. VL - 82 SP - 1407 KW - anti-acetylcholine KW - autoantibody KW - myasthenia KW - receptor AU - Matthews, I AU - Sims, G AU - Ledwidge, S AU - Stott, D AU - Beeson, D AU - Willcox, N AU - Vincent, A PY - 2002/10// UR - http://view.ncbi.nlm.nih.gov/pubmed/12379775 ER -