A Role for BAFF Receptor (BAFF-R; CD268) and Its Ligand Variant(s) in Early-Onset Myasthenia Gravis Thymus (P2.082)

OBJECTIVE This work aims to investigate BAFF-R expression on ex vivo thymocytes during maturation to uncover a role of BAFF signalling in intrathymic T cell B cell homeostasis in Myasthenia gravis thymus. BACKGROUND In the thymus of autoimmune Myasthenia gravis (MG) patients expression of B-Cell Activating Factor (BAFF) is described on macrophages and lymphocytes. Early-onset MG is a T-cell mediated autoimmune disease characterized by thymus conversion into a secondary lymph organ containing active germinal centers generating autoantibodies against AChR. Beside BAFF affinity to three receptors (BAFF-R, BCMA, TACI) largely expressed on B cells and on small subsets of activated T cells, only BAFF-R is unique for BAFF. As a co-stimulator BAFF influences T cell differentiation by modulation of cytokine profiles of T helpers in secondary lymph organs. Cleavage and multimerization of BAFF molecules lead to functional cytokine-like soluble BAFF, which was found to be enriched in sera of MG patients and other T cell mediated autoimmune diseases. In mouse and in human cell lines a splice variant ΔBAFF was identified to associate with “active” BAFF leading to reduction of BAFF membrane exposition and subsequently to less BAFF release. METHODS Thymocytes from untreated MG patients (EOMG*) were isolated and analyzed by flow cytometry according to published methods. Transcript detection for baff was performed by gene specific RT-PCR. RESULTS BAFF-R surface expression on ex vivo CD3+ thymocytes from untreated EOMG* patients is increased compared to healthy donors. During thymocyte maturation relative proportion of BAFF-R+ immature thymocytes increased along upcoming CD27 expression in the double positive (DP) and CD4+ single positive (CD4SP) compartment. On the molecular level immature thymocytes are sources for both BAFF-R and concurrently for variants of its ligand BAFF. CONCLUSIONS The data suggest a self-regulating role of BAFF signaling in regulation of early thymocyte maturation and for intrathymic T cell and B cell homoeostasis. Disclosure: Dr. Putz has nothing to disclose. Dr. Dobold has nothing to disclose. Dr. Stelmach has nothing to disclose. Dr. Schlegel has nothing to disclose. Dr. Happel has nothing to disclose. Dr. Oertel has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals Inc., Cephalon, Merck & Co. Inc., Merck Sharp & Dohme Ltd., Merck Serono, Mundipharma, Novartis, Schwarz Pharma, Neuroscience /UCB Pharma, Pfizer Inc., Synovia, Teva Neuroscience, and Desitin. Dr. Oertel holds stock and/or stock options in Roche Diagnostics Corp. which sponsored research in which Dr. Oertel was involved as an investigator. Dr. Oertel has received research support from UCB Pharma, Teva Neuroscience, International Parkinson Foundation, and the Michael J Fox Foundation. Dr Seipelt has received personal compensation for activities with Biogen Idec, Genzyme Corp. and Novartis. Dr Eienbroker has received personal compensation for activities with Biogen Idec, Novartis, and Temmler Pharma. Dr. Tackenberg has received personal compensation for activities with Bayer Pharmaceuticals Corp., Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Tackenberg has received research support from Bayer Pharmaceuticals Corp., Biogen Idec, and Novartis.