Follicular helper T cells are required for systemic autoimmunity
Production of high-affinity pathogenic autoantibodies appears to be central to the pathogenesis of lupus. Because normal high-affinity antibodies arise from germinal centers (GCs), aberrant selection of GC B cells, caused by either failure of negative selection or enhanced positive selection by follicular helper T (T(FH)) cells, is a plausible explanation for these autoantibodies. Mice homozygous for the san allele of Roquin, which encodes a RING-type ubiquitin ligase, develop GCs in the absence of foreign antigen, excessive T(FH) cell numbers, and features of lupus. We postulated a positive selection defect in GCs to account for autoantibodies. We first demonstrate that autoimmunity in Roquin(san/san) (sanroque) mice is GC dependent: deletion of one allele of Bcl6 specifically reduces the number of GC cells, ameliorating pathology. We show that Roquin(san) acts autonomously to cause accumulation of T(FH) cells. Introduction of a null allele of the signaling lymphocyte activation molecule family adaptor Sap into the sanroque background resulted in a substantial and selective reduction in sanroque T(FH) cells, and abrogated formation of GCs, autoantibody formation, and renal pathology. In contrast, adoptive transfer of sanroque T(FH) cells led to spontaneous GC formation. These findings identify T(FH) dysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity.
|Authors||Linterman, M.A.; Rigby, R.J.; Wong, R.K.; Yu, D.; Brink, R.; Cannons, J.L.; Schwartzberg, P.L.; Cook, M.C.; Walters, G.D.; Vinuesa, C.G.|
|Publisher Name||J EXP MED|
|Published Date||2009-03-16 00:00:00|
|OpenAccess Link||https://publications.gimr.garvan.org.au/download.php?10200_10325/09 Linterman JEM561.pdf|