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¹ Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
² Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
³ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
⁴ Department of Immunology and ⁵ Department of Renal Medicine, The Canberra Hospital, Canberra, ACT 2605, Australia
⁶ Australian National University Medical School, Canberra, ACT 2605, Australia

CORRESPONDENCE Carola G Vinuesa: carola.vinuesa{at}anu.edu.au

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.

© 2009 Linterman et al.
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