EFFECTS OF THE LPR MUTATION ON ELIMINATION AND INACTIVATION OF SELF-REACTIVE B-CELLS

Mice homozygous for the lymphoproliferation (lpr) mutation, which disr upts expression of the Fas cell surface molecule, develop an autoimmun e syndrome with a spectrum of autoantibodies resembling human SLE. It is not known how the loss of Fas leads to autoantibody production. To study the fate of autoreactive B cells in lpr/lpr mice, C57BL/6 (B6) s train transgenic mice expressing hen egg lysozyme (HEL) as a model aut oantigen in soluble or membrane-bound forms and carrying HEL-specific Ig (Ig) transgenes were mated onto the congenic B6-lpr/lpr background. Despite the absence of Fas, elimination of self-reactive lpr/lpr B ce lls recognizing membrane-bound autoantigen occurred as efficiently as in autoreactive B cells bearing the wild-type (+/+) Fas gene. Function al inactivation of autoreactive B cells binding soluble HEL also occur red normally in most young lpr/lpr animals. Nevertheless, breakdown of B cell tolerance to soluble lysozyme occurred in one of eight young l pr/lpr animals and in four of seven old animals with lymphadenopathy. Interestingly, the presence of the rearranged Ig transgenes markedly d elayed the onset of lymphadenopathy. These results demonstrate that Fa s is not an essential molecule in the biochemical pathways mediating a utoreactive B cell elimination or inactivation. The breakdown of toler ance observed in a considerable fraction of older animals nevertheless confirms that autoantibody production in this model of SLE involves a defect in active censoring of autoreactive B cells. The possible basi s for that defect is discussed.