RESTING B-CELL FROM AUTOIMMUNE LUPUS-PRONE NEW-ZEALAND BLACK AND (NEW-ZEALAND BLACK X NEW-ZEALAND WHITE)F-1 MICE ARE HYPER-RESPONSIVE TO T-CELL-DERIVED STIMULI

To determine whether B cells from New Zealand Black (NZB) and (New Zea land Black x New Zealand White)F-1(NZB/W) mice possess intrinsic defec ts that lead to altered immune responsiveness, we purified resting B c ells from these mice and compared their surface phenotype and function with those of resting B cells isolated from BALB/c and DBA/2 nonautoi mmune mouse strains. Flow cytometric analysis of freshly isolated rest ing B cells revealed that NZB and NZB/W resting B cells are convention al B2-type cells similar to their nonautoimmune counterparts. Despite this, resting B cells from young NZB and NZB/W mice express lower leve ls of CD23 on their surface and aberrant levels of intracellular IgM. Upon stimulation, resting B cells from young NZB and NZB/W mice demons trate increased proliferation, IgM secretion, or enhanced expression o f constimulatory molecules in response to a variety of different T cel l-derived stimuli, including cytokines and signals generated through C D40. Therefore, B cell hyper-responsiveness to T cell stimuli is immun odominant or codominant in NZB/W mice. Taken together, our results sug gest that intrinsic B cell hyper-responsiveness may play a role in the pathogenesis of autoimmune disease in NZB and NZB/W mice. The increas ed clonal expansion of these B cells together with increased Ig produc tion and enhanced costimulatory capacity serve to amplify the immune r esponse. In the context of normal but incomplete T cell tolerance, B c ell hyperresponsiveness to the limited signals provided by partially t olerant T cells may be sufficient to yield an autoantibody response.