MRL-lpr/lpr and MRL-+/+ mice develop a disease that resembles human SLE, including the production of autoantibodies to small nuclear ribonucleoprotein particles (snRNPs) and to chromatin (DNA and histones), and development of immune-complex glomerulonephritis. Current data indicates that disease-specific and pathogenic autoantibodies in murine and human lupus undergo somatic mutation and affinity maturation. These findings have given rise to the paradigm that autoreactive B cells in lupus require cognate, presumably autoantigen-specific, and contact- dependent, alphabetaT cell help. To further investigate the role of conventional alphabeta T cell help in autoantibody production, alphabeta T cell-deficient MRL-lpr/lpr mice and MRL-lpr/lpr mice that lack CD40 ligand (CD40L), an essential T cell signal for initiating immunoglobulin synthesis and class switching by B cells, have been generated. Notably, these animals developed hypergammaglobulinemia and IgG anti-snRNP antibodies. Certain ones (alphabeta T cell-deficient MRL-lpr/lpr mice) also developed renal immune deposits and delayed renal insufficiency; however, both the alphabeta T cell- and CD40L-deficient MRL mice lacked high titer, high-affinity anti-DNA antibodies and overt, early nephritis typical of wild type MRL disease. Based upon these findings, hypotheses are offered that autoantibody production in murine lupus does not absolutely depend upon conventional, alphabeta T cell help, and that the MRL phenotype is a consequence of both alphabeta cell-dependent and alphabeta T cell-independent mechanisms. To address these hypotheses, genetic approaches and reconstitution experiments will be used to determine the respective requirements for conventional alphabeta and non- conventional B cell help for autoantibody production and renal injury in MRL lupus. The features of alphabeta T cells that contribute to the genesis of the wild type MRL phenotype will also be assessed. Finally, the autoantibodies that arise in mice lacking conventional T cell help will be characterized, and their in vivo pathogenicity assessed.
Showing the most recent 10 out of 53 publications
