Central targets of the humoral immune response in systemic lupus? erythematosus are small nuclear ribonucleoprotein particles (snRNPs) and? chromatin (DNA and histones). MRL/Mp-lpr/lpr mice (MRL/lpr mice) and? MRL/Mp-+/+ mice (MRL-+/+mice) develop a disease which resembles SLE in? humans, including the production of affinity-matured IgG autoantibodies to? snRNPs and to chromatin. In MRL mice, B cells that produce anti-snRNP and? anti-chromatin antibodies appear to require the presence of the self? antigens for activation and affinity maturation, although direct evidence? for this notion is lacking. These B cell responses also require T cell? help, but the precise mechanisms of activation of such T cells in vivo, and? their antigenic specificity, are unknown/? The hypothesis to be tested is that autoreactive T cells, specific for? peptides of snRNPs, are present in the MRL repertoire, and that they? provide cognate help for synthesis of anti-snRNP antibodies. Moreover,? production of these autoantibodies by B cells requires intact particles as? antigens, and certain proteins of these particles are immunodominant.? These beliefs are supported in part by recent observations that snRNP-? specific, autoreactive T cells are present in the normal murine repertoire,? and that they can be activated to provide help for IgG anti-snRNP antibody? production. snRNP-specific T cells also appear to be present in the? autoimmune MRL repertoire, and anti-snRNP antibody production in these mice? diversifies in patterns that suggest a reliance upon intact snRNPs as? autoantigens. To address the hypothesis, T cells that proliferate in? response to self snRNPs will be sought from MRL-+/+ mice, and T cell? hybrid clones derived from these mice will be assessed for their ability to? recognize self snRNPs. Next, T cell lines capable of providing B cell help? for in vitro autoantibody synthesis will be derived from these animals.? Third, MRL-+/_ mice deficient in the CD40 ligand (CD40L; gp39) will be? generated to determine if cognate T-B interactions are necessary for? autoantibody production. These animals will be compared to MRL-+/+ mice? treated with anti-CD40L. Finally, the capability of autoreactive and? control T cell lines to provide help for anti snRNP antibody synthesis in? vivo in young MRL-+/+ mice and in MRL-+/+ mice deficient int eh CD40L will? be determined, and the ability of T cell lines specific for a defined snRNP? peptide to provide help for the array of anti-snRNP antibodies will be? assessed.? These experiments will address three questions. First, do snRNP-specific? autoreactive T cells reside in the MRL repertoire, and if so, do they drive? autoantibody production? Is expression of CD40L necessary for this? synthesis; i.e., does autoantibody production require cognate T-B? interactions: Finally, can T cells specific for a single snRNP peptide? drive autoantibodies to the array of snRNP proteins, analogous to that seen? in spontaneous disease? The long term goal of this work, after carefully? defining the characteristics of snRNP-specific T cells as outlined above,? is to determine how autoreactive T cells are spontaneously activated and? regulated in normal and autoimmune environments.?
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