IMMUNE RESPONSES IN LUPUS

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

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