Lymphocyte-Bound Complement Activation Products: Clues to SLE Pathogenesis

Allegheny-Singer Research Institute, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease, is characterized by aberrant immune responses including polyclonal lymphocyte activation, autoantibody production, immune complex formation, and complement activation. The consequences of complement activation with regard to lymphocyte function are largely unexplored. It has been reported that significant levels of complement activation products (CAPs), particularly C4d, are present on surfaces of erythrocytes, reticulocytes, and platelets of SLE patients. Recently, we discovered that C4d are also present, in conjunction with anti-lymphocyte autoantibodies (ALAs), on the surface of SLE T cells. This observation has led us to hypothesize that ALA-triggered complement activation may result in generation and deposition of C4d in situ on T cells. Binding of C4d to T cell surface molecules critical for cellular signaling and functioning may cause dysregulation of these cells, thereby initiating and/or augmenting pathogenic mechanisms of tissue damage in SLE. The proposed research is aimed at verifying this hypothesis through four specific aims. Specific Aim 1 is to characterize the CAP-bearing phenotype of T cells in SLE patients and elucidate the mechanism(s) causing this phenotype, focusing particularly on the ALA-dependent mechanism. Specific Aim 2 is to characterize ALAs and identify their candidate antigen targets. Specific Aim 3 is to investigate the impact of ALA and T cell-bound CAPs (T-CAP) on T cell function in SLE. Specific Aim 4 is to determine the correlation between ALA/T-CAP levels, T cell dysfunction, and SLE disease activity. The proposed studies will be accomplished by 1) flow cytometric analysis of T cells with regard to their phenotype and the mechanisms underlying the binding/deposition of ALAs/CAPs, 2) biochemical and immunological characterization of ALAs, 3) immunological and molecular analyses of the function of ALA/CAP-bearing T cells, and 4) statistical analysis of potential associations between the ALA/T-CAP phenotype and clinical course of SLE. The proposed research is expected to yield insightful clues to SLE pathogenesis that in turn may lead to identification of novel targets for therapeutic intervention.