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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI077591-03
Application #
7918943
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2008-09-25
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
3
Fiscal Year
2010
Total Cost
$327,443
Indirect Cost
Name
Allegheny-Singer Research Institute
Department
Type
DUNS #
033098401
City
Pittsburgh
State
PA
Country
United States
Zip Code
15212
Liu, Chau-Ching; Manzi, Susan; Ahearn, Joseph M (2014) Antilymphocyte autoantibodies generate T cell-C4d signatures in systemic lupus erythematosus. Transl Res 164:496-507
Borschukova, O; Paz, Z; Ghiran, I C et al. (2012) Complement fragment C3d is colocalized within the lipid rafts of T cells and promotes cytokine production. Lupus 21:1294-304
Liu, Chau-Ching; Manzi, Susan; Kao, Amy H et al. (2010) Cell-bound complement biomarkers for systemic lupus erythematosus: from benchtop to bedside. Rheum Dis Clin North Am 36:161-72, x
Liu, Chau-Ching; Ahearn, Joseph M (2009) The search for lupus biomarkers. Best Pract Res Clin Rheumatol 23:507-23
Liu, Chau-Ching; Kao, Amy H; Hawkins, Douglas M et al. (2009) Lymphocyte-bound complement activation products as biomarkers for diagnosis of systemic lupus erythematosus. Clin Transl Sci 2:300-8