Evidence for multiple mechanisms of polyclonal T cell activation in murine lupus.
Individuals with systemic autoantibody-mediated diseases such as lupus have polyclonal T and B cell activation. Yet, autoantibody production is restricted to certain autoantigens. The mechanisms underlying this phenomenon remain unclear. We propose three potential mechanisms by which autoreactive helper T cell responses diversify to become polyclonal, yet are restricted to certain antigens. First, using a model where self-Ig peptides spontaneously activate T cells and modulate disease in lupus mice, we demonstrate that the numbers of autoantibody-augmenting T helper peptides increased across the Ig molecule as mice aged ("intramolecular determinant spreading"). Secondly, a single T cell hybridoma established from a (NZB x NZW)F1 mouse immunized with one self-Ig peptide recognized several Ig-derived determinants, which had little sequence homology with the immunizing peptide. Such determinant degeneracy can lead to polyclonality. To explore a mechanism for restriction to certain autoantigens, a protein database search was done for homologies with sequences of selected stimulatory Ig peptides. Identical sequences of such determinants were not found in murine proteins other than Ig. These occurred infrequently in nonautoantibody Ig, but quite commonly in lupus-related autoantibodies such as antibodies to DNA, cardiolipin, and erythrocytes. Thus, determinant spreading and degenerate recognition in T cells coupled with recurring use of T cell determinant sequences among autoantibodies result in polyclonality that is restricted to certain autoantigens.
Singh
R R
RR
Autoimmunity and Tolerance Laboratory, Department of Medicine, UCLA, Los Angeles, California 90095, USA. rasingh@med1.medsch.ucla.edu
Hahn
B H
BH
Tsao
B P
BP
Ebling
F M
FM
D000375:Aging; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D004247:DNA / Q000276:immunology; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D007136:Immunoglobulins / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D000097682:Lamin B Receptor
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D004247:DNA; D007074:Immunoglobulin G; D007136:Immunoglobulins; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor