Inhibition of soluble antigen-induced T cell proliferation by warm-reactive antibodies to activated T cells in systemic lupus erythematosus.

Abstract

bstract. One of the fundamental immunologic characteristics of systemic lupus erythematosus (SLE) is a depressed T cell proliferative response to various specific and nonspecific stimuli. Both intrinsic cellular defect(s) and inhibitory influences of humoral factors, e.g., antilymphocyte autoantibodies or immune complexes, have been postulated to underly this functional abnormality. Because patient serum can induce SLE-like T cell dysfunction in normal cells, an extrinsic mechanism is probably responsible, but the nature and site of action of this humoral activity has not been defined. This laboratory recently described a novel antibody specific for activated T cells in SLE, which raised the possibility that suppression of T cell proliferation by SLE serum involved antibodies directed to surface determinants expressed during the process of activation. In experiments to examine this concept further, relatively warm-reactive antibodies to T cell blasts were found to inhibit strongly the well-characterized T cell response to tetanus toxoid. These antibodies were distinct from conventional cold-reactive IgM antibodies to resting T cells, which exhibited little inhibitory activity. Inhibition involved noncytotoxic effects on early activation events at the level of the responding T cell, which markedly reduced the expression of receptors for interleukin 2. Inhibitory effects on antigen-pulsed macrophages or on T cells already committed to proliferate were not demonstrable. Anti-T blast antibodies were characteristic of active SLE and were detected only occasionally in Address reprint requests to Dr. Winfield.

Cell‐type specificity of anti‐CD45 autoantibodies in systemic lupus erythematosus

“…First, a combination of absorption and elution experiments demonstrate that IgM anti-CD45 autoantibodies in SLE react with native CD45 on the surface of viable cells. This observation suggests that SLE autoantibodies to CD45 potentially could mimic natural ligands of CD45 and anti-CD45 MAb in stimulating or inhibiting phosphatase activity, a hypothesis consistent with earlier data showing that SLE antilymphocyte autoantibodies inhibit early-phase activation events in the T cell proliferative response to tetanus toxoid (43). Second, the specificity of autoantibodies in this system exhibits considerable variability for CD45 purified from lymphocytes of different cell types and in different stages of activation.…”

“…Investigators at our laboratory are attempting to determine whether autoantibodies to CD45 have the capacity to be comitogenic in this manner or, alternatively, to inhibit T cell responses, as has been shown previously both for anti-CD45 MAb and for IgM antilymphocyte autoantibodies to an as-yet-undefined antigen(s) on activated peripheral T cells (43). Preliminary data in this regard suggest that anti-CD45 autoantibodies in SLE can inhibit T cell activation events, such as ~21'"" activation (50).…”

Are anti-ribosomal P protein antibodies a type of anti-lymphocyte antibody?

“…Thus, reactivity of T cells to IgM ALAB was shown to be dependent primarily on the presence of antigen(s) that are shared by CD4 + and CD8 + subsets, with a superimposed specificity for an additional antigen(s) expressed on CD4 + T cells [7]. Activated T cells, which exhibit a higher density of many surface membrane antigens than do resting cells and also express neoantigens, were found to be special targets of such autoantibodies [8] Most patients with SLE express IgM ALAB, which vary in titre with disease activity status in the same fashion as anti-dsDNA autoantibodies [6,20]. This association with disease flares and lymphopenia forms one line of evidence for a potential role of IgM ALAB in T cell depletion and cellular immune dysfunction in SLE.…”

“…Their multivalency, together with the local density of reactive antigens on the cell surface, confers a capacity for a variety of immunoregulatory and non-specific physiologic roles in the immune system and in autoimmune disease [21]. Although still poorly understood, certain evidence has been obtained for several potential mechanisms by which this could occur: elimination of lymphocytes by complement-mediated lysis [20] and/or opsonization; modulation of surface determinants [22]; interaction with soluble products of activated cells [23,24]; and up-regulation or down-regulation by cross-linking cell surface receptors [8].Of the various IgM ALAB targets listed above, CD45 is of special interest. CD45 is an unusually abundant transmembrane protein expressed on lymphocytes and other haematopoietic cells as a series of isoforms.…”

“…Thus, reactivity of T cells to IgM ALAB was shown to be dependent primarily on the presence of antigen(s) that are shared by CD4 + and CD8 + subsets, with a superimposed specificity for an additional antigen(s) expressed on CD4 + T cells [7]. Activated T cells, which exhibit a higher density of many surface membrane antigens than do resting cells and also express neoantigens, were found to be special targets of such autoantibodies [8]. Considerable information also has accrued concerning IgM ALAB target antigens: IL-2 receptor [9]; b 2 -microglobulin [10,11]; HLA class I heavy chains [12]; a DR framework epitope [13]; IgD, which functions as an antigen receptor on B cells [14]; B and T cell membrane glycosphingolipids [15]; CD45 [16][17][18]; and synthetic T cell receptor (TCR) peptides [19].…”