B-Cell superantigens: Definition and potential impact on the immune response

Abstract

Superantigens have been extremely helpful tools in exploring fundamental questions in immunobiology including mechanisms of cell activation, tolerance, and autoimmunity. Until recently, attention has been focused exclusive on T-cell superantigens. However, new data suggest that there are superantigens that directly activate B cells. By definition, these agents (1) stimulate a high frequency of B cells, (2) target B cells that have restricted usage of VH or VL family genes, and (3) bind to immunoglobulins outside the sites that bind conventional antigens. A candidate B-cell superantigen that has received considerable attention in this laboratory is staphylococcal protein A. This agent is best known to the immunologist because of its ability to bind to the Fc fragment of IgG. This binding has been localized to two alpha-helical structures on each of four or five homologous regions that comprise the extracellular domain of protein A. However, it is now clear that protein A contains a second site that binds to determinants on the Fab regions of certain immunoglobulins independently of their heavy-chain isotype. In man this so-called alternative site appears to bind only to immunoglobulins that utilize heavy-chain genes of the VH3 subfamily. In the mouse this type of binding is restricted to immunoglobulins using heavy chains belonging to the S107 and J606 VH families. In this review, we examine the growing list of microbial products that dominate B-cell superantigenic properties. Using staphylococcal protein A as a model for a B-cell superantigen, we consider the potential impact of this novel class of antigens on the immune response. We focus on the ability of B-cell superantigens to influence the expression of the B-cell repertoire. In addition, we consider the hypothesis that the interaction of a B-cell superantigen with its reactive serum immunoglobulins activates the classical complement cascade and thus represents a powerful stimulant of tissue inflammation.

Restrictive usage of monoclonal immunoglobulin λ light chain germline in POEMS syndrome

“…24 However, the higher R/S mutation ratio in the CDRs and retention of cysteine residues in FR1 and FR3, which were critical to structure, suggest that these specific light chains might interact with VEGF-related protein at FRWs but not CDRs like B-cell superantigen. 25 In conclusion, IGL-M protein in POEMS syndrome belongs to the V1 subfamily and is markedly restricted to a very limited number of germlines. Although exact mechanisms responsible for this syndrome are still unclear, these data suggest that the restricted use of IGL plays an important role in pathogenesis and may represent a new clinical entity.…”

Immunoglobulin Gene Mutations and Frequent Use of VH1-69 and VH4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma

“…A restricted usage of VH genes, as well as binding of an immunoglobulin outside the CDRs, which are the sites that bind conventional antigens, are characteristic aspects of B-cell superantigens that are supposed to directly activate B cells. 36 In particular, certain portions of the FRs seems to be important for superantigen binding and these would be preserved in a superantigen selection pressure. 37 Interestingly, staphylococcal enterotoxins A and D, that function as a human B superantigen, are able to rescue B cell-expressing VH3 and VH4 (including VH4-34) genes inducing cell survival in in vitro experiments.…”

Superantigens and nasal polyps

“…Studies, predominantly with SPA, have demonstrated that this superantigen influences the activity of B cells by binding the fragment, antigen-binding (Fab) region of human Igs, whose heavy chains are encoded by V (H) cluster III genes [47,56,57]. SAE A fails to induce Bcell proliferation and differentiation in the absence of T cells.…”

“…Although there have been conflicting reports on the superantigenic nature of these agents, a recent study has demonstrated that highly purified ETA and ETB induce selective polyclonal expansion of human T cells [46]. Studies of staphylococcal virulence factor, protein A, have suggested that this toxin directly influences the activity of a subset of B cells and leads to a T-cell-independent depletion of these cells in vivo [47,48]. Staphylococcal protein A (SPA) is known to bind preferentially to the VH3 family of Ig heavy-chain variable gene products.…”