Human monoclonal natural autoantibodies against the T‐cell receptor inhibit interleukin‐2 production in murine T cells

Abstract

SUMMARYNatural autoantibodies (NAAbs) specific for the T-cell receptor (TCR) are present in all human sera, but individuals with rheumatoid arthritis (RA) generally produce higher titres of immunoglobulin M (IgM) isotype autoantibodies (AAbs) against Vb TCR epitopes. To investigate possible correlations between the specificity of such AAbs and their role in immunomodulation, we generated seven B-cell hetero-hybridomas, secreting monoclonal IgM NAAbs, from the synovial tissue and peripheral blood of patients with RA. Here we report three anti-TCR monoclonal autoantibodies (mAAbs) -OR2, OR5 and Syn 2H-11 -with the ability to bind subsets of murine T cells, including the ovalbumin-specific DO-11.10 clone. These antibodies did not induce apoptosis in vitro, but prevented interleukin-2 (IL-2) production by antigen-specific T cells. These findings suggest an immunomodulatory function for NAAbs to TCR V-region epitopes and serve as the foundation for testing human anti-TCR mAAbs in animal models with the eventual goal of using them as therapeutic agents in human disease.

Protective autoantibodies: Role in homeostasis, clinical importance, and therapeutic potential

“…Anti-TCR antibodies may constitute another significant level of regulation, but their occurrence and regulatory role have been poorly investigated. Natural autoantibodies specific for the TCR are produced spontaneously at low levels in some healthy human sera, and at higher levels in patients with RA and SLE (34).…”

Structural, antigenic and evolutionary analyses of immunoglobulins and T cell receptors

“…The murine monoclonals were synergistic with bacterial superantigens selective to different Vb subsets (Dehghanpisheh and Marchalonis, 1997). The human molecules did not induce apoptosis in T cells to which they bound, but inhibited the antigendriven production of the pro-inflammatory cytokine IL-2 (Robey et al, 2002b). The monoclonal antibodies used in these studies were of the IgM isotype, but IgG antibodies are normally produced as demonstrated by their presence in intravenous immunoglobulin preparations (Marchalonis et al, 1992b), by the finding that some human IgG myeloma proteins bind to T cell receptor V domain epitopes (Marchalonis et al, 1997a) and by our generation of IgG mAbs from peripheral B cells of individuals with SLE (Adelman, Schluter and Marchalonis, unpublished observations).…”

FcγRII and multi-system autoimmune disease

“…FcγRIIb also down-regulated autoimmune plasma cell activation signals after cross-linking with activating FcR [26]. Considering that low level autoimmunity may well be required to maintain the diversity of adaptive immune responses [38,73], the balance between activation and inhibition of FcR functions is crucial in maintaining "tolerance" to self-antigens [45] and preventing inflammatory autoimmune disease. Animal models were particularly useful for investigating the role of FcγRIIb in auto-immunity and are discussed in more detail below.…”