A new twist on superantigen-activated autoimmune disease
Andrew L. Mason, Doaa Waly, Mohammed S. Osman
Andrew L. Mason, Doaa Waly, Mohammed S. Osman
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Commentary

A new twist on superantigen-activated autoimmune disease

Abstract

Superantigen-induced (Sag-induced) autoimmunity has been proposed as a mechanism for many human disorders, without a clear understanding of the potential triggers. In this issue of the JCI, McCarthy and colleagues used the SKG mouse model of rheumatoid arthritis to characterize the role of Sag activity in inflammatory arthritis by profiling arthritogenic naive CD4+ T cells. Within the diseased joints, they found a marked enrichment of T cell receptor–variable β (TCR-Vβ) subsets that were reactive to the endogenously encoded mouse mammary tumor virus (MMTV) Sag. Arthritis was improved using reverse transcriptase inhibitors. Moreover, depletion of MMTV Sag-activated TCR-Vβ subsets affected the ability of transferred activated CD4+ T cells to induce disease in mice with severe combined immunodeficiency (SCID). Further virological studies should determine whether endogenous or exogenous MMTV is necessary or sufficient to trigger inflammatory arthritis in the SKG model.

Authors

Andrew L. Mason, Doaa Waly, Mohammed S. Osman

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Figure 1

The SKG mouse model of RA supports an endogenous and/or exogenous MMTV Sag-driven autoimmune response.

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The SKG mouse model of RA supports an endogenous and/or exogenous MMTV S...
T cells develop in the thymus and progress through positive and negative selection. (A) In WT BALB/c mice, thymocytes that react with endogenous MMTV encoded Sags are actively deleted. (B) In contrast, the SKG mouse model with a hypomorphic ZAP-70 protein results in positively selected Sag-reactive and autoimmune T cells that have impaired signaling downstream of the TCR/peptide-MHC complex. (C) Sags may promote arthritis via two potential models: (i) In the periphery, endogenously encoded Mtv Sag activates cognate TCR-Vβ subsets, and these autoimmune naive arthritogenic CD4+ T cells home to SKG joints to initiate disease; or (ii) exogenous MMTV arises as a result of resurrected endogenous retroelements in the setting of immunodeficiency and replicates in proliferating cognate TCR-Vβ T cells activated by viral Sags. These lymphocytes home to infect joints, where autoimmune and CD8+ cytotoxic T cell responses to MMTV instigate arthritis. pMHC, peptide MHC.