CD40 and autoimmunity: the dark side of a great activator

Abstract

CD40 is a tumor necrosis factor receptor superfamily member expressed by immune and non-immune cells. CD40:CD154 interactions mediate T-dependent B cell responses and efficient T cell priming. Thus, CD40 is a likely candidate to play roles in autoimmune diseases in which activated T and B cells cause pathology. Diseases in which CD40 plays a pathogenic role include autoimmune thyroiditis, type 1 diabetes, inflammatory bowel disease, psoriasis, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This review discusses the role of CD40:CD154 interaction in human and mouse autoimmunity, human polymorphisms associated with disease incidence, and disrupting CD40:CD154 interactions as an autoimmune therapy.

Figure 1. Potential mechanisms by which CD40:CD154 interactions contribute to autoimmune disease

CD40 signaling may potentially contribute to autoimmune disease in several ways. 1) At the level of T cell selection in the thymus, potentially allowing autoreactive T cell clones to escape deletion. 2) In the secondary lymphoid organs, where T cells are primed by B cells or other APC. 3) Within the target tissue, where CD40 signaling leads to production of pro-inflammatory cytokines and chemokines which contribute to tissue destruction and inflammatory cell influx.