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Numerous cell types and molecules influence inflammation. The ideal scenario would be the discovery of a biomarker ‘master switch’, affecting many of the control elements that drive the inflammatory process during pathologies. A master switch would extend our understanding of the disease process and provide an easy means of controlling inflammation. While such a master switch may not exist, growing experimental evidence suggests that CD40 plays a substantial, multi-faceted role in inflammation. This 45 kDa type 1 membrane protein is a cell surface receptor that was originally discovered on the surface of B lymphocytes [1]. At this time it was described as inducing antibody class switching, a process that allows the body to produce the wide array of immunoglobulins necessary for immune protection and, in terms of autoimmunity, is necessary for the generation of autoantibodies. Autoantibodies are detected in numerous classical autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes. Indeed, the presence of more than one type of autoantibody can be, and often is, a decisive diagnostic component for each of these diseases. Mechanistically, autoantibodies contribute to disease pathology, thus providing the first link between CD40 and disease pathology. The role of CD40 in inflammatory processes is not confined to B cell function, with a greater degree of involvement implicated by the finding that other antigenpresenting cells (APCs), including macrophages and dendritic cells (DCs), express CD40 [2, 3]. APCs form part of the innate, rather than the adaptive, arm of the immune system, but, importantly, CD40 engagement on macrophages induces the production of pro-inflammatory cytokines, including TNF-α, IL-6 [2] and IL-1β [4]. CD40 engagement on DCs results in ‘licensing’, which is needed for DC–T cell interactions. Specifically, CD40-licensing of DCs endows these cells with the ability to appropriately co-stimulate CD4 and CD8 T cells [5]. Consequently, blockade of the interaction between DCs and T cells inhibits T cell responses to viruses and other exogenous antigens [6]. A new insight into the part played by CD40 in inflammation was provided by the identification of a unique T cell subset that expresses CD40, referred to as Th40 cells [7–10]. These CD40 T cells can give rise to pathogenic effector T cells [8–11], which are capable of altering receptor expression on peripheral T cells. This has significant implications for autoaggressive T cell generation, as the newly generated TCR molecules are not subject to central tolerance. In addition, CD40 is a highly effective co-stimulus for Th40 cells [12, 13]. In fact, for pathogenic, autoaggressive Th40 cells, CD40 provides stronger co-stimulation than CD28, inducing the production of pro-inflammatory cytokines such as TNF-α, interferon-γ and IL-6 production [11–13]. In another twist, CD40 has proved to be far more ubiquitously expressed than was originally anticipated. Expression on endothelial cells, smooth muscle cells, astroglial and microglial cells has been documented [14], and now, in this issue of Diabetologia, Poggi et al. demonstrate another fascinating result—that CD40 is Diabetologia (2009) 52:997–999 DOI 10.1007/s00125-009-1357-0

The co-evolution of our understanding of CD40 and inflammation