The immune system has evolved to distinguish self from non-self, and to identify and eliminate foreign invaders that pose a danger to the host. However, the destructive power of the immune system is sometimes directed against host molecules and organs, or against harmless foreign substances, leading to autoimmunity and allergic diseases. Most autoimmune diseases arise from complex interactions of environmental and genetic factors. Nevertheless, a common theme to autoimmunity is that cells and molecules that normally function to combat infection are regulated inappropriately, leading to tissue damage. Hence, a central challenge in autoimmunity research is to identify the cell types and molecules whose aberrant function promotes the development of particular disease states. Because intra- and inter-cellular communication impacts immune regulation at myriad levels, many investigators have chosen to focus on cellular signal transduction, defined as the mechanisms by which cells translate extracellular signals into altered cell behavior. Changes in the function of individual receptors or intracellular signaling molecules can have profound effects on immune cell development and function, leading to loss of self-tolerance or generalized inflammatory conditions.
This special issue of Autoimmunity is devoted to a set of review articles describing various aspects of signal transduction in the context of autoimmune disease states. The articles are written by a group of leading experts in the field, and represent a diverse view of signal transduction events from the receptor level to the nucleus. The general focus is on T and B lymphocytes and dendritic cells, cell types that are crucial to most autoimmune diseases.
The compendium of reviews starts at the “cell surface”. Lawrence Kane describes how TIM family proteins are emerging as important regulators of T cell function and autoimmunity. TIM genes are chromosomally linked and polymorphisms in this locus are associated with autoimmune and other diseases. Tatyana Tarasenko, Jonathan Deane and Silvia Bolland follow with a review focusing on the inhibitory IgG receptor FcγRIIB. This receptor is critical for fine-tuning antibody responses and loss of FcγRIIB in mice produces a lupus-like syndrome that is strain-dependent, offering an opportunity to investigate complex genetics of autoimmunity in an animal model. The next two reviews examine receptor-signaling mechanisms that regulate the induction of lymphocyte anergy. Francis Conrad and John Cambier discuss B cell anergy and how the interplay between the B cell receptor and other receptors such as CD19, CD22, TLR9 and the BAFF receptor determine whether B cells enter the anergic state. Paul Zarek and Jonathan Powell describe emerging evidence that extracellular adenosine, acting through the A2A receptor, inhibits T cell effector function. This article considers the possibility that adenosine A2A receptor signaling regulates T cell anergy.
The next three reviews deal with signaling proteins acting in the cytoplasm to control lymphocyte activation. Jean Oak and David Fruman review the role of phosphoinositide 3-kinase (PI3K) in lymphocyte signaling. They discuss how a fine balance of PI3K signaling is essential for proper immune regulation, with too much or too little output from this pathway leading to autoimmunity. Martina Gatzka and Craig Walsh discuss apoptotic signal transduction in T cells. This review describes the mechanisms that control apoptosis, how these molecules impact T cell tolerance and homeostasis, and how autoimmunity develops when certain apoptotic signaling pathways are disrupted. Tomas Mustelin and colleagues (Torkel Vang, Ana Miletic and Nunzio Bottini) discuss exciting work identifying PTPN22, encoding a tyrosine phosphatase, as a human autoimmune disease gene. A single nucleotide polymorphism in this gene is associated with type I diabetes and several other autoimmune diseases. Stanford Peng covers the FOXO family of transcription factors and their roles in immune regulation. These proteins are regulated by extracellular signals including the PI3K pathway, and their expression and function is altered in autoimmune states in both humans and mice. In the last review of this issue of Autoimmunity, Grant Hughes and Edward Clark assess the disparate signaling of steroid hormones on dendritic cell function and how they impact autoimmune development. As has long been known, females are much more susceptible to certain autoimmune diseases, especially systemic lupus erythematosus. Thus, the review focuses on the differential effects of sex-hormones on autoimmune susceptibility, implicating dendritic cell function as key targets of these hormones in the genesis of autoimmunity.
Together these articles provide a diverse set of vantage points from which to consider how autoimmune disease develops. We hope that the autoimmunity research community finds the reviews helpful and that the articles stimulate progress and fruitful new approaches in the field. It is our conviction that many of the keys to unlocking the mysteries of autoimmunity will be found in complex signaling networks. Thus, while much is known, as evidenced by the pages to follow, much is yet left to be done.