Current Molecular Medicine (v.9, #1)

The immune system provides a vital protective system for living organisms from infection. Most organisms from the simplest to the most complex have some form of innate immune system, to provide the relatively non-specific early response against invasion of pathogens. Apart from the physical barriers to infection, the non-specific enzymes such as lysozyme in tears and saliva and anti-bacterial peptides that include defensins, there are an array of cells including natural killer (NK) and natural killer T (NKT) cells, macrophages, and#947;and#948; T cells, neutrophils, eosinophils, basophils and mast cells that all play an important role in this first line of defence. These cells recognize common patterns of pathogens via a large array of receptors that include the Toll-like receptors (TLR) that recognize both extracellular and intracellular stimuli, the nucleotide oligomerization domain (NOD) like receptors (NLR), RIG-I like receptors (RLR), which are reactive to nucleic acids, and caspase recruitment domain (CARD) proteins, which recognize predominantly intracellular molecules. These receptors signal intracellularly through a number of adaptors, that include Myeloid Differentiation primary response gene 88 (MyD88), MyD88 adaptor-like/ TIR domain containing adaptor protein (MAL), Toll-IL-1-resistance domain containing adaptor inducing interferon beta (TRIF), TRIF-related adaptor molecule (TRAM) and Sterile-alpha and Armadillo motif containing protein (SARM) leading to the activation of NFand#954;B, as reviewed in this issue by Page and colleagues [1]. Recent studies suggest that stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor for RLR [2]. These receptors not only detect pathogens in the external environment, but may also respond to tissue damage and initiate responses to endogenous signals [3]. Cytokines and chemokines produced by the innate cells in early response attract more innate cells and as dendritic cells become involved in endocytosing antigen and traffick to local lymph nodes, an adaptive, more specific response involving T and B cells will be initiated. Although occurring sequentially, the immune response is a very complex and inter-related series of events. Although innate and adaptive immune responses are traditionally thought of as being somewhat compartmentalized, it is now clear that these two types of immune responses are highly interconnected at many levels. In this light, it is not surprising that this interaction will not only be seen in the context of infection but also in other settings where chronic inflammation is prominent, such as in autoimmune disease. Many autoimmune diseases occur through adaptive immune response effectors against autoantigens. Both selfreactive T cells and autoantibody producing B cells are found in the diseases that include multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes and autoimmune liver disorders. Whether the role of autoreactive B or T cells is more dominant depends on the individual disease. Genetic susceptibility has been identified in many autoimmune diseases and certain HLA types predispose to different diseases. However, environmental factors play a critical role in determining whether susceptible individuals develop autoimmune disease, although the nature of these factors is not well defined. Increasing evidence suggests that both the external as well as the internal environment are important in disease onset and progression.

Natural Killer T Cells and Autoimmune Disease by Lan Wu, Luc Kaer (4-14).
Natural killer T (NKT) cells are an unusual subset of innate immune cells that express a surface receptor generated by somatic DNA rearrangement, a hallmark of cells of the adaptive immune system. NKT cells express a highly restricted repertoire of T cell receptors that recognize glycolipid antigens bound with the antigen-presenting molecule CD1d. A hallmark of NKT cells is their capacity to produce copious amounts of immunomodulatory cytokines upon antigenic stimulation, which endows these cells with potent immunoregulatory properties. Consequently, NKT cells have been implicated in regulating a wide variety of immune responses, including immune responses against autoantigens. In patients and mice with a variety of autoimmune diseases, numbers and functions of NKT cells are disturbed, but the relevance of these findings to the etiology of autoimmunity remains to be fully established. Nevertheless, in some mouse models of autoimmunity, NKT cell-deficiency exacerbates disease, suggesting that NKT cells play a role in suppressing autoimmunity. Conversely, specific activation of NKT cells with glycolipid antigens generally protects mice against the development of autoimmunity. Most of these studies have employed the potent sponge-derived NKT cell antigen and#945;-galactosylceramide (and#945;-GalCer). However, and#945;-GalCer treatment in mice was associated with detrimental side effects and treatment efficacy was influenced by a variety of parameters, resulting sometimes in disease exacerbation rather than protection. Recent efforts have focused on developing NKT cell agonists with superior treatment efficacy than and#945;-GalCer. Collectively, these studies have identified NKT cells as attractive targets for treatment of human autoimmune diseases.

and#947;and#948; T cells are a multifaceted group of cells which have both innate and adaptive characteristics and functions. Although they are most commonly known for their response to mycobacterium and their locations at mucosal sites, their roles in autoimmunity are still unclear. and#947;and#948; T cells have been seen in the CSF and lesions of Multiple Sclerosis patients and although their function is not entirely understood, it is clear these cells may have roles in regulating autoimmune inflammation in the CNS. Recent studies have focused on the role of and#947;and#948; T cells in MS and EAE as both pathogenic and protective, their functions within the CNS, the types of subsets and a possible role in Th17 inflammation. In this review we will examine the data acquired from both human patients and the murine models of MS, experimental autoimmune encephalomyelitis (EAE), in order to gain a clear picture of how and#947;and#948; T cells influence pathogenesis of EAE and MS.

Monocyte Dependent Regulation of Autoimmune Inflammation by Lindsay Nicholson, Ben Raveney, Markus Munder (23-29).
In chronic inflammation, across a number of quite different pathological conditions, monocytes accumulate. In autoimmune disease, these cells are widely recognised to play an inflammatory and tissue destructive role. But these cells also inhibit T cell proliferation by a range of different mechanisms that are accompanied by the depletion of specific amino acids in the local microenvironment and the downregulation of the T cell receptor and#950; chain. This occurs within the pro-inflammatory environment and in the presence of Th1 (IFNand#947;) and Th17 (IL-17) cytokines. In tumours, related cells are part of a population called myeloid-derived suppressor cells (MDSC) and they are associated with immunosuppression. Their depletion can lead to clinical improvement. In organ specific autoimmune disease, where such cells can be found in the spleen and in target organs, recent evidence indicates that they may play a role in limiting the T cell response to autoantigens in the target tissue. This occurs by a targeted disruption of T cell division. In this review we discuss evidence for the presence on MDSC in murine and human autoimmune disease and the mechanisms by which such cells inhibit T cell proliferation.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease resulting from the specific destruction of insulin-producing pancreatic and#946;-cells, culminating in a state of hypoinsulinemia and hyperglycemia. Pathogenesis of T1D comprises complex series of events from the initial sensitization of antigen-presenting cells (APCs) to and#946;-cell antigens to almost total insulin deficiency due to islet destruction. Although it is established that the interaction of environmental factors with genetic traits plays a pivotal role in the pathogenesis of T1D, in most cases, the exact trigger of anti-islet autoimmunity and how genetic and environmental factors regulate its progression, ultimately leading to the development of T1D remain elusive. In this review, based on the recent advances in understanding the role of innate immunity in development of autoimmune diseases, we focus on the possibility that aberrant regulation of the innate immune system frequently observed in animal models and patients with T1D, induces T1D by triggering anti-islet autoimmunity in the context of the autoimmuneprone environment; this information might provide an insight into possibilities for therapeutic intervention modulating innate immunity to mitigate or prevent T1D.

Innate Immunity and Primary Biliary Cirrhosis by Carlo Selmi, Ana Lleo, Simone Pasini, Massimo Zuin, M. Gershwin (45-51).
There has been a rapid growth in our understanding of the molecular bases of primary biliary cirrhosis (PBC). These efforts were initiated when the immunodominant mitochondrial autoantigen was cloned and sequenced. Using the recombinant cloned antigen as a tool, research has focused on the effector mechanisms of disease and the uniqueness of the primary target tissue, the intrahepatic bile ducts. Most recently, there have been experimental data suggesting that innate immunity changes may be critical to the initiation and perpetuation of the autoimmune injury, as in the case of the enhanced response of monocytes and memory B cells to infectious stimulation and environmental mimics. These observations are important as they help fill in the many gaps which remain on the most difficult subject of autoimmunity, etiology. Indeed, based on the available data, several experimental models of PBC have been developed. These models illustrate and suggest that PBC can be initiated by several mechanisms, all of which lead to loss of tolerance to the mitochondrial antigens. However, once this adaptive response develops, it appears that much of the subsequent pathology is exacerbated by innate responses. We suggest that future therapeutic efforts in PBC will depend heavily on understanding the nature of this innate immune responses and methodology to blunt their cytotoxicity.

Toll-like receptors (TLRs) and the innate immune system play a key role in sensing and eliminating microbial infections. Interactions between TLRs and their ligands expressed by microbial pathogens induce a cascade of intracellular signaling events, culminating in the upregulation of proinflammatory pathways. Over the past two decades, numerous studies have established the role of the acquired immune system in the mechanism triggering type 1 diabetes (T1D). The recent discovery of TLRs has led to the recognition that the innate immune system may act, under some circumstances, as a double-edged sword. In addition to its beneficial role in host defense, it may lead to upregulation of proinflammatory autoimmune responses, islet destruction and diabetes. Indeed, recent observations are consistent with the hypothesis that altered innate functions exist in patients with T1D and could be part of the mechanism leading to disease onset, but the underlying mechanisms and the relevance of these alterations to early events triggering disease remain to be identified. Data obtained from mouse and rat models of T1D implicated TLR pathways in both disease induction and prevention. In both the NOD mouse and diabetes-prone BB (BBDP) rat, TLR upregulation can suppress disease. In the BioBreeding Diabetes Resistant (BBDR) rat, however, diabetes induced by virus infection involves the upregulation of TLR9 pathways, and generic TLR upregulation synergizes with virus infection on diabetes induction. Studies performed in mouse models of T1D with spontaneous or induced T1D implicate TLR1, TLR2, TLR3, and TLR7 in disease mechanisms. The finding that TLR pathways are involved in mediating islet inflammation holds great promise for identifying new molecules that could potentially be targeted to specifically suppress the autoimmune process in individuals at high risk for disease development. The potential link between TLR upregulation and autoimmunity emphasizes the need for caution in using new therapies involving TLR agonists as vaccine adjuvants.

Tyrosine Kinases and Inflammatory Signalling by Theresa Page, Maria Smolinska, Justin Gillespie, Anna Urbaniak, Brian Foxwell (69-85).
The activity of tyrosine kinases is central to many cellular processes, and accumulating evidence suggests that their role in inflammation is no less profound. Three main tyrosine kinase families, the Src, Tec and Syk kinase families are intimately involved in TLR signalling, the critical first step in cellular recognition of invading pathogens and tissue damage. Their activity results in changes in gene expression in affected cells. Key amongst these genes are the cytokines, which orchestrate both the duration and extent of inflammation. Tyrosine kinases also play important roles in cytokine function, and are implicated in signalling through both pro- and anti-inflammatory cytokines such as TNF, IL-6 and IL-10. Thus, strategies to modulate tyrosine kinase activity have significant therapeutic potential in combating the chronic inflammatory state that is typical of many major health issues that face us today, including Rheumatoid Arthritis, Cardiovascular disease and cancer. Here we review current knowledge of the role of tyrosine kinases in inflammation with particular emphasis on their role in TLR signalling.

Atypical Chemokine Receptors in Inflammatory Disease by Manish Patel, Iain McInnes, Gerard Graham (86-93).
There is considerable interest in the therapeutic utility of inhibiting cellular trafficking in a variety of inflammatory diseases. Approaches including inhibition of adhesion molecule function and in particular of chemokine effector function have met with high levels of success in many models of disease but have been of less value in application to clinical disease states. Although this may in part be explained by pharmacokinetic and pharmacodynamic issues surrounding therapeutic agents tried thus far, it is also likely that functional redundancy in the chemokine network may pose significant problems for achieving potent inflammation suppression. The atypical chemokine receptors comprise a novel group of receptors capable of binding to several chemokine activities and to inhibiting their function. This review will describe the basic biology of such receptors and speculate on their potential as therapeutic agents moving forward.