TNF ligands and receptors in autoimmunity: an update

Over two decades of research have increased the interest in factors from the tumor necrosis factor family. The vast majority of these factors are powerful modulators of critical immune functions and participate in pathogenic mechanisms leading to autoimmune disease. This field constantly evolves with the addition of new family members and the discovery of their function. During the past few years several additional factors from this family, such as BAFF, RANKL, TRAIL and GITRL, have emerged with novel functions that regulate both T and B cell immune tolerance and participate in tissue destruction in autoimmunity. These new findings revealed exciting innovative strategies for the treatment of autoimmune diseases.     

Pathogenic roles of B cells in human autoimmunity; insights from the clinic

The pathogenic roles of B cells in human autoimmune diseases involve a multitude of mechanistic pathways and include the well-established contributions of autoantibodies and immune complexes that induce local inflammatory reactions and tissue destruction. Recent results using several novel B cell-directed therapies have provided new insights into additional roles of B cells in human autoimmunity. In this review, we will highlight some of these studies and discuss how clinical insights parallel murine models of normal immunity and autoimmunity.     

Interferon alpha--a potential link in the pathogenesis of viral-induced type 1 diabetes and autoimmunity

The incidence of type 1 diabetes has been rapidly rising. Environmental factors such as viruses have been implicated as a possible agent accounting for this rise. Enteroviruses have recently been the focus in many research studies as a potential agent in the pathogenesis of type 1 diabetes. The mechanism of viral infection leading to beta cell destruction not only involves multiple pathways but also the cytokine-interferon alpha (IFN-alpha). Our hypothesis is that activation of toll receptors by double-stranded RNA or poly-IC (viral mimic) through induction of IFN-alpha may activate or accelerate immune-mediated beta cell destruction. Numerous clinical case reports have implicated that IFN-alpha therapy is associated with autoimmune diseases and that elevated serum IFN-alpha levels have been associated with type 1 diabetes. In multiple animal models, given specific genetic susceptibility, poly-IC can induce insulitis or diabetes. Therapeutic agents targeting IFN-alpha may potentially be beneficial in the prevention of type 1 diabetes and autoimmunity.     

A genetic basis for shared autoimmunity in mouse models

Development of autoimmune disease is the result of activation of the immune system that subsequently leads to tissue destruction. Although the clinical outcome significantly differs between autoimmune diseases, some pathogenic pathways could be shared. During the recent years, intense efforts to find the genetic factors behind development of the complex and polygenic autoimmune diseases have been undertaken. The difficulties in addressing what genetic factors predispose for autoimmunity in humans underline the importance of animal models in the understanding of the general mechanisms behind the initiation of disease. Interestingly, it has been observed in studies of experimental models of autoimmune diseases, that many of the genetic linkages to disease development are located in the same genetic regions and potentially could be controlled by the same gene. Furthermore, comparison of the mouse/rat genetic regions with regions of association to human inflammatory diseases, also demonstrates some homologous loci between species. Some mouse strains can develop disease in more than one model for autoimmunity. This not only argues for some general mechanisms, but it also supports mechanisms related to the specific tissues attacked in the various autoimmune diseases. Here, we will discuss some aspects of shared autoimmunity in mouse models from a genetic point of view.     

A genetic basis for shared autoimmunity in mouse models

Development of autoimmune disease is the result of activation of the immune system that subsequently leads to tissue destruction. Although the clinical outcome significantly differs between autoimmune diseases, some pathogenic pathways could be shared. During the recent years, intense efforts to find the genetic factors behind development of the complex and polygenic autoimmune diseases have been undertaken. The difficulties in addressing what genetic factors predispose for autoimmunity in humans underline the importance of animal models in the understanding of the general mechanisms behind the initiation of disease. Interestingly, it has been observed in studies of experimental models of autoimmune diseases, that many of the genetic linkages to disease development are located in the same genetic regions and potentially could be controlled by the same gene. Furthermore, comparison of the mouse/rat genetic regions with regions of association to human inflammatory diseases, also demonstrates some homologous loci between species. Some mouse strains can develop disease in more than one model for autoimmunity. This not only argues for some general mechanisms, but it also supports mechanisms related to the specific tissues attacked in the various autoimmune diseases. Here, we will discuss some aspects of shared autoimmunity in mouse models from a genetic point of view.     

Parasitic infection and autoimmunity

The studies summarized in this paper indicate that parasitic infections can serve as a trigger factor of autoimmune reactivity by several mechanisms. The relationship between parasites and autoimmunity could be manifested by the presence of autoantibodies or T-cells with autoreactivity. In spite of the evidence that has accumulated, the specific association between infection and autoimmunity is still obscure. The reasons for tissue damage in parasitic diseases are controversial. Some believe it is the result of pathogenic autoantibodies or autoreactive T-cells. Others argue against the causative role of autoimmunity in the formation of tissue lesions. The parasite itself could be the cause of tissue destruction, thus releasing high amounts of self antigens which might stimulate the autoreactivity. There is now little doubt that some degree parasite/host cross-reactivity occurs, and definition of cross-reacting antigens and epitopes is now taking place. It seems likely that a combination of events could result in cross-reactivity including: parasites themselves have cross reactive molecules and altered self antigens by adsorbing of parasite material to surrounding host cells. The mechanisms involved in parasites autoimmunity are complex and numerous, requiring a rigorous experimental approach to rationalize each step and determine its clinical importance. The developed methods in immunochemistry, monoclonal antibodies and hybridoma technology, and recombinant DNA research not only facilitate this kind of approach but also allow optimism for a successful outcome.     

Fas/Fas ligand on the road: an apoptotic pathway common to AIDS, autoimmunity, lymphoproliferation and transplantation.

There is considerable interest in the role of Fas protein as it induces apoptotic cell death when ligated by its natural ligand (FasL). Interaction between Fas and FasL is a crucial mechanism for clonal deletion and immune tolerance and privilege, control of T cell expansion during immune responses and killing by cytotoxic T lymphocytes. Loss of function of the system can block lymphocyte apoptosis and cause lymphoproliferation and autoimmunity but, when the system overfunctions, it can end to tissue injury and destruction. Recent studies have demonstrated that the Fas/FasL system is implicated in the pathogenesis of several human diseases ranging from AIDS to autoimmunity and lymphoproliferation, hepatitis, multiple sclerosis and transplant rejection. It is conceivable that modulating the activity of the Fas/fasL pathway would have clinical applications for the treatment of these patients.     

Cellular stress and innate inflammation in organ-specific autoimmunity: lessons learned from vitiligo

For decades, research in autoimmunity has focused primarily on immune contributions to disease. Yet recent studies report elevated levels of reactive oxygen species and abnormal activation of the unfolded protein response in cells targeted by autoimmunity, implicating cellular stress originating from the target tissue as a contributing factor. A better understanding of this contribution may help to answer important lingering questions in organ-specific autoimmunity, as to what factors initiate disease and what directs its tissue specificity. Vitiligo, an autoimmune disease of the skin, has been the focus of translational research for over 30 years, and both melanocyte stress and immune mechanisms have been thought to be mutually exclusive explanations for pathogenesis. Chemical-induced vitiligo is a unique clinical presentation that reflects the importance of environmental influences on autoimmunity, provides insight into a new paradigm linking cell stress to the immune response, and serves as a template for other autoimmune diseases. In this review, I will discuss the evidence for cell stress contributions to a number of autoimmune diseases, the questions that remain, and how vitiligo, an underappreciated example of organ-specific autoimmunity, helps to answer them.     

Fas-FasL interactions: a common pathogenetic mechanism in organ-specific autoimmunity

Organ-specific autoimmunity is characterized by the accelerated loss of selected cell types, resulting in specific tissue destruction and disease. The role of different genetic or environmental factors in initiating the autoimmune reactivity is still unclear. However, novel mechanisms responsible for tissue destruction have recently been revealed. Here, Ruggero De Maria and Roberto Testi propose that Fas ligand may represent a common weapon during the destructive phase of organ-specific autoimmunity.     

T cell metabolism in metabolic disease-associated autoimmunity

This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro-environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease-associated autoimmunity.     

From ocular immune privilege to primary autoimmune diseases of the eye

After the discovery of ocular immune privilege, exhaustive research has been performed, and advances have been made in the field of ocular immunology. Currently, it is clear that local and systemic pathways are involved in maintaining a well-preserved environment to guarantee normal vision. The development of autoimmunity in the eye is still a subject of research; however, it has been suggested that microglial cells could act as a gateway for initiating autoimmunity. Moreover, based on the fact that ocular involvement in systemic autoimmune diseases is well described, we aimed to collect and describe ocular diseases with a proposed primary autoimmune pathogenic mechanism. It should be noted that the autoimmune classification in several entities is a topic of discussion among authors.     

Autoimmunity and hepatitis C

Hepatitis C is a widespread chronic liver disease leading to cirrhosis and to the complications of portal hypertension. Based on biochemical and clinical features, it is almost indistinguishable from autoimmune hepatitis, which is characterized by the absence of viral infection, and other causes of chronic liver diseases, and represents a classical autoimmune disease with loss of immunological tolerance of liver tissue. Although the differentiation between both diseases is not difficult due the availability of diagnostic viral markers, it is well recognized that not only are autoantibodies present in autoimmune hepatitis frequently detected in hepatitis C, but also that an array of immune-mediated symptoms and diseases occur in patients with chronic hepatitis C. This has prompted research aimed at identifying a link between hepatitis C and autoimmunity, and autoimmune hepatitis in particular. This review focuses on the general immunological mechanisms linking viral infections with autoimmunity and includes the specific features of hepatitis C- and D-associated autoimmunity. Virus infection remains at the center of molecular and cellular research aimed at identifying the forces driving human autoimmunity and autoimmune diseases.     

Renal autoimmunity: The role of bacterial and viral infections,an extensive review

Autoimmunity is a process by which the loss of self-tolerance results in an immune attack against the body own tissues and organs. For autoimmunity to occur, various elements serving as triggers were described by which infections are considered one of the leading factors. In turn, renal involvement in autoimmune diseases, whether by an organ-specific attack, or as part of a systemic disease process, is well known. As bacterial and viral infections are considered to be common triggers for autoimmunity in general, we aimed to study their association with renal autoimmunity in particular. We performed an extensive search of the recent and relevant medical literature regarding renal autoimmunity syndromes such as infection-associated glomerulonephritis and vasculitis, associated with bacterial and viral infections. By utilizing PubMed and Google Scholar search engines, over 200 articles and case reports were reviewed. Among other mechanisms, direct infection of the renal parenchyma, molecular mimicry, induction of B-cells or secretion of superantigens, bacterial and viral pathogens were found to correlate with the development of renal autoimmunity. Nevertheless, this was not true for all pathogens, as some mimic autoimmune diseases and others show a surprisingly protective effect. The exact immunopathogenesis is yet to be determined, however. For conclusion, bacterial and viral infections are linked to renal autoimmunity by both direct damage and as mediators of systemic diseases. Further research particularly on the immunopathogenetic mechanisms of renal autoimmunity associated with infections is required.     

Autoimmunity, immunologic tolerance, and gene therapy

Research in our laboratory focuses on three major themes:

1. Costimulation and cell death in autoimmunity.
2. Molecular mechanisms of immunologie tolerance.
3. Gene therapy of autoimmune diseases.

We have performed a large series of experiments using T cell receptor (TCR) transgenic mice examining mechanisms of autoimmunity and peripheral T cell tolerance. A major focus of our current research is to understand the roles of costimulation and cell death in T cell tolerance and T cell-mediated autoimmune diseases. This involves studies of the TCR, the costimulatory molecules, and the cytokines. We are also exploring novel strategies for the treatment of autoimmune diseases by gene transfer.     

Cytokines in autoimmunity: role in induction, regulation, and treatment

Cytokines play a pivotal role in the pathogenesis of autoimmune diseases. The precise triggers for the breakdown of self-tolerance and the subsequent events leading to the induction of pathogenic autoimmune responses remain to be defined for most of the naturally occurring autoimmune diseases. Studies conducted in experimental models of human autoimmune diseases and observations in patients have revealed a general scheme in which proinflammatory cytokines contribute to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate the regression of inflammation and recovery from acute phase of the disease. This idea is embodied in the T helper (Th) 1/Th2 paradigm, which over the past two decades has had a major influence on our thinking about the role of cytokines in autoimmunity. Interestingly, over the past decade, the interleukin (IL)-17/IL-23 axis has rapidly emerged as the new paradigm that has compelled us to critically re-examine the cytokine-driven immune events in the pathogenesis and treatment of autoimmunity. In this 2-volume special issue of the journal, leading experts have presented their research findings and viewpoints on the role of cytokines in the context of specific autoimmune diseases.     

Superantigens.

Over the past three years superantigens have come to the forefront of immunological research. Studies in a number of laboratories have indicated that superantigens play a central role in shaping the T-cell repertoire in the development of tolerance, autoimmunity and immunodeficiency. This is in addition to their classic role in the pathogenesis of a number of infectious diseases.     

Tweaking the immune system: Gene therapy-assisted autologous haematopoietic stem cell transplantation as a treatment for autoimmune disease

Autoimmune diseases represent a major challenge for medical research. The aberrant self-recognition by the immune system leads to a range of pathologies for which cures have not been forthcoming. Treatments are commonly non-specific and often lead to unwanted side-effects. A number of strategies are currently being explored to tackle autoimmunity; aimed at eliminating existing pathogenic clones and the induction of immune tolerance through resetting or regulating the immune system. Autologous haematopoietic stem cell transplantation (HSCT) is one such strategy and is being trailed in a number of autoimmune diseases. However, a common feature of this strategy is disease relapse and may indicate incomplete tolerance mechanisms. It is well known that bone marrow derived cells have a major influence on immune tolerance. It is also well documented that ectopic expression of antigens within the immune system can promote robust tolerance. This review considers these observations in the context of promoting a strategy involving genetic manipulation of haematopoietic stem cells together with HSCT to induce immune tolerance and tackle autoimmunity.     

Stimulation of the developing immune system can prevent autoimmunity

Both genetic and environmental factors contribute to the development of autoimmunity. Animals and humans exposed to natural infections have a reduced rate of autoimmune diseases. There is increasing evidence that immune stimulation prevents autoimmune diseases. Our hypothesis is that the process of the development of pathogenic cells involved in autoimmunity can be modulated by early stimulation of the immune system in autoimmunity prone individuals This allows for the upregulation of cytokines and growth factors that influence the generation of regulatory cells involved in autoimmunity. As we live in a 'cleaner environment' the decreasing chances of natural infection in the general population may contribute to the induction of autoimmunity because the developing immune system is not exposed to stimulation that may be necessary to generate regulatory cells involved in the modulation and prevention of autoimmunity. Immunization with certain vaccines may provide an alternative approach to stimulate the immune system to modulate or prevent the generation of pathogenic cells involved in autoimmunity by induction of regulatory cells.