γδ cells regulate autoimmunity

γδ cells are attractive candidates for mediators of autoimmune disease. They can expand in germ-free mice, probably through recognition of autoantigens, and γδ-cell-deficient mice, unlike mice deficient in αβ T cells or B cells, show no severe defects in the immune response to foreign antigen challenge. A capacity of γδ cells to effect or regulate tissue damage is also plausible, given their ready localization to tissues, and their myriad of effector functions. Added to this, attempts to reconstruct the physiological course of autoimmune diseases with only autoreactive αβ T cells seem invariably to fall short for lack of other unidentified players. γδ cells and their putative ligands have been linked to autoimmune conditions, and recent experiments confirm that γδ cells play a significant role in autoimmune disease in vivo.     

The role of antigen-presenting cells in the regulation of allergen-specific T cell responses

Allergic reactions in atopic patients follow from a generalized enhanced polarization of Th cells, predominantly imposed by factors derived from antigen-presenting cells from a pathogen-stressed tissue; these sample information not only on antigen structures but also on the nature of the stress. Antigen-presenting cells of atopic individuals show aberrant characteristics which, through a highly interactive communication network, play an active role in aberrant Th-cell polarization. This generalized bias may follow from intrinsic abnormalities of antigen-presenting cells and also from a low degree of cross-regulation by micro-organisms.     

Biology and genetics of atopic disease

Several immunological disorders including allergic rhinitis, bronchial asthma, atopic dermatitis, food allergies, urticaria, nonhereditary angioedema, systemic anaphylaxis, and allergic conjunctivitis are associated with a positive family history, and share a positive response in the Prausnitz-Kuster (wheal and flare) reaction. Studies have shown that 20–30% of the population has a strong genetic predisposition for this condition, termed atopy, whose hallmark is a greatly elevated serum IgE concentration. A great deal is known about the cellular interactions that mediate the sensitization, immediate and late-phase reactions that follow encounters with allergen, as well as about the cell surface and signaling events that result in mediator release from inflammatory cells. Less is known of the genes that confer genetic predisposition for atopy; however, a worldwide effort to identify atopy genes is making significant progress.     

Mechanisms of enhanced prevalence of asthma and atopy in developed countries

Atopy — a T helper 2 cell driven hypersensitivity to innocuous antigens (allergens) which causes most cases of asthma — is of complex genetic and environmental origins. There is compelling epidemiological evidence for a rise in atopic disease in ‘westernised’ communities. The changing pattern of microbial exposure in early childhood is suggested to be the principal candidate mechanism for this rise.     

Regulation of self-tolerance by CD80/CD86 interactions

Antigen presentation by CD80/CD86-positive ‘professional APCs’ induces T-cell activation, whereas antigen presentation in the absence of sufficient CD80/CD86 costimulation may induce a form of tolerance. Blocking CD80/CD86 costimulation inhibits autoimmune disease progression in a variety of animal models, but whether these effects result from restoration of self-tolerance or temporary disease blockade is still unclear. The individual roles of CD80 and CD86 in autoimmune diseases are complicated by multiple factors in vivo. Data from B7 gene knockout mice further clarify the importance of CD80/CD86 in the regulation of T-cell activation and tolerance.     

FcεRI on antigen-presenting cells

The high-affinity receptor for IgE, FcεRI, expressed on antigen-presenting cells such as monocytes and Langerhans' cells exhibits profound differences to its homologue expressed on mast cells and basophils. The lack of the β chain, the presence of an intracellular pool of preformed α chains, highly variable surface expression, and its function (to provide antigen focusing for T cells) are some of the main issues which have led us to consider the functional role of this receptor in a new light.     

B cells in systemic autoimmune disease: recent insights from Fas-deficient mice and men

In mice functionally deficient for either Fas or Fas ligand expression, the failure of Fas-ligand-expressing cytotoxic T cells to eliminate autoreactive B cells can result in excessive autoantibody production. Recent in vitro studies have shown that B cells activated by CD40 ligand become extremely sensitive to Fas-mediated apoptosis while IL-4 and/or surface IgM receptor engagement protects B cells from Fas ligand cytolysis. Potential in vivo sites for Fas ligand regulation of self-reactive B cells have been suggested and implications for human disease have been investigated.     

T cells and cytokines in Crohn's disease

Recent findings indicate that activated T lymphocytes, showing restricted T-cell receptor repertoire and a Th1-like profile of cytokine production, are responsible for macrophage activation and release of inflammatory cytokines, toxic oxygen metabolites and nitric oxide, which initiate and maintain the transmural intestinal inflammation in Crohn's disease. A critical event in the promotion of Th1-type response at gut level may involve up-regulation of IL-12 production and the breakdown of tolerance against the intestinal flora.     

Manipulation of the Th1/Th2 balance in autoimmune disease

Many autoimmune diseases are caused by autopathogenic Th1 cells. Because in vitro Th1 and Th2 cells cross-regulate each other, it is likely that the induction of self-antigen-specific Th2 cells can prevent autoimmune disease. In the past year, investigators have further defined the role of Th1 and Th2 cytokines in the induction and regulation of autoimmunity. Furthermore, the role of MHC—antigen—T-cell avidity (strength of signal) in inducing such protective immune responses has been elucidated.     

T cell selection and autoimmunity: flexibility and tuning

Peptide-MHC interactions govern the fate of T cells in the thymus and the peripheral T cell repertoire. Recent progress has involved investigating how different peptides influence T cell selection and mature T cell function and the subsequent implications for tolerance and autoimmunity.     

Virus-induced autoimmune disease

The braking of tolerance or unresponsiveness to self-antigens, involving the activation of autoreactive lymphocytes, is a critical event leading to autoimmune diseases. The precise mechanisms by which this can occur are mostly unknown. Viruses have been implicated in this process, among other etiological factors, such as genetic predisposition and cytokine activity. Several ways have been proposed by which a viral infection might break tolerance to self and trigger an autoreactive cascade that ultimately leads to the destruction of a specific cell type or an entire organ. The process termed ‘molecular mimicry’ and the use of transgenic models in which viral and host genes can be manipulated to analyze their effects in causing autoimmunity have been particular focuses for research. For example, there is a transgenic murine model of virus-induced autoimmune disease, in which a known viral gene is selectively expressed as a self-antigen in β cells of the pancreas. In these mice, insulin-dependent diabetes develops after either a viral infection, the release of a cytokine such as IFN-γ, or the expression of the costimulatory molecule B7.1 in the islets of Langerhans. Recent studies using this model have contributed to the understanding of the pathogenesis of virus-induced autoimmune disease and have furthered the design and testing of novel immunotherapeutic approaches.     

Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity

The thymus expresses many genes previously thought to be specific for cell types in other organs. Thus, insulin genes are expressed in rare cells of the thymic medulla. Thymus transplantation demonstrates a functional capability of such expression for self-tolerance induction. Correlative studies suggest that impaired thymic expression confers susceptibility to autoimmune disease.     

Costimulation and autoimmunity

The past year has seen significant advances in our understanding of the role of the B7-CD28/CTLA-4 pathway in T cell activation and self-tolerance. Recent studies have demonstrated that CTLA-4 is a critical negative regulator of T cell activation and autoreactivity, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. Manipulation of this costimulatory pathway in animal models of autoimmunity has shown an important role for this pathway in both the initiation and progression of autoimmune diseases.     

Cytokines in autoimmunity

The past few years have witnessed exciting developments regarding the role of cytokines in autoimmune diseases, particularly in rheumatoid arthritis and Crohn's disease, with the demonstration that anti-TNFα therapy is clinically beneficial and provides reproducible results. Recent contributions to this field, derived from in vivo studies in animal models of autoimmunity, and increasingly from clinical trials, have greatly enhanced our understanding of this field.     

Downstream signals initiated in mast cells by FcεRI and other receptors

The significant contributions this past year to our understanding of IgE receptor (FcεRI) signaling in mast cells include studies with truncated Syk in a vaccinia expression system and Syk-negative variants of rat basophilic (RBL-2H3) cells. These studies demonstrate an essential role for Syk in initiating signals for secretion and release of arachidonic acid via phospholipase A₂ and mitogen-activated protein kinase. A newly recognized addition to the repertoire of FcεRI-mediated signaling systems is the activation of sphingosine kinase, which contributes to calcium mobilization in mast cells. Advances have been made in our understanding of other receptors that regulate proliferation and differentiation of mast cells, and in our understanding of the ability of mast cells to mount acquired and acute responses to antigenic and bacterial challenge.     

Organ-specific autoimmunity

The past year has seen advances in our understanding of the mechanisms that control the expression of organ-specific autoimmunity. Attempts to develop therapeutic strategies for the prevention of autoimmune disease have largely been based on deviation of the T-cell response away from an autoaggressive, pro-inflammatory Th1 response. Manipulation of the cytokine environment at the site of antigen uptake or presentation, the source of endogenous antigen, costimulatory molecules or peptides processed and presented has yielded interesting results.     

Epitope spreading

Epitope (determinant) spreading is the development of immune responses to endogenous epitopes secondary to the release of self antigens during a chronic autoimmune or inflammatory response. The past year has seen considerable advances in our understanding of the contribution of epitope spreading to the chronic pathogenesis of experimental T-cell-mediated and antibody-mediated autoimmune diseases. Most significantly, conclusive functional evidence for a major role for epitope spreading in the chronic pathogenesis of murine relapsing-remitting experimental autoimmune encephalomyelitis, a CD4⁺ T-cell-mediated model of multiple sclerosis, was forthcoming.