Systemic autoimmune disease as a consequence of defective lymphocyte death

A major group of systemic autoimmune diseases is associated with abnormal lymphoproliferation, as a result of defects in the termination of lymphocyte activation and growth. Recent progress has been made in understanding the causes and consequences of these abnormalities. At the molecular level, the defects in CD95 and its ligand are only the most obvious reasons for the breakdown of ‘clonal contraction’ which in fact requires the participation of multiple gene products, including the IL-2—IL-2-receptor system, to set up a functional apoptotic machinery.     

Langerhans cells and chemical allergy

Epidermal Langerhans cells (LCs) play a pivotal role in the induction of cutaneous immune responses, including those provoked by chemical allergens. The delivery by LCs of allergen to draining lymph nodes requires cell migration from the skin, a process that is dependent upon the availability of epidermal cytokines — particularly TNF-α and IL-1β. Here we consider the ways in which these cytokines interact with LCs to both induce and regulate their mobilization in response to skin sensitization. In addition, the effects of these cytokines on both the selectivity of LC migration from the skin and protection of LCs from cell death are considered. Finally, the possible counter-regulatory activity of other cutaneous cytokines and the influence of LCs on the development of selective T lymphocyte responses are explored.     

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.     

Genetic susceptibility factors in type 1 diabetes: linkage, disequilibrium and functional analyses

Continuing progress has been made in elucidating the genetic factors involved in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]) in the past year. Two genome scans suggested additional susceptibility intervals and provided supporting evidence for several previously reported linkages. Other studies focused on the confirmation of linkage using multipoint sibpair analyses with densely spaced markers and multiethnic collections of families. Although significant and consistent linkage evidence was reported for the susceptibility intervals IDDM8 (on human chromosome 6q27), IDDM4 (on 11q) and IDDM5 (on 6q25), evidence for most other intervals varies in different data sets — probably due to a weak effect of the disease genes, genetic heterogeneity or random variation. Linkage disequilibrium mapping has become an increasingly important tool for both the confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations. Functional studies indicate, firstly, that the susceptible and protective HLA class II molecules HLA-DR and -DQ bind and present nonoverlapping peptides and, secondly, that the variable number of tandem repeats at the 5′ end of the insulin gene (susceptibility interval IDDM2) regulates insulin expression in the thymus.     

Genetics of susceptibility to chronic experimental encephalomyelitis and arthritis

The recent developments in genetic techniques and the development of more appropriate animal models for rheumatoid arthritis and multiple sclerosis make it possible to use a new approach for understanding these complex diseases. Thus it is now meaningful to address the question of which genes are causing the diseases. Several new associations with loci outside the MHC region have now been identified in models for both rheumatoid arthritis and multiple sclerosis. Some of these are shared between diseases — for example loci on mouse chromosome 3 (experimental allergic encephalomyelitis, collagen-induced arthritis and Theiler's encephalomyelitis) and rat chromosome 4 (collagen-induced arthritis and the experimental allergic encephalomyelitis induced by myelin oligodendrocytic glycoprotein).     

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.     

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.     

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.     

Regulation of autoimmunity by proinflammatory cytokines

Studies extending over a decade have provided compelling evidence to suggest that chronic expression of proinflammatory cytokines in vivo leads to unique regulatory properties that target the cognate immune response in a way that appears to be beneficial to the host. This review focuses on the prototypic proinflammatory cytokine tumour necrosis factor α, because recent studies of autoimmune disease in mice and man have unraveled a novel and unexpected immunosuppressive role for this inflammatory mediator during the effector phase of the autoimmune process. So far, T lymphocytes would appear to be important cellular targets of this immunoregulatory effect.     

Autoreactivity versus autoaggression: a different perspective on human autoantigens

Antigen-specific B and T cell responses against myelin basic protein, as well as responses against β-islet-cells or joint tissue, are commonly found both in patients with autoimmune disease and in normal control subjects with disease-associated HLA-DR/DQ alleles. Thus, autoreactive immune responses are not disease-specific; however, the presence of certain autoantibodies may have prognostic value and may aid in disease management.     

Autoimmune ovarian disease: mechanism of disease induction and prevention

Investigation of the versatile models for autoimmunity of the ovary and other selected organs has contributed to our understanding of the following aspects of autoimmunity: the mechanism of T cell molecular mimicry; T→B epitope spreading, as a basis for autoantibody diversification, and as a link between organ-specific and systemic autoimmunity; the localization of genetic loci potentially influencing multiple autoimmune diseases; and the elucidation of regulatory T cells as a component of physiological self tolerance.     

The genetics of human systemic lupus erythematosus

Major advances in understanding the genetic foundation of systemic lupus erythematosus are in the offing. Genetic association studies suggest multiple effects that include those encoded by the HLA region, the genes for Fcγ receptors and other genes such as that for the mannose-binding protein. Genome scan studies suggest many (at least twelve) genetic linkages with lupus. Identifying the genes linked with lupus is likely to require many years of concerted effort, as well as the availability and evaluation of much larger pedigree collections.     

Activation of autoreactive T cells by peptides from human pathogens

Activation of autoreactive T cells is a necessary — but not sufficient — step in the development of T cell mediated autoimmunity. Autoreactive T cells can be activated by viral and bacterial peptides that meet the structural requirements for MHC molecule binding and T cell receptor recognition. Due to the degenerate nature of MHC class II molecule binding motifs and a certain degree of flexibility in T cell receptor recognition, such microbial peptides have been found to be quite distinct in their primary sequence from the self-peptide they mimic.     

Topographic mapping of the EEG: An examination of accuracy and precision

Summary The accuracy and precision of topographic maps depicting scalp potentials and scalp potentials squared have been examined. Electrode placement was that specified by the International 10–20 System and the methods of interpolation bilinear and bicubic splines. The results indicate that, for these interpolation methods, the maximum error expected between the measured scalp quantities and those predicted by interpolation is positively correlated to the root-mean-square value of the measured quantity. Both interpolation methods produce accurate estimates of the interelectrode quantities. Both methods produce precise estimates of the scalp potential in the delta, theta and alpha frequency bands but only poor estimates in the beta band. The precision of the estimates of the scalp potentials squared is poor in all frequency bands. This result indicates that another look at the now common practice of topographically mapping the power-spectral components of the EEG is in order. In general, the bilinear and bicubic spline methods of interpolation perform about equally. This result is used to suggest that because of its additional computational complexity, use of the bicubic method for potential mapping may not be warranted. Advantages of the bicubic method, particularly in radial-current mapping, are however discussed.This research is supported by the National Health Research and Development Program, Government of Canada and the Alberta Heritage Foundation for Medical Research.     

T cell immunity to oral allergens

Considerable light has been thrown on the mechanisms of oral tolerance (or, more correctly, orally-induced systemic tolerance) in the past 12–18 months. While it is very clear that T cell anergy and apoptosis can occur after being fed antigen, a major pathway that has been described in different models is the induction of regulatory T cells which secrete transforming growth factor β. These cells have been designated Th3 cells but their relation to the in-vitro-generated Tr cells, which inhibit tissue-damaging T cell responses in the gut mucosa, is not known. An important discovery is that food antigens have major systemic effects on T cells, similar in many ways to those seen following intravenous injection of soluble antigens. This conceptually moves us away from the notion that there is something special about mucosal (compared to systemic) lymphoid tissue to the notion that it is the type of antigens seen in the gut (i.e. digested, soluble polypeptides) which dictates the types of response seen there. After initial excitement, clinical trials using oral tolerance to treat autoimmune disease have been somewhat disappointing.     

CD8 T cells in atopic disease

In recent years there has been a tremendous expansion in our understanding about CD8⁺ T cells. We now know that, as for CD4⁺ T cells, they can be divided into subsets (Tc1 and Tc2) according to the cytokines they secrete. These subsets may differ in their capacity to kill and may even, in some cases, provide help for B cell antibody production or be involved in the induction of inflammatory responses. In addition, there is a host of cross-regulatory networks between different CD4⁺ and CD8⁺ subsets that control the magnitude and duration of immune responses. The observation that some antigens that are normally presented by MHC class II and seen by CD4⁺ T cells can be presented by MHC class I and stimulate CD8⁺ T cells increases the possibility for such interactions. During the next few years we can expect that our understanding of the biology of CD8⁺ T cells and their role in immunity will increase.     

Modélisations des écoulements pulsés à deux phases, en conduites déformables ou rigidesPulsating flow of two phases in deformable or rigide tubes

A numerical solution of pulsatile flow of two-phases non Newtonian fluid — Newtonian fluid through three different tubes (rigid, elastic, viscoelastic) is presented. The type of this flow exists in blood microcirculation. The iterative process with an implicit difference method is used to solve the both local and integral systems, and to determine the axial velocity profiles, the pressure, the flow rate and the radius distributions at all sections and at every moment.     

Indoor versus outdoor allergens in allergic respiratory disease

Immediate hypersensitivity to indoor or outdoor allergens is strongly associated with asthma or hay fever, respectively. Recent progress has defined the sequences, tertiary structures and enzymatic functions of many of the proteins involved; furthermore, the immune responses to these proteins have been examined; however, the mechanisms responsible for the dichotomous response remain elusive. The resolution of such mechanisms may explain the large increase in the prevalence of eosinophil-rich inflammation of the lower respiratory tract.     

The role of MHC class II molecules in susceptibility and resistance to autoimmunity

The mechanism by which particular MHC class II alleles mediate susceptibility to a given autoimmune disease is unknown. During the past year, reports have indicated that the effects of MHC class II alleles which protect against type I diabetes in the nonobese diabetic mouse strain may, in some cases, be due to negative selection of diabetogenic T cell receptors and, in other cases, to positive selection of other T cells with a suppressive action on the diabetic process. Progress towards understanding the mechanisms of susceptibility continues to lag.     

Genetic basis of systemic lupus erythematosus

Recent studies have emphasized that systemic lupus erythematosus is a complex genetic trait with contributions from the MHC and multiple non-MHC genes. Genome-wide linkage studies in murine models of lupus have mapped the positions of a number of non-MHC loci, but the contributing genes have not yet been identified. Recent studies in human systemic lupus erythematosus have found an association with a particular FCGR2A allele. Although susceptibility genes in lupus are unlikely to involve mutations with severe functional consequences, murine knockout models that develop lupus-like features may provide insight into the pathogenetic mechanisms and contributing genes in the human disease.