Understanding Of Autoimmunity Research Articles

Role of helper T cells in the loss of B cell anergy mediated by the absence of Tregs (115.6)

Abstract Regulatory T cells (Tregs) are crucial for the maintenance of immune tolerance and the absence of Tregs results in significant autoantibody production. This suggests that Tregs play a key role in B cell tolerance. The mechanism by which Tregs regulate B cell tolerance has yet to be resolved but has important implications for our understanding of autoimmunity. Using both constitutive and inducible models, we show that the absence of Tregs results in autoantibody production, due to the loss of B cell anergy. Further studies show that this is dependent on the presence of helper T cells. We propose that the absence of Tregs results in the dysregulation of helper T cells that drive the loss of B cell anergy. Interestingly, our studies show the expansion of a CD4+GL7+ population in the absence of Tregs. Subsequent analysis shows that many of these cells express CXCR5 and thus resemble germinal-center TFH cells, an observation confirmed by their expression of Bcl6 and IL-21. We hypothesize that the absence of Tregs drives the expansion of TFH cells that play a role in the loss of B cell anergy. Characterization of this proposed mechanism may unveil new strategies for the treatment or prevention of autoantibody-mediated autoimmune diseases.

Clustering and commonalities among autoimmune diseases

The concept that autoimmune diseases are characterized by shared (common) threads is well illustrated by their propensity to co-associate in a patient or direct relatives, as coexistences or overlaps. Recognized are two major autoimmune clusters, “thyrogastric” (mostly organ-specific) and “lupus-associated” (mostly multisystem). Additionally, some autoimmune diseases distribute within either cluster and a few appear not to associate. Also, within each cluster there are overlaps constituting virtually a distinct syndrome. These patterns of coexistence/overlaps depend predominantly on genetic determinants as judged by data accruing from numerous highly powered genome-wide association studies. Gene polymorphisms thus revealed include those that may determine tissue targeting particularly HLA alleles (and others), the (numerous) genes that influence orderly progression (or tolerogenesis) among immune responses from innate immunity to effector processes, genes that influence pathways of apoptosis, and genes that influence vulnerability of target organs to immune-mediated damage. A telling illustration is provided by immune-mediated colonic diseases wherein there is now a demonstrated capability to allocate the multiple risk genes to either Crohn's disease, ulcerative colitis, or both as inflammatory bowel disease. Precisely accurate clinical data-bases and serological reactivities, combined with deepening molecular genetic analyses, have much promise for a better understanding of autoimmunity.

Autoimmunity, Infectious Immunity, and Atherosclerosis

Vascular inflammation is common in certain systemic autoimmune diseases and contributes to the oxidation of low-density lipoprotein (oxLDL) and oxLDL/beta2-glycoprotein I (beta2GPI) complex formation. These complexes have been implicated as proatherogenic autoantigens that participate in the development of atherosclerotic disease. We have demonstrated that the in vitro macrophage uptake of oxLDL/beta2GPI complexes increases in the presence of IgG anti-beta2GPI antibodies and that IgG immune complexes containing oxLDL/beta2GPI upregulate the expression of both scavenger and Fcgamma receptors to activate beta2GPI specific T cells. Some persistent infections may cause immune responses that promote atherogenesis. Cellular immunity (Th1) against Helicobacter pylori (H. pylori) derived heat shock protein 60 (Hp-HSP60) cross-reacts with endogenous HSP60 to cause cardiovascular disease likely by molecular mimicry. Infectious cellular response may be proatherogenic,while the humoral response (antibody production) maybe protective. We review the recent progress in our understanding of autoimmunity and infectious immunity that promote atherosclerosis.

A New Year in Autoimmunity

Over the past year there have been several new developments in our understanding of autoimmunity, as well represented by several lines of evidence obtained from basic, translational, and clinical research alike. To summarize novel findings reported in 2008 this article will review selected publications from the most prominent scientific journals and ultimately suggest some links in the field of autoimmune diseases from leading journals dedicated to autoimmunity. The take-home message from these readings is that autoimmunity ultimately becomes a uniform scenario in which similarities between conditions significantly outnumber differences in terms of pathogenesis and mechanisms.

A Lesson in Tolerance — Maternal Instruction to Fetal Cells

Maternal microchimerism in fetal blood and tissue, which is probably a consequence of the induction of the regulatory T cells in fetal lymph nodes, has implications for immunosuppression and our understanding of autoimmunity.

Immunotherapy of autoimmunity and cancer: the penalty for success

Advances in our understanding of autoimmunity and tumour immunity have led to improvements in immunotherapy for these diseases. Ironically, effective tumour immunity requires the induction of the same responses that underlie autoimmunity, whereas autoimmunity is driven by dysregulation of the same mechanisms that are involved in host defence and immune surveillance. Therefore, as we manipulate the immune system to treat cancer or autoimmunity, we inevitably unbalance the vital mechanisms that regulate self tolerance and antimicrobial resistance. This Science and Society article aims to dissect the conundrum that is inherent to the concept of immunotherapy and highlights the need for new and more specific therapeutic approaches.

Disease-Modifying Agents for Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS. Currently, six medications are approved for immunmodulatory and immunosuppressive treatment of the relapsing disease course and secondary-progressive MS. In the first part of this review, the pathogenesis of MS and its current treatment options are discussed. During the last decade, our understanding of autoimmunity and the pathogenesis of MS has advanced substantially. This has led to the development of a number of compounds, several of which are currently undergoing clinical testing in phase II and III studies. While current treatment options are only available for parenteral administration, several oral compounds are now in clinical trials, including the immunosuppressive agents cladribine and laquinimod. A novel mode of action has been described for fingolimod, another orally available agent, which inhibits egress of activated lymphocytes from draining lymph nodes. Dimethylfumarate exhibits immunomodulatory as well as immunosuppressive activity when given orally. All of these compounds have successfully shown efficacy, at least in regards to the surrogate marker contrast-enhancing lesions on magnetic resonance imaging. Another class of agents that is highlighted in this review are biological agents, namely monoclonal antibodies (mAb) and recombinant fusion proteins. The humanized mAb daclizumab inhibits T-lymphocyte activation via blockade of the interleukin-2 receptor. Alemtuzumab and rituximab deplete leukocytes and B cells, respectively; the fusion protein atacicept inhibits specific B-cell growth factors resulting in reductions in B-cells and plasma cells. These compounds are currently being tested in phase II and III studies in patients with relapsing MS. The concept of neuro-protection and -regeneration has not advanced to a level where specific compounds have entered clinical testing. However, several agents approved for conditions other than MS are highlighted. Finally, with the advent of these highly potent novel therapies, rare, but potentially serious adverse effects have been noted, namely infections and malignancies. These are critically reviewed and put into perspective.

Autoimmunity since the 1957 clonal selection theory: a little acorn to a large oak

Knowledge on autoimmunity is examined from the launch of clonal selection theory 1957-1959. Crucial elements then were 'forbidden clones' of immunocytes as agents of tissue damage, somatic mutations that generated such clones and 'homeostatic mechanisms' that controlled them. The understanding of autoimmunity over the succeeding 50 years has expanded immensely, and many more diseases now come under this rubric. Examined here are current problems of definition including 'adaptive' and 'innate' types of autoimmunity, estimations of population burdens of autoimmune diseases, the nature of autoepitopes in the context of the diabetes autoantigen GAD65, and the complexities of immune tolerance and the genetic influences thereon, leading to the nomination of multiple 'tolerance/autoimmunity' genes as critical components of pathogenesis. Burnet's concept of mutagenesis as a basic feature of various pathologies including autoimmunity is given a contemporary focus, his views on deletional tolerance have been well vindicated, his 'forbidden clones' remain as unphysiological as before albeit phenotypically resembling normal lymphocytes, and his 'homeostatic mechanisms' can be now interpreted in terms of immunoregulatory networks.

The BLyS/BAFF family of ligands and receptors: key targets in the therapy and understanding of autoimmunity

The B lymphocyte stimulator (BLyS; also termed BAFF) family of ligands and receptors plays a central role in B lymphocyte development, selection, and homoeostasis. Members of this family can independently...

Autoimmunity and complement in the pathogenesis of chronic urticaria

Chronic urticaria is a debilitating skin disease that is believed to have an underlying autoimmune etiology in 35% to 50% of cases. Patients with autoimmune urticaria have functional antibodies in their sera that release histamine from basophils and mast cells. The C5a component of complement is required for mast cell degranulation in this process and at least augments basophil histamine release. In this article, the evidence that is key to our understanding of autoimmunity and complement in the pathogenesis of a subset of patients with chronic urticaria is outlined. Some of the issues in testing for and treating autoimmune urticaria are discussed.

Autoimmune channelopathies

Autoimmune disorders of the neuromuscular junction remain a paradigm for our understanding of autoimmunity. Since the role of autoantibodies to acetylcholine receptors in the pathogenesis of myasthenia gravis was first recognized in the 1970s, a range of antibody-mediated disorders of the neuromuscular junction have been described, each associated with an autoantibody to a specific ligand-gated receptor, voltage-gated ion channel or related protein. In addition, antibodies to a ganglionic form of acetylcholine receptor have been detected in autoimmune forms of autonomic neuropathy. In the past few years, a role for antibodies in disorders of the CNS has begun to emerge, challenging our previous concepts regarding the blood-brain barrier and the role of the humoral immune system in CNS pathology. Although it has not yet been definitively shown that these CNS conditions are antibody-mediated, the detection of the specific antibody supports a trial of immunosuppressive therapy to which many patients appear to respond. In this article, we review the roles of antibodies to receptors and ion channels in the peripheral and central nervous systems, concentrating on the recently defined autonomic and CNS conditions and on the role of antibody measurement in diagnosis and management.

Goodpasture Syndrome

Goodpasture Syndrome

Update on paraneoplastic syndromes

This review discusses the varied clinical spectrum of neurologic paraneoplastic disorders, describes recent advances in our understanding of autoimmunity in these disorders, and outlines a practical clinical approach to patient management. Paraneoplastic disorders may affect any part of the central or peripheral nervous system. Although relatively uncommon, these disorders are a significant cause of severe and permanent neurologic disability. Syndromes such as limbic encephalitis or opsoclonus-myoclonus should always raise suspicion of a paraneoplastic condition, but any paraneoplastic syndrome can also occur in patients without a neoplasm. Most neurologic paraneoplastic disorders are thought to be caused by an autoimmune reaction directed against 'onconeural' antigens expressed by neurons and tumor cells. Some syndromes such as Lambert-Eaton myasthenic syndrome and neuromyotonia are clearly mediated by autoantibodies. Much less is known about the immunopathogenesis of syndromes that affect the central nervous system, although a growing body of evidence implicates cellular immune effectors in causing neuronal injury. Many patients have circulating antineuronal antibodies, which can be useful in identifying a neurologic disorder as paraneoplastic and in finding the associated neoplasm. Early diagnosis of the neurologic disorder and prompt initiation of tumor treatment probably increase the likelihood of neurologic improvement. Neurologists must be able to recognize the clinical manifestations of neurologic paraneoplastic disorders, and to distinguish them from other causes of neurologic dysfunction in cancer patients. Early diagnosis of paraneoplastic syndromes maximizes the likelihood of a favorable oncologic and neurologic outcome.

FOXP3 acts as a rheostat of the immune response

The study of a rare human X-linked disease resulting in a characteristic clinical phenotype of multiple autoimmune disorders and the in-depth exploration of a spontaneous mouse model, scurfy (sf), have contributed to a better understanding of the regulation of immunologic responses, particularly to self. Forkhead box P3 (FOXP3), the gene responsible for IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) and sf is located on the X chromosome and is of crucial importance for the generation of CD4+ CD25+ regulatory T cells. Loss of FOXP3 function and the resultant lack of regulatory T cells result in lethal auto-aggressive lymphoproliferation, whereas overexpression of this modulator results in severe immunodeficiency. The in-depth analysis of FOXP3 regulation and elucidation of the precise mechanisms by which FOXP3 exerts its regulatory effect will provide important insights into the understanding of autoimmunity and should predictably result in new therapeutic possibilities.

Apoptosis, subcellular particles, and autoimmunity

Firm evidence links the process of apoptosis to the induction of autoimmune disease. However, questions remain regarding the precise interactions of dying cells with the immune system. Genetic analyses indicate that deficiencies in serum proteins or receptors that mediate clearance of apoptotic cells increase the risk of autoimmunity. Moreover, administration of apoptotic cells to naive animals elicits transient autoimmune responses. Because known autoantigens are covalently modified and redistributed to cell surface blebs during the execution stage of apoptosis, increasing attention is being directed at this stage of programmed cell death, and researchers have identified a variety of autoantigens that are sequestered within blebs. However, blebs are merely a transition stage toward the complete cellular fragmentation, as blebs quickly convert into apoptotic bodies, subcellular particles (SCPs) of heterogeneous size, surface composition, and cargo. Because certain types of subcellular particles represent packets of highly enriched autoantigens, we propose that they are relevant to our understanding of autoimmunity.

Observations on Recent Studies Showing Increased Co-occurrence of Autoimmune Diseases

The co-occurrence of autoimmune diseases has been epidemiologically studied and has aided in our understanding of autoimmunity. However, as new perspectives develop on the pathogenesis and natural history of autoimmune diseases, a refinement in the methodology for the study of the co-occurrence of disease is warranted in order to maximize the information that one may realize from such studies. This paper presents some recent results of co-occurrence studies and then proposes several refinements in the design of epidemiological studies in light of current understanding of the natural history of autoimmune diseases. It also suggests an historical perspective on the results of past studies as to the type of information that can be inferred from them.

Neuronal Survival after CNS Insult Is Determined by a Genetically Encoded Autoimmune Response

Injury to the CNS is often followed by a spread of damage (secondary degeneration), resulting in neuronal losses that are substantially greater than might have been predicted from the severity of the primary insult. Studies in our laboratory have shown that injured CNS neurons can benefit from active or passive immunization with CNS myelin-associated antigens. The fact that autoimmune T-cells can be both beneficial and destructive, taken together with the established phenomenon of genetic predisposition to autoimmune diseases, raises the question: will genetic predisposition to autoimmune diseases affect the outcome of traumatic insult to the CNS? Here we show that the survival rate of retinal ganglion cells in adult mice or rats after crush injury of the optic nerve or intravitreal injection of a toxic dosage of glutamate is up to twofold higher in strains that are resistant to the CNS autoimmune disease experimental autoimmune encephalomyelitis (EAE) than in susceptible strains. The difference was found to be attributed, at least in part, to a beneficial T-cell response that was spontaneously evoked after CNS insult in the resistant but not in the susceptible strains. In animals of EAE-resistant but not of EAE-susceptible strains devoid of mature T-cells (as a result of having undergone thymectomy at birth), the numbers of surviving neurons after optic nerve injury were significantly lower (by 60%) than in the corresponding normal animals. Moreover, the rate of retinal ganglion cell survival was higher when the optic nerve injury was preceded by an unrelated CNS (spinal cord) injury in the resistant strains but not in the susceptible strains. It thus seems that, in normal animals of EAE-resistant strains (but not of susceptible strains), the injury evokes an endogenous protective response that is T-cell dependent. These findings imply that a protective T-cell-dependent response and resistance to autoimmune disease are regulated by a common mechanism. The results of this study compel us to modify our understanding of autoimmunity and autoimmune diseases, as well as the role of autoimmunity in non-autoimmune CNS disorders. They also obviously have far-reaching clinical implications in terms of prognosis and individual therapy.

The pathogenesis of autoimmunity in New Zealand

Objective: New Zealand mice were the, first spontaneous animal model ofhuman systemic lupus erythematosus (SLE). Since their initial discovery in 1959, studies of these mice have provided insights into the immunopathogenesis and genetics of lupus and have had a substantial impact on our understanding of autoimmunity. Methods: We extensively reviewed published data for the past 40 years, including work in cellular immunology and molecular biology, to provide new information on the role of lymphoid subpopulations, cytokines, costimulatory molecules, apoptosis, and genetic susceptibility in the natural history of immunopathology in murine lupus. Results: Genetic factors constitute the- most important contribution toautoimmunity in New Zealand mice, and specific major susceptibility loci have been described. In addition, there is evidence for a pluripotent stem cell defect, which has implications for developmental and functional defects of T and B cells. The end result of these defects is a breakdown of self-tolerance and production of autoantibodies. Further studies will undoubtedly shape our understanding of this murine model and provide the basis for novel diagnostic and therapeutic approaches in humans. Conclusions: The advent of molecular biology, including the use of monoclonalantibody therapy in New Zealand mice, has been instrumental in our understanding of the loss of self-tolerance in SLE. Finally; identification of genetic susceptibility loci in the murine system has also led to important comparable studies in humans with SLE. Relevance: The observations in New Zealand mice are of particular importance to systemic lupus erythematosus (SLE).

Expression of a type II collagen-specific TCR transgene accelerates the onset of arthritis in mice.

Animal models of autoimmune diseases have been instrumental in advancing our understanding of autoimmunity in humans. Collagen-induced arthritis in mice is an autoimmune disease model of rheumatoid arthritis, which is MHC class II restricted and CD4 T cell dependent. To better understand the fundamental role of T cells in arthritis, we have generated a transgenic mouse carrying the rearranged Valpha11.1 and Vbeta8.2 TCR chain genes isolated from a type II collagen (CII)-specific T cell hybridoma. Cell surface analysis indicated that Vbeta8.2 chain was expressed on the surface of nearly all peripheral T cells. Analysis of T cell subsets in transgenic mice revealed a profound skewing in peripheral T cells towards the CD4 population. Although peripheral T cells were not tolerant to CII and responded to CII stimulation in vitro, transgenic mice did not develop spontaneous arthritis. However, a rapid onset of arthritis with severe clinical signs was detected in transgenic mice after immunization with CII in complete Freund's adjuvant. Histological analysis of inflamed joints showed a great resemblance to arthritic joints in man. This unique transgenic mouse model provides valuable insights into the mechanism of arthritis and into potential specific immune interventions.

Pediatric rheumatology: autoimmune mechanisms and therapeutic strategies

Increased basic immunological knowledge has greatly advanced our understanding of autoimmunity, but has had little impact on the treatment of autoimmune diseases so far. Immunologists and pediatric rheumatologists met recently 1 The meeting `From Basic Immunology to Pediatric Rheumatology: Closing the Cleft?' was held at Tübingen, Germany, on 13–14 October 1997. 1 to assess the autoimmune process, review current treatment strategies and explore options for future therapy.