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PubMed2004

Degenerate self-reactive human T-cell receptor causes spontaneous autoimmune disease in mice.

Thyroid autoimmune disorders comprise more than 30% of all organ-specific autoimmune diseases and are characterized by autoantibodies and infiltrating T cells. The pathologic role of infiltrating T cells is not well defined. To address this issue, we generated transgenic mice expressing a human T-cell receptor derived from the thyroid-infiltrating T cell of a patient with thyroiditis and specific for a cryptic thyroid-peroxidase epitope. Here we show that mouse major histocompatibility complex molecules sustain selection and activation of the transgenic T cells, as coexpression of histocompatibility leukocyte antigen molecules was not needed. Furthermore, the transgenic T cells had an activated phenotype in vivo, and mice spontaneously developed destructive thyroiditis with histological, clinical and hormonal signs comparable with human autoimmune hypothyroidism. These results highlight the pathogenic role of human T cells specific for cryptic self epitopes. This new 'humanized' model will provide a unique tool to investigate how human pathogenic self-reactive T cells initiate autoimmune diseases and to determine how autoimmunity can be modulated in vivo.

Animals↗

PubMed1998

Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease. Part 1: rheumatologic and renal diseases.

When cytotoxic agents were initially introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease. During the course of this use, however, it became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward the treatment of non-neoplastic diseases in which autoimmune mechanisms were considered important to pathogenesis. As a result of these investigations, cytotoxic agents and, more recently, cyclosporine have emerged to become an important part of the therapeutic regimen for many autoimmune diseases. Nonetheless, these medications may still cause treatment-induced illness or even death. It is therefore particularly important to weigh the benefits and risks of cytotoxic therapy when treating a non-neoplastic disease. This two-part Clinical Staff Conference reviews data on the efficacy and toxicity of cytotoxic drugs and cyclosporine in selected autoimmune diseases. Part 1 examines the manner in which these agents have been used to treat rheumatologic and renal diseases.

Autoimmune Diseases↗

PubMed2000

Stem cell transplantation for treatment of severe autoimmune diseases: current status and future perspectives.

Autoimmune diseases include a heterogeneous group of disorders with variable presentation and severity. Immunosuppressive and immunomodulatory therapies are often used for treatment with considerable success in some cases. These diseases may also be severe and refractory to conventional treatment. Thus more aggressive intervention might be indicated in a subset of patients. Animal studies suggest that high-dose therapy supported by stem cell transplantation may lead to remissions in experimental autoimmune disease models. Anecdotal case reports suggest that the same may be the case in some human autoimmune diseases as well. This review attempts to summarise some current concepts and future perspectives on stem cell transplantation in the treatment of severe autoimmune diseases.

Acute Disease↗

PubMed2002

Experimental basis of hematopoietic stem cell transplantation for treatment of autoimmune diseases.

Experiments with animal models of autoimmune disease provided the rational and stimulus for the current, clinical studies of autologous stem cell transplantation for the treatment of a variety of severe, refractory, autoimmune diseases. The discoveries that led to the recognition of the key role of hematopoietic stem cells and the successful treatment of autoimmune diseases with bone marrow transplants are reviewed. The relevance of spontaneous and induced autoimmune disease models for the development of clinical treatment regimens is discussed. Most of the investigations with autologous stem cell transplantation have been performed with induced autoimmune disorders: in rats with adjuvant arthritis and in rats or mice with experimental, allergic encephalomyelitis, the current model for multiple sclerosis. The main aspects of this translational research were the conditioning regimens and the degree of T cell depletion of the graft as determinants of remission induction and the incidence of relapses. The emerging recommendations are compared with the outcome so far of the clinical studies.

Acquired Immunodeficiency Syndrome↗

PubMed1980

Prevalence of autoimmune diseases and autoantibodies in Ethiopia.

Analysis of 7,966 hospital admissions and other available data suggest that disease associated with autoimmunity are rare in Ethiopia. Sera from 107 patients with dyspepsia and 80 healthy Ethiopians were studied for autoantibodies. Using the immunofluorescence technique and anti-Fab-FITC conjugate, a search for organ-specific autoantibodies against thyroid (microsomal and thyroglobulin) cells as well as for non-organ-specific autoantibodies against nuclear material, smooth muscle, mitochondria, cardiolipin, glomerular basement membrane and connective tissue (reticulin antibodies) revealed that they were uncommon. Thus, both clinical and serological studies confirm that previously held views concerning the rarity of autoimmune diseases in many parts of Africa are also true in Ethiopia. It is suggested that the few Ethiopians who develop autoimmune diseases may have an overwhelming hereditary predisposition which is unable to overcome inhibitory factors in the environment.

Adult↗

PubMed2005

[The possible role of microchimerism in the aetiology of autoimmune diseases].

The aetiology of several autoimmune diseases has not yet been elucidated. Microchimerism, the persistence of small numbers ofallogeneic cells in an individual, has been mentioned recently in connection with the occurrence of autoimmune diseases such as systemic sclerosis and juvenile inflammatory idiopathic myopathy. These allogeneic cells can originate from mutual foeto-maternal exchange of blood cells during pregnancy or from a donor after blood transfusion or (organ) transplantation. In some cases, a syndrome then develops that resembles the chronic graft-versus-host reaction after stem-cell transplantation, in which allogeneic cells react with autologous cells. Studies on microchimerism in patients with systemic sclerosis and juvenile inflammatory idiopathic myopathy, compared to controls, sometimes reveal a clearly increased prevalence of microchimerism in patients. However, microchimerism can also be found in healthy individuals. Direct proof of a causal relation between microchimerism and autoimmune diseases does not exist. Additional genetic or environmental factors may be partly responsible for a disturbed balance between tolerance and aggression.

Autoimmune Diseases↗

PubMed1997

HLA-DR restrictive supertypes dominate promiscuous T cell recognition: association of multiple HLA-DR molecules with susceptibility to autoimmune diseases.

The association of individual autoimmune diseases with multiple HLA molecules has remained an enigma. That T cells can recognize the same peptide presented by several different HLA-DR alleles (i.e., promiscuous recognition) has been well documented. To explain this, we propose the "DR restrictive supertype pattern (DR RSP)" hypothesis. We focus on the known amino acid polymorphisms at positions beta 70, beta 71, and beta 74 located within pocket 4 of the DR molecule and their potential influence on promiscuous T cell recognition. We have shown that HLA-DR alleles may be grouped, on the basis of their polymorphisms at these positions, into at least 6 sets of DR alleles, 4 of which share, respectively, one of the RSP: A (Q/RR/KA), D (DE/R[K]A/L), E (Q/RRE), or R (QKR/Q) and 2 of which share the restrictive patterns Q (DRQ) or a (QAA). Most of the RSP have been shown to be associated with promiscuous T cell recognition of antigenic peptides. We also provide a rationale on how different DR alleles, exhibiting a particular RSP, might be capable of binding an antigenic peptide and presenting it, in a promiscuous fashion, to peptide-specific T cells. By identifying these RSP represented by DR alleles that have been clinically associated with certain autoimmune disease, we also extend the DR RSP hypothesis to account for the association of certain autoimmune diseases with multiple HLA-DR alleles.

Arthritis, Rheumatoid↗

PubMed2004

Nucleosome-specific regulatory T cells engineered by triple gene transfer suppress a systemic autoimmune disease.

The mechanisms of systemic autoimmune disease are poorly understood and available therapies often lead to immunosuppressive conditions. We describe here a new model of autoantigen-specific immunotherapy based on the sites of autoantigen presentation in systemic autoimmune disease. Nucleosomes are one of the well-characterized autoantigens. We found relative splenic localization of the stimulative capacity for nucleosome-specific T cells in (NZB x NZW)F(1) (NZB/W F(1)) lupus-prone mice. Splenic dendritic cells (DCs) from NZB/W F(1) mice spontaneously stimulate nucleosome-specific T cells to a much greater degree than both DCs from normal mice and DCs from the lymph nodes of NZB/W F(1) mice. This leads to a strategy for the local delivery of therapeutic molecules using autoantigen-specific T cells. Nucleosome-specific regulatory T cells engineered by triple gene transfer (TCR-alpha, TCR-beta, and CTLA4Ig) accumulated in the spleen and suppressed the related pathogenic autoantibody production. Nephritis was drastically suppressed without impairing the T cell-dependent humoral immune responses. Thus, autoantigen-specific regulatory T cells engineered by multiple gene transfer is a promising strategy for treating autoimmune diseases.

Abatacept↗

PubMed2003

Immunosuppressants in advanced clinical development for organ transplantation and selected autoimmune diseases.

Immunosuppressants dampen the immune response or restore balance among immune system components. They are primarily used to prevent allograft rejection after organ transplantation and to prevent or treat disease flares in autoimmune diseases. Immunosuppressants available at present include the calcineurin inhibitors (cyclosporin, tacrolimus), antimetabolites (azathioprine, leflunomide, methotrexate, mycophenolate mofetil), antiproliferatives (sirolimus), monoclonal antibodies to T lymphocyte (basiliximab, daclizumab, muromonab-CD3) and anticytokines (anakinra, etanercept, infliximab). The immunosuppressive market grows at a rate of > 10% yearly, with total sales in 2001 of US$2.7 billion. Immunotherapy in transplantation and autoimmune diseases is tending towards the use of multi-drug regimens tailored for the individual patient. At least 23 new immunosuppressants are currently in advanced clinical testing or preregistration, and can be divided into three groups. First, emerging drugs targeting intracellular ligands in immune cells are primarily analogues of currently-marketed agents, which attempt to provide improved pharmaceutical or safety profiles compared with the prototype compound. They are largely being developed in organ transplantation. Second, emerging drugs targeting cell surface ligands on immune cells attempt to antagonise novel molecular sites to interfere with immune cell activation via costimulatory signals, immune cell adhesion to tissues or the vasculature and immune cell trafficking. These agents are being primarily developed in rheumatoid arthritis, psoriasis and/or multiple sclerosis. Finally, emerging drugs acting as anticytokines, which largely follow on from the success of those on the market, by antagonising the function of tumour necrosis factor or a narrow selection of interleukins. All are being assessed in rheumatoid arthritis. Drug development of immunosuppressants is increasingly attempting to intervene in disease progression over the long term. These efforts bring with them trial design and regulatory issues, such as what markers can be used as trial outcome measures, over what duration do trials need to be conducted and what labelling claims are allowed. With the intensive activity in this field, it is likely that several new drugs will reach the market in the coming decade. One caveat, however, is that emerging immunosuppressants that are likely to capture a reasonable share of this increasingly-fragmented market must demonstrate the ability to achieve disease remission or long-term slowing of disease progression.

Animals↗

PubMed2006

The Autoimmune Disease Database: a dynamically compiled literature-derived database.

BACKGROUND: Autoimmune diseases are disorders caused by an immune response directed against the body's own organs, tissues and cells. In practice more than 80 clinically distinct diseases, among them systemic lupus erythematosus and rheumatoid arthritis, are classified as autoimmune diseases. Although their etiology is unclear these diseases share certain similarities at the molecular level i.e. susceptibility regions on the chromosomes or the involvement of common genes. To gain an overview of these related diseases it is not feasible to do a literary review but it requires methods of automated analyses of the more than 500,000 Medline documents related to autoimmune disorders. RESULTS: In this paper we present the first version of the Autoimmune Disease Database which to our knowledge is the first comprehensive literature-based database covering all known or suspected autoimmune diseases. This dynamically compiled database allows researchers to link autoimmune diseases to the candidate genes or proteins through the use of named entity recognition which identifies genes/proteins in the corresponding Medline abstracts. The Autoimmune Disease Database covers 103 autoimmune disease concepts. This list was expanded to include synonyms and spelling variants yielding a list of over 1,200 disease names. The current version of the database provides links to 541,690 abstracts and over 5,000 unique genes/proteins. CONCLUSION: The Autoimmune Disease Database provides the researcher with a tool to navigate potential gene-disease relationships in Medline abstracts in the context of autoimmune diseases.

Autoimmune Diseases↗

PubMedDate not supplied

Costimulatory molecules and their ligands as therapeutic targets in autoimmune disease.

The initiation and progression of autoimmune diseases are complex processes that depend on a selective breakdown of tolerance and additional factors like genetic susceptibility and environmental factors, e.g. drugs, infections, toxins and UV light. The causative failure of the immune system to tolerate self can be initiated by molecular mimicry or polyclonal activation with the consequence of a breakdown of anergy or a failure of activation induced cell death. It presents itself in multiple forms including a disturbed balance between TH1 and TH2, alterations in the cytokine milieu and undue modulation of the expression of costimulatory molecules. Although all these features may vary between patients and within the individual patient depending on the state of disease, recent years have provided convincing evidence that, in particular, disease progression is markedly influenced by the expression profile of costimulatory molecules. Since in many forms of autoimmune diseases the causative self-antigen(s) are unknown, therapy largely depends on anti-inflammatory agents or in severe cases on a general immunosuppression. Increasing knowledge of the functional activities of costimulatory molecules in autoimmune disease now provides a new and promising therapeutic modality, which in a more selective way interferes with the pathological activities of immune cells. Here I discuss evidence for the involvement of costimulatory molecules, particularly of CD44 variant isoforms, in autoimmune diseases and their possible use as a therapeutic target. Due to the regulated and restricted expression of these molecules, treatment should not be burdened by severe side effects.

Autoimmune Diseases↗

PubMed1989

[Dilated cardiomyopathy--heart muscle disease of unknown origin or an autoimmune disease? New aspects of etiology, pathogenesis and clinical practice].

Recent evidence suggests that the most common form of idiopathic cardiomyopathy in our altitudes, the dilated cardiomyopathy (DCM), is a post-infectious autoimmune disease which is triggered by virus infections. In animal experiments, the development of the coxsackie virus B3 myocarditis to a congestive cardiac insufficiency resembling the clinical picture of DCM was demonstrated. In mice, species-dependent varying disease courses could be observed, which point to a genetically different behaviour of the animals' immunological reactions, either humoral or T-cell mediated immune reactions being responsible. In comparison with non-DCM patients, patients with DCM and chronic myocarditis exhibit significantly higher coxsackie virus antibody titres. Obviously, also a differently long viral persistency in the cardiac muscle plays a role, as enterovirus-specific RNA was detected in myocardial biopsies from patients with DCM. Along with myocardial fibroses, endomyocardial biopsies in DCM frequently reveal mononuclear cellular infiltrates, which, however, only in 20-25% of the cases may be regarded as chronic persisting myocarditis. The clinical and paraclinical findings in DCM and in the so-called latent cardiomyopathy are presented. In congestive heart failure, the best therapeutic results are achieved by the ACE inhibitors, along with vasodilator agents, digitalis glycosides and diuretics. Ultima ratio is the orthotopic heart transplantation, as it is only this intervention that will be able to improve the primarily bad prognosis decisively. Whether the treatment with immunosuppressive drugs exerts an influence upon the prognosis, has thus far remained an open question.

Animals↗

PubMed1997

[Autoimmune diseases: frequent misdiagnosis].

False diagnosis of autoimmune diseases may have many different reasons. It may be caused by the relative rareness of these rather complicated diseases, by sometimes mono- or oligosymptomatic courses, and by the highly variable clinical presentations. In addition, many physicians lack experience in the treatment of these rheumatologic-immunological diseases. A first shot diagnosis, inadequate technique in obtaining a correct history or in performing a physical examination, as well as an incomplete evaluation of differential diagnosis, are possible causes of wrong diagnosis in the context of autoimmune diseases and may delay effective therapy. To illustrate these problems, three examples of patients with autoimmune diseases are discussed, namely a patient with polyarthritis and fever, a patient with polymyalgia rheumatica, and a patient with an ulcerative skin lesion. These examples serve to discuss the difficulty of correct diagnosis in complicated courses of autoimmune diseases, which are also relatively common in general practice.

Arthritis, Rheumatoid↗

PubMed2001

Intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice.

Intractable autoimmune diseases in chimeric resistant MRL/lpr mice were treated by a new bone marrow transplantation (BMT) method consisting of fractionated irradiation, 5.5 Gy x 2, followed by intra-bone marrow (IBM) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice (5.5 Gy x 2 + IBM). In MRL/lpr mice treated with this method, the number of donor-derived cells in the bone marrow, spleen, and liver rapidly increased (almost 100% donor-derived cells by 14 days after the treatment), and the number of donor-derived hemopoietic progenitor cells concomitantly increased. Furthermore, donor-derived stromal cells were clearly detected in the cultured bone pieces from MRL/lpr mice treated with 5.5 Gy x 2 + IBM. All the recipients thus treated survived more than 1 year (> 60 weeks after birth) and remained free from autoimmune diseases. Autoantibodies decreased to almost normal levels, and abnormal T cells (Thy1.2(+)/B220(+)/CD4(-)/CD8(-)) disappeared. Hematolymphoid cells were reconstituted with donor-derived cells, and newly developed T cells were tolerant to both donor (B6)-type and host (MRL/lpr)-type major histocompatibility complex determinants. Successful cooperation was achieved among T cells, B cells, and antigen-presenting cells when evaluated by in vitro antisheep red blood cell responses. These findings clearly indicate that this new strategy (IBM-BMT) creates the appropriate hemopoietic environment for the early recovery of hemopoiesis and donor cell engraftment, resulting in the complete amelioration of intractable autoimmune diseases in chimeric resistant MRL/lpr mice without recourse to immunosuppressants. This strategy would therefore be suitable for human therapy.

Animals↗

PubMed1972

Virus-associated immunopathology: animal models and implications for human disease. 2. Cell-mediated immunity, autoimmune diseases, genetics, and implications for clinical research.

Part 2 of this memorandum describes further mechanisms whereby the interaction of a virus with the host's immune system may lead to tissue damage. Cell-mediated immunity plays a vital role in promoting recovery from virus infections, but under some circumstances tissue damage may be caused by the reaction of immune cells with viral antigens. When mice are infected with lymphocytic choriomeningitis virus neonatally or as adults while receiving immunosuppressive drugs, widespread invasion of cells is seen but there is little overt disease. If, however, normal adults are infected or if immune cells are transfused into tolerant mice, cell injury and death follow. Viruses have long been suspected of contributing to the pathogenesis of autoimmune diseases. Antibodies directed against normal cell constituents have been reported in several virus infections. Viruses may conceivably unmask or release host antigens, alter host antigens and act as "helper determinants", or perhaps in other ways provoke immune responses against normal body constituents. The immunopathological manifestations caused by viruses may also be influenced by the host's genetic makeup. Certain observations indicate that, in addition to controlling susceptibility to virus infection, genetic factors partly determine the effectiveness of the immune response. The memorandum calls attention to the possible implications of these concepts and findings for clinical research. Some of the diseases of animals and man that serve as models for studies of virus-associated immunopathology are briefly described.

Anemia↗

PubMed2005

Therapeutic potential of glycolipid ligands for natural killer (NK) T cells in the suppression of autoimmune diseases.

NKT cells emerge as important regulatory cells in autoimmune responses. Abnormalities in the numbers and functions of natural killer T (NKT) cells have been observed in patients with autoimmune diseases as well as in a variety of mouse strains that are genetically predisposed for development of autoimmune diseases. Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens presented by the non-polymorphic MHC class I-like protein, CD1d. Recently, we and other groups have demonstrated that administration of glycolipid ligands such as alpha-galactosylceramide (alpha-GC ) or its sphingosine truncated derivative, OCH suppressed autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), diabetes in NOD mice and collagen-induced arthritis (CIA) by inducing T helper (Th) 2 bias of autoimmune T cells. OCH is a unique ligand to stimulate NKT cells to selectively produce Th2 cytokines whereas alpha-GC induces both interleukin (IL)-4 and interferon (IFN)-gamma, and is more beneficial for treatment of a wide variety of Th1-mediated autoimmune diseases. The lack of polymorphism of CD1d and cross-reactive responses of mouse and human NKT cells to the same ligand indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as type I diabetes (T1D), multiple sclerosis (MS) and rheumatoid arthritis (RA). The present review will focus on the potential roles of NKT cells in the pathogenesis of autoimmune diseases and the recent advances in glycolipid therapy for autoimmune disease models. The molecular mechanism of OCH-induced Th2-selective cytokine secretion will also be discussed.

Animals↗

PubMed2002

Coexistence of four autoimmune diseases in one patient: the kaleidoscope of autoimmunity.

Genetic, immune, hormonal, and environmental factors are associated with the multifactorial origin of autoimmunity. When one or more of these factors are altered, a "switch" from one autoimmune condition to another can occur, developing the so called "kaleidoscope phenomenon" of autoimmunity. We present the case of a 30-year-old woman with myasthenia gravis and hypothyroidism probably resulting from autoimmune thyroiditis. A thymectomy was performed, and 1 year later, rheumatoid arthritis was diagnosed based on clinical, radiological, and serological features. Nine years after thymectomy, systemic lupus erythematosus was diagnosed based on skin, renal, hematologic, and immunologic manifestations. We suggest that the immune system function was modified when thymectomy was performed, playing an important role in the development of the new autoimmune conditions. Thymectomy increases the risk of developing a new autoimmune disease because it modifies, by mechanisms not well defined, the equilibrium and normal function of the immune system. This patient presents the infrequent association of four autoimmune conditions. When a patient has one autoimmune disease, she is at risk for another.

Journal Article↗

PubMed2005

alpha-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles.

Autoimmune responses are normally kept in check by immune-tolerance mechanisms, which include regulatory T cells. In recent years, research has focused on the role of a subset of natural killer T (NKT) cells - invariant NKT (iNKT) cells, which are a population of glycolipid-reactive regulatory T cells - in controlling autoimmune responses. Because iNKT cells strongly react with a marine-sponge-derived glycolipid, alpha-galactosylceramide (alpha-GalCer), it has been possible to specifically target and track these cells. As I discuss here, although preclinical studies have shown considerable promise for the development of treatment with alpha-GalCer as a therapeutic modality for autoimmune diseases, several obstacles need to be overcome before moving alpha-GalCer therapy from the bench to the bedside.

Animals↗