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PubMed1976

Experimental autoimmune orchitis: in vitro induction of an autoimmune disease.

Experimental autoimmune orchitis (EAO) can be induced in vitro. Normal lymph node lymphocytes cultured with autologous dissociated testis cells form rosette-like aggregates and later undergo blast transformation and proliferation. These stimulated lymphocytes cause in vivo EAO lesions, when injectd into syngeneic recipients. Moreover, their autoimmune reactivity can be monitored by an in vitro cytostasis assay. Density gradient analysis of the early lymphocyte-testis cultures reveals that the autoimmune reactive lymphocytes are enriched in the rosette populations. It therefore appears that testicular self-antigens are recognized by clonally preformed autologous lymphocytes.

Animals↗

PubMed1992

[Hearing loss in autoimmune diseases].

Several autoimmune disorders are associated with inner ear involvement. The resulting sensorineural loss of hearing may be improved by treatment with immunosuppressive agents. We describe a patient with oral ulcerations, systemic vasculitis, iridocyclitis and bilateral sudden deafness. After a course of systemic steroid treatment the hearing improved. Atypical Cogan's syndrome is the most likely diagnosis.

Aged↗

PubMed2006

Estrogen regulation of nitric oxide and inducible nitric oxide synthase (iNOS) in immune cells: implications for immunity, autoimmune diseases, and apoptosis.

Nitric oxide plays a central role in the physiology and pathology of diverse tissues including the immune system. It is clear that the levels of nitric oxide must be carefully regulated to maintain homeostasis. Appropriate levels of nitric oxide derived from iNOS assist in mounting an effective defense against invading microbes. Conversely, inability to generate nitric oxide results in serious, even fatal, susceptibility to infections. Further, dysregulation or overproduction of nitric oxide has been implicated in the pathogenesis of many disorders, including atherosclerosis, neurodegenerative diseases, inflammatory autoimmune diseases, and cancer. Therefore, depending upon the levels of nitric oxide generated, the potential exists for nitric oxide to behave like a "double-edged" biological sword. Taking these issues into consideration, it is thus pivotal to understand the regulation of nitric oxide. Nitric oxide is regulated by many endogenous factors including hormones such as estrogens. While the effects of estrogen on the generation of nitric oxide in non-immune tissues are relatively well documented, the effect of estrogen on iNOS/nitric oxide in immune cells is only now becoming apparent. Our laboratory has recently shown that estrogen treatment of mice markedly upregulates the levels of iNOS mRNA, iNOS protein, and nitric oxide in activated splenocytes. This upregulation of nitric oxide is in part mediated through interferon-gamma (IFN-gamma), a pro-inflammatory cytokine that is enhanced by estrogen. These findings are important considering that estrogens are not only involved in regulation of normal immune responses, but also are implicated in many autoimmune and inflammatory diseases. To date, there are no reviews on the effects of estrogen on immune tissue-derived nitric oxide and therefore this review will address this critical gap in the literature. Given the increasing importance of immune-tissue-derived iNOS in health and disease, studies on estrogen-induced regulation of iNOS may offer a better understanding of diseases and aid in devising new therapeutic interventions.

Animals↗

PubMed2004

Autoimmune disease 2002: an overview.

Autoimmune disease includes a large spectrum of clinically distinct entities that share a common etiology, a misguided, self-directed immune response. Collectively, they are major contributors to morbidity and mortality. Normally, the body utilizes a number of strategies to avoid the pathologic consequences of autoimmune reactions, but these defenses may fail for a combination of hereditary and environmental factors. Infection has long been regarded as a common environmental trigger of autoimmune disease. Our laboratory has developed a mouse model of myocarditis induced by Coxsackievirus B3 infection and demonstrated some of the steps involved in the transition from an infection to an autoimmune disease. Such basic studies may suggest improved treatment or preventive measures for this group of diseases.

Autoimmune Diseases↗

PubMed2001

The epidemiology and significance of autoimmune diseases in health care.

Autoimmune diseases are conditions in which the immune system damages normal components of the individual. Some estimates indicate that more than 20% of the population suffer from one or another autoimmune disease. Ten key points are briefly reviewed in this article to emphasise the significance of autoimmune diseases in health care. These include, among others, the great variety and worldwide distribution of these conditions, the clinical importance of some of these diseases such as systemic lupus erythematosus, the antiphospholipid syndrome, Sjögren's syndrome or systemic sclerosis, or the relationship between autoimmunity and virus infections, atherosclerosis, malignancy and Psychiatry.

Antiphospholipid Syndrome↗

PubMed2006

Therapeutic strategies in autoimmune diseases by interfering with leukocyte endothelium interaction.

The interaction of leukocytes with the vessel endothelium to facilitate the extravasation into the tissue represents a key process of the body's defense mechanisms. Excessive recruitment of leukocytes into the inflamed tissue in chronic diseases like autoimmune disorders could be prevented by interfering with the mechanisms of leukocyte extravasation. Significant progress in elucidating the molecular basis of the trafficking of leukocytes from the blood stream to the extravascular tissue has been achieved that enables new strategies for therapeutic approaches. The multistep process of leukocyte rolling, firm adhesion and transmigration through the endothelial wall is facilitated by a dynamic interplay of adhesion receptors on both leukocytes and endothelial cells as well as chemokines. In preclinical studies using various animal models, promising results have been received demonstrating that blocking of adhesion receptors of the selectin and integrin families improved the inflammation process in models of ulcerative colitis, autoimmune encephalomyelitis or contact hypersensitivity. In addition to the targeting of adhesion receptors by antibodies, small molecules that mimic epitopes of adhesion receptor ligands have been developed and successfully applied in animal models. Clinical studies revealed a limited response using antibodies to selectins or LFA-1 integrins compared with animal models. However, using humanized antibodies to the alpha4- integrin subunit significant efficacy has been demonstrated in autoimmune diseases like psoriasis, multiple sclerosis and inflammatory bowel disease.

Animals↗

PubMed1992

[Virus and autoimmune disease. An excursion exemplified by autoimmune hepatitis].

At least since the discovery of the acquired immune deficiency syndrome and the "human immune deficiency virus" (HIV) it has been widely accepted, that viruses infect lymphocytes (mainly especially CD 4 positive helper lymphocytes) and can also be responsible for their deletion. However, since the HIV can only be found in a small proportion of the dying lymphocytes, other viruses as well as other (nonviral) cytotoxic agents and mechanisms must be taken into consideration. The conception of involved autoimmune phenomena is being accepted increasingly. Storch's hypothesis put forward in 1975, of primary or secondary viral infection of lymphocytes as pathogenetical principle of autoimmune hepatitis (infected B- and T-lymphocytes stimulate directly or indirectly the antibody synthesis and also trigger abnormal cellular immune reactions) was confirmed. Teleologically regarded, in most cases it remains open if the demonstrable autoantibodies and immune cells are pathogenic, protective, or indifferent for the individual. Analogous to symbiosis and parasitism, this postulate can be extended to pathogenic viral infections. Assuming that the human organism is anxious to remain unharmed and, like viruses maintain its adaptability by a system of multiform control systems one can imagine, that the autoimmunity induced by and therefore directed primarily against viruses can be regarded as "physiological", thus representing a protective mechanism against disturbing exogenous and endogenous factors. It can be considered part of the "prophylaxien" (Holle, 1989). Likewise, in autoimmune hepatitis as well, new findings speak for a participation of several (various) viruses in its aetiopathogenesis. It is hypothesized, that so-called "autogenes" exist which lead to autoimmune disease (like oncogenes involved in the pathogenesis of malignancies).

Autoantibodies↗

PubMed2004

Pulmonary manifestations of systemic autoimmune disease.

Patients with systemic autoimmune disease may present with a number of different pulmonary manifestations. In order to recognise, diagnose and manage these manifestations, it is necessary to have a working knowledge of the anatomy and physiology of the thorax. This chapter will describe the clinical symptoms and clinical examination findings in patients who may have underlying pulmonary disease. It will describe the investigations that can be used to confirm or refute a possible diagnosis and describe approaches to managing these complex clinical cases. The importance of multidisciplinary team working using the skills of clinicians, radiologists and pathologists will be highlighted. The use of high-resolution computed tomography scanning of the thorax to help to delineate the type of interstitial lung disease will be described and some of the newer modalities available for the treatment of pulmonary hypertension introduced. By the end of the chapter, the reader should understand that patients with a single underlying autoimmune disease may present with one or more pulmonary manifestations and that different autoimmune diseases may present with similar pulmonary manifestations. This heterogeneity poses both diagnostic and treatment challenges, and many questions still remain regarding optimal treatment.

Autoimmune Diseases↗

PubMed2003

Recombinant autoantigens for diagnosis and therapy of autoimmune diseases.

The characteristic of autoimmune diseases resides in the existence of T- and B-cell autoreactivity when directed against self-proteins. Thus autoantibodies are considered to be of diagnostic relevance. The advent of recombinant protein expression technology has made it possible to produce economically high-quality autoantigens for use in immunoassays for detecting autoantibodies in patients' sera. The intention of this short review is to give the reader a brief description of autoantigen production methodologies with their advantages, disadvantages and the limitations of these techniques in the diagnostics of autoimmune diseases. Further possible usage of recombinant autoantigens as tools in investigation and therapy of autoimmune diseases is discussed.

Autoantigens↗

PubMed1996

Does malarial tolerance, through nitric oxide, explain the low incidence of autoimmune disease in tropical Africa?

Autoimmune disease is generally rare in tropical rural populations. Plasma concentrations of nitrite plus nitrate (reactive nitrogen intermediates), reflecting high nitric-oxide production somewhere in the body, can be high in patients who have cerebral malaria, but even higher in symptom-free parasitised individuals, who are termed malaria-tolerant. We propose that the nitric oxide causing high serum levels of reactive nitrogen intermediates in malaria-tolerant individuals is generated in macrophages during the establishment and maintenance of malarial tolerance, and makes autoimmune disease rare in many tropical rural populations by minimising proliferation of autoreactive T cells. Conversely, innately low levels of nitric-oxide generation in these populations, selected by malarial disease in tropical areas, could rationalise their high frequency of autoimmune disease and hypertension when living in western societies.

Africa↗

PubMed2001

A novel role for interleukin-18 in human natural killer cell death: high serum levels and low natural killer cell numbers in patients with systemic autoimmune diseases.

OBJECTIVE: Patients with systemic autoimmune diseases have been reported to have reduced numbers of peripheral blood natural killer (NK) cells compared with healthy subjects. The ability of selected cytokines to trigger NK cell death prompted us to compare the levels of peripheral blood cytokines with the numbers of NK cells in patients with various systemic autoimmune diseases. METHODS: We used enzyme-linked immunosorbent assays to measure the concentration of selected cytokines (interleukin-18 [IL-18], IL-15, IL-12, IL-2, interferon-gamma [IFNgamma], and tumor necrosis factor alpha [TNFalpha]) in sera from 58 patients with systemic autoimmune diseases and 33 healthy controls. The absolute number of T cells and NK cells in the peripheral blood was measured in parallel using flow cytometry. The ability of selected cytokines to induce NK cell death was then measured using 3,3'-dihexyloxacarbocyanine iodide dye, propidium iodide staining, and caspase 3 activity. RESULTS: Levels of IL-18, IL-15, IFNgamma, and TNFalpha were elevated in sera from patients with systemic autoimmune diseases compared with normal controls. The percentage of NK cells and natural killer T cells were significantly decreased in the peripheral blood of patients with systemic autoimmune diseases compared with normal controls. Serum concentrations of IL-18, IL-15, and TNFalpha were inversely related to the number of NK cells in both patients and healthy controls. The combination of IL-18 and IL-15 or IL-18 and IL-12 induced NK cell death in vitro. The combination of IL-18 and IL-15 or IL-18 and IL-12 enhanced IFNgamma and TNFalpha production by NK cells in vitro. Cytokine-induced NK cell death is caspase-dependent and is partially blocked by neutralizing antibodies against TNFalpha. CONCLUSION: High levels of IL-18 and IL-15 are associated with the decreased number of NK cells that is observed in patients with systemic autoimmune diseases.

Adolescent↗

PubMed1987

[Plasmapheresis treatment in 3 simultaneously occurring autoimmune diseases: Hashimoto thyroiditis with hyperthyroidism, autoimmune thrombopenia and autoimmune hemolytic anemia].

A 49 year-old women with a 2-year history of a Coombs-positive autoimmune haemolytic anaemia was hospitalized with Hashimoto's thyroiditis and thyrotoxic crisis. The clinical course was further complicated by an autoimmune thrombocytopenia. Primary resection of the thyroid thus seemed to be too risky, so we decided to perform therapeutic plasma exchange. This led to clinical improvement, enabling us to perform a thyroidectomy. The present investigation reveals the high efficiency of plasmapheresis in the treatment of combined autoimmune diseases. Therapeutic plasma exchange resulted in a reduction of both the relevant autoantibodies and the level of circulating thyroid hormones.

Anemia, Hemolytic, Autoimmune↗

PubMedDate not supplied

[Immunoablation or otherwise followed by hematopoietic cell stem as intensive treatment of severe autoimmune diseases].

The treatment of severe autoimmune diseases has been recently revitalized by the increasing utilization of clinical interventions aimed at ablating/abrogating autoimmune lymphoid clones followed (but not in certain procedures) by transplantation of allogeneic, but also autologous, hematopoietic stem cells. Two different investigative avenues have paved the way to specific clinical studies. The first originates from the epochal murine experiments of the '70s, and has been greatly expanded in the last decade. A graft-versus-autoimmunity effect could also be demonstrated. In addition, it could also be shown that induced experimental autoimmune diseases such as adjuvant arthritis and autoimmune encephalomyelitis could, surprisingly, be cured following autologous transplantation. The first results in humans were observational and derived from studies including patients with coincidental diseases (severe autoimmune diseases plus leukemia/aplasia) treated with allogeneic hematopoietic stem cell transplants. Although the concept of an allogeneic transplant is indisputably more appealing, very few patients with an isolated severe autoimmune disease have been treated using such a therapeutic approach. Reduced intensity conditioned transplants relying on subsequent graft-versus-autoimmunity effects strengthened by donor lymphocyte infusions are being explored cautiously. On the other hand, autologous transplants are being performed quite extensively. To date, transplanted severe autoimmune diseases include multiple sclerosis, connective tissue diseases (systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis) and many others. It is uncertain if the main mechanism is solely immunoablative, or whether tolerized lymphocytes may also develop during a postulated "window of opportunity" following the transplant.

Animals↗

PubMed2002

Developments in hematopoietic stem-cell transplantation in the treatment of autoimmune diseases.

Intractable forms of autoimmune diseases follow a rapid course, with a significantly shortened life expectancy sometimes comparable to that of malignant diseases. Immunoablative therapy, including high dose cytotoxic agents and hematopoietic autologous stem-cell rescue, was recently introduced as an aggressive approach to treat autoimmune diseases that have a rapid course and are resistant to conventional therapy. The most frequent indication for this type of treatment is multiple sclerosis, seconded by systemic sclerosis. The results of immunoablative treatment with documented responses in both diseases are encouraging. The data are mature enough to begin comparative randomized studies of immunoablative versus conventional treatment to validate the benefit of the aggressive approach. A randomized trial involving SSc was recently launched (ASTIS) and a trial involving MS is in preparation. Considerably less experience with immunoablative treatment has been gained in systemic lupus erythematosus, rheumatoid arthritis, and other disorders with an autoimmune pathophysiology. Autologous hematopoietic stem cell transplantation in humans offers more long-lasting immunosuppression than reeducation of lymphocytes. In fact, allogeneic transplantation may replace the whole immune system. However, this attractive approach is still associated with considerable morbidity and mortality and is not yet justified for treatment of autoimmune diseases. Non-myeloablative allogeneic transplantation and sub-myeloblative high dose cyclophosphamide without stem cell support are alternative approaches that could be explored in pilot studies.

Arthritis, Rheumatoid↗

PubMed1990

Dysregulated expression of the T cell cytokine Eta-1 in CD4-8- lymphocytes during the development of murine autoimmune disease.

The development of autoimmune disease in the MRL/MpJ-lpr inbred mouse strain depends upon the maturation of a subset of T lymphocytes that may cause sustained activation of immunological effector cells such as B cells and macrophages. We tested the hypothesis that abnormal effector cell activation reflects constitutive overexpression of a T cell cytokine. We found that a newly defined T cell cytokine, Eta-1, is expressed at very high levels in T cells from MRL/l mice but not normal mouse strains and in a CD4-8- 45R+ T cell clone. The Eta-1 gene encodes a secreted protein that binds specifically to macrophages, possibly via a cell adhesion receptor, resulting in alterations in the mobility and activation state of this cell type (Patarca, R., G. J. Freeman, R. P. Singh, et al. 1989. J. Exp. Med. 170:145; Singh, R. P., R. Patarca, J. Schwartz, P. Singh, and H. Cantor. 1990. J. Exp. Med. 171:1931). In addition, recent studies have indicated that Eta-1 can enhance secretion of IgM and IgG by mixtures of macrophages and B cells (Patarca, R., M. A. Lampe, M. V. Iregai, and H. Cantor, manuscript in preparation). Dysregulation of Eta-1 expression begins at the onset of autoimmune disease and continues throughout the course of this disorder. Maximal levels of Eta-1 expression and the development of severe autoimmune disease reflect the combined contribution of the lpr gene and MRL background genes.

Animals↗

PubMed2006

Anti-thyroid autoantibody-associated interface dermatitis in individuals with undifferentiated connective tissue disease--an unrecognized subset of autoimmune disease?

OBJECTIVE: Skin conditions in individuals with undifferentiated connective tissue disease (UCTD) are poorly classified and characterized, and autoantibodies in serum can be heterogeneous and not always specific. We have identified a new subset of individuals with UCTD, interface dermatitis, and increased anti-thyroid antibodies. METHODS: We retrospectively reviewed 892 cases of individuals with UCTD. Serologic markers for CTD and autoantibodies against microsomes and/or thyroglobulin were analyzed. Skin lesions and medication history were documented, and persistent or recurrent skin lesions were biopsied. RESULTS: Anti-thyroid antibodies for thyroglobulin and/or microsomes (ATAb) were positive in 526 (59%). The ATAb(+) and ATAb(-) groups had similar antinuclear antibody (ANA) positivity (32% vs 28%, respectively), average age (59 vs 58 yrs), and female-male ratio (8:1 vs 6:1). ATAb positivity was significantly associated with a dermatitis manifested as erythematous macules/patches or papules on legs, upper arms, back, and shoulders in 9% (47/526) of ATAb(+) individuals versus 2% (7/366) in ATAb(-) individuals (p < 0.0001). Seventeen individuals with dermatitis, 15 ATAb(+) and 2 ATAb(-), had biopsies. Twelve biopsies (80%) from ATAb(+) individuals and one ATAb(-) individual showed a cell-poor lymphocytic interface dermatitis with vaculopathy of basal layer keratinocytes, dermal mucin deposition, and perivascular mononuclear inflammatory cell infiltrates in the upper dermis that spared eccrine glands. The interface dermatitis was not significantly associated with hypo- or hyperthyroidism, or medications. CONCLUSION: We describe an ATAb-associated interface dermatitis in roughly 9% of ATAb(+) patients with UCTD, which may represent a new subset of autoimmune disease. ATAb may be a useful marker for some individuals with UCTD.

Adolescent↗

PubMed2000

Transgenic animal models for virus-induced autoimmune diseases.

In the pathogenesis of autoimmune diseases, tolerance against self-determinants is lost and autoreactive lymphocytes are activated leading to pathological damage of single or multiple organs. Viral and other microbial infections have been implicated in these processes. Viruses may induce immunopathological damage by maintaining a chronic immune response against the locally persisting infectious agent. Alternatively, viruses may help to initiate anti-self immunoreactivity, e.g. by induction of an inflammatory milieu needed to overcome tolerance against self-antigens. Presentation of viral antigens and/or previously immunologically ignored self-antigens in secondary lymphoid organs is most probably the key event in the initiation of autoimmune diseases. Translocation of antigens to secondary lymphoid organs and primary induction of T cell responses is primarily mediated by dendritic cells (DCs). We discuss here two transgenic models of autoimmune diseases where DC-mediated antigen transport initiated autoimmune responses against microbial neoself antigens. In the first model, dose and timing of antigen delivery by DCs and turnover of antigenic peptides presented by DCs are the main parameters regulating the outcome of autoimmune diabetes. In the second model, chronic stimulation of organ-specific immune responses via DCs leads to severe cardiovascular immunopathology with arteritis, myocarditis and eventually dilated cardiomyopathy. Taken together, transgenic mouse models are valuable tools for delineating basic pathogenic mechanisms and evaluating therapeutic strategies to interfere with early detrimental processes that lead to manifest autoimmune diseases.

Animals↗

PubMed2004

Familial clustering of autoimmune diseases in patients with dilated cardiomyopathy.

In this study, we examined the hypothesis that dilated cardiomyopathy (DCM) shares genetic risk factors with other diseases of presumed autoimmune etiology, and, therefore, the same multiple genes in combination with environmental factors lead to numerous different autoimmune diseases. In accordance with this hypothesis, we showed an increased prevalence of autoimmune diseases in first-degree relatives of patients with DCM. Also, T-cell activation, as reflected in high levels of the soluble interleukin-2 receptor, appears to identify patients with DCM with a clustering of autoimmune diseases.

Adult↗