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PubMed1994

[Genetics of autoimmune diseases].

Strategies for studying the genetics of autoimmune diseases have undergone a considerable evolution during the last years, especially due to molecular biology techniques and to systematic genome studies. Genetic factors account for 20 to 40% of the risk, and environmental elements play a major role. The major histocompatibility complex comprising HLA genes remains the immunogenetic system most studied and most closely associated with various autoimmune diseases. These associations are mainly observed with HLA class II genes polymorphisms; the precise knowledge of their structure has allowed to define HLA sequence polymorphisms which are themselves risk markers: specific combinations of HLA-DQA and DQB alleles in insulin-dependent diabetes mellitus or a given DR, DQ haplotype for multiple sclerosis. No strong association with HLA-DP has been demonstrated. In all cases the genes involved have a normal structure and the disease is secondary to the combination of a given set of genes with environmental factors. The present knowledge of insulin-dependent diabetes mellitus and multiple sclerosis genetics is rather advanced. Other genes of the HLA region might also be involved in the genetic susceptibility. Results about other immunogenetic systems (T cell receptor genes or heavy chain immunoglobulin genes) are still contradictory but no major gene for autoimmune susceptibility seems to exist in these regions; however autoimmune diseases are under polygenic control; susceptibility genes shared between different diseases often occurring within the same families (Graves' disease and insulin-dependent diabetes mellitus) and genes specific for a given disease (insulin gene region in diabetes) both exist. The present rapid progress in this area is due to the use of highly polymorphic markers randomly distributed across the genome (microsatellites being most informative) and that of animal models: the list of "candidate genes or regions" potentially involved in the genetics of autoimmune diseases is enlarging; the development of coordinated epidemiological studies of molecular genetics along with the sharing of biological resources between different teams allow to build up powerful informative studies which will confirm or refute those "candidates". However, once the list of genes involved is established their mechanism of action will still take time to elucidate.

Autoimmune Diseases↗
PubMed1980

Effect of castration on male-determined acceleration of autoimmune disease in BXSB mice.

The autoimmune disease of BXSB mice is markedly accelerated by a Y chromosome-associated male-specific factor. In order to investigate the mechanism of this effect, we castrated male and female BXSB mice at 10 days of age and compared the course of development of their autoimmune syndrome with that of sham-operated, sex-matched, littermate controls. Orchiectomy did not delay the early onset of fatal immunopathology in males, and oophorectomy did not exacerbate the indolent progression of morbidity in females. We conclude, therefore, that the male-specific effect that accelerates BXSB autoimmune disease is not hormonally mediated.

Animals↗
PubMed1993

Autoimmune diseases--at the molecular level.

Autoimmunity and autoimmune diseases are the focus of intensive research using the concepts and tools of immunology, molecular genetics and cell biology. A group of scientists recently gathered to discuss recent developments in organ-specific and systemic autoimmune diseases in both human and animal models. In this article, we hope to convey some of the excitement and enthusiasm evident at the meeting which placed emphasis on work at the molecular level.

Animals↗
PubMed2004

TLR4 contributes to disease-inducing mechanisms resulting in central nervous system autoimmune disease.

Environmental factors strongly influence the development of autoimmune diseases, including multiple sclerosis. Despite this clear association, the mechanisms through which environment mediates its effects on disease are poorly understood. Pertussis toxin (PTX) functions as a surrogate for environmental factors to induce animal models of autoimmunity, such as experimental autoimmune encephalomyelitis. Although very little is known about the molecular mechanisms behind its function in disease development, PTX has been hypothesized to facilitate immune cell entry to the CNS by increasing permeability across the blood-brain barrier. Using intravital microscopy of the murine cerebromicrovasculature, we demonstrate that PTX alone induces the recruitment of leukocytes and of active T cells to the CNS. P-selectin expression was induced by PTX, and leukocyte/endothelial interactions could be blocked with a P-selectin-blocking Ab. P-selectin blockade also prevented PTX-induced increase in permeability across the blood-brain barrier. Therefore, permeability is a secondary result of recruitment, rather than the primary mechanism by which PTX induces disease. Most importantly, we show that PTX induces intracellular signals through TLR4, a receptor intimately associated with innate immune mechanisms. We demonstrate that PTX-induced leukocyte recruitment is dependent on TLR4 and give evidence that the disease-inducing mechanisms initiated by PTX are also at least partly dependent on TLR4. We propose that this innate immune pathway is a novel mechanism through which environment can initiate autoimmune disease of the CNS.

Animals↗
PubMed1995

[Quantitative flowcytometric analysis of B cell surface antigens in patients with autoimmune diseases].

In 47 cases of autoimmune diseases (25 SLE, 9 MCTD, 6 PSS, 7 RA), two B cell surface antigens, CD19 and CD20 were quantitatively measured with a flowcytometer. When compared with the results of healthy controls, CD19 antigens were observed to be ca. 10% decreased in SLE and ca. 20% increased in RA. CD20 antigens were observed to be ca. 25% increased in SLE and no changes in RA. No significant increase nor decrease was observed with MCTD and PSS patients. In SLE patients, the amount of CD19 antigen expression was positively related to serum C3 levels, and that of CD20 antigen was negatively related to it. It is not obvious in what mechanism the expression of these antigens are regulated, however, from the point that the expression relates to the amount of serum C3 level, the quantitative measurement of CD19 and CD20 antigens is possibly be a good marker to detect the state of autoimmune disease such as SLE.

Antigens, CD↗
PubMed2001

Lymphopenia in occupational pulmonary silicosis with or without autoimmune disease.

An increased prevalence of autoimmune diseases such as rheumatoid arthritis has been demonstrated in silica-exposed patients. The aim of this study was to determine the peripheral blood lymphocyte phenotype in a population of silicotic workers employed in the slate mines of the district. Silicosis was assessed in 58 patients according to the International Labor Office's criteria. Clinical and biological data including flow cytometric evaluation of the lymphocyte subsets were compared with those from 41 healthy volunteers. The silicotic patients had a higher prevalence of autoimmune diseases (6/58 versus 0/41: P < 0.05) and of elevated antinuclear antibody titres compared to the control group. A very significant decrease of total lymphocyte count (P < 0.001) involving B, T and Natural Killer cells was found in silicotic patients as compared with matched healthy volunteers. A significant increase in the percentage of activated T cells (12.3%) was observed in the silicotic group as compared to 6.5% in the control group (P = 5 x 10(-5)). Our results show that in silicotic patients, the absolute number of circulating lymphocytes is diminished with an increased proportion of activated T cells. Whether these findings could predispose to the development of autoimmune disorders is discussed.

Adult↗
PubMed2003

Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases.

I hypothesize that human chronic autoimmune diseases are based on infection of autoreactive B lymphocytes by Epstein-Barr virus (EBV), in the following proposed scenario. During primary infection, autoreactive B cells are infected by EBV, proliferate and become latently infected memory B cells, which are resistant to the apoptosis that occurs during normal B-cell homeostasis because they express virus-encoded anti-apoptotic molecules. Genetic susceptibility to the effects of B-cell infection by EBV leads to an increased number of latently infected autoreactive memory B cells, which lodge in organs where their target antigen is expressed, and act there as antigen-presenting cells. When CD4(+) T cells that recognize antigens within the target organ are activated in lymphoid organs by cross-reactivity with infectious agents, they migrate to the target organ but fail to undergo activation-induced apoptosis because they receive a co-stimulatory survival signal from the infected B cells. The autoreactive T cells proliferate and produce cytokines, which recruit other inflammatory cells, with resultant target organ damage and chronic autoimmune disease.

Autoimmune Diseases↗
PubMed1997

Role of alfacalcidiol on bone quality and immunomodulation in autoimmune disease and organ transplantation.

In autoimmune diseases, as well as in organ transplantation, corticosteroids are often an obligatory part of the treatment regimen. The deleterious effect of corticosteroids on bone metabolism is well known, although still controversial [1-3]. It is easier to maintain bone mass than to restore it. Although the treatment of choice for prevention of bone loss is hormone replacement therapy, it cannot always be applied, and for many reasons compliance is low over the world. Alternative strategies to prevent bone loss are now tried out in many centers. Calcitonin and bisphosphonates are well-known antiresorbing drugs, but costs and long-term efficiency for calcitonin and fear for bone toxicity for the bisphosphonates limits their use for prevention. An attractive strategy to prevent osteoporosis is the treatment with alfacalcidiol because it is a natural product with important effects on bone metabolism in physiological and pharmacological dosages. Calcium absorption from the gut and mineralization of the bone matrix are optimalized by alfacalcidiol. The purpose of this paper is to report on our experience with alfacalcidiol concerning bone mass and quality in corticosteroid-induced osteoporosis in experimental animals and on long-term bone quality in autoimmune diseases and organ transplantation. We have studied the effects of alfacalcidiol on bone mass and quality in ovariectomized animals with and without corticosteroids. In these fundamental studies we have found that alfacalcidiol had a profound protective and curative effect not only on bone mass but also on bone quality as tested by mechanical testing, namely, impact torsional loading test of whole bones. The combination of alfacalcidiol with estrogens was less effective than alfacalcidiol, but more effective than estrogens alone [4-6] (Fig. 1).

Autoimmune Diseases↗
PubMed2004

Is primary biliary cirrhosis a model autoimmune disease?

Primary biliary cirrhosis (PBC) has been coined a model autoimmune disease. In fact, it does share many similarities with other autoimmune diseases, but there are striking differences that illustrate the uniqueness of the immunopathology. Firstly, similar to other autoimmune diseases, there is an intense humoral and cellular response to an intracytoplasmic antigen. There is also an overlap of the epitopes recognized by autoreactive CD4(+), CD8(+) T cells as well as B cells. Patients with PBC are also predominantly female, and there is a higher family history of other autoimmune diseases. In contrast, however, there are no specific HLA associations in PBC. Further, there are no spontaneous or induced animal models of PBC. In addition, early in the biliary lesions of PBC, there is an eosinophilic infiltration and, often, there are granulomas. Finally, unlike several other human autoimmune diseases, patients with PBC have recognition of but one major epitope, and there is no evidence for determinant spreading. Hence, although the immune response of PBC has been vigorously defined, there remain major gaps in understanding the most difficult issue of all, namely etiology.

Autoantigens↗
PubMed1998

Dietary n-6 and n-3 fatty acids in immunity and autoimmune disease.

Clearly there is much evidence to show that under well-controlled laboratory and dietary conditions fatty acid intake can have profound effects on animal models of autoimmune disease. Studies in human autoimmune disease have been less dramatic; however, human trials have been subject to uncontrolled dietary and genetic backgrounds, infection and other environmental influences, and basic trial designs have been inadequate. The impact of dietary fatty acids on animal autoimmune disease models appears to depend on the animal model and the type and amount of fatty acids fed. Diets low in fat, essential fatty acid-deficient, or high in n-3 fatty acids from fish oils increase the survival and reduce disease severity in spontaneous autoantibody-mediated disease, whilst linoleic acid-rich diets appear to increase disease severity. In experimentally-induced T-cell-mediated autoimmune disease, essential fatty acid-deficient diets or diets supplemented with n-3 fatty acids appear to augment disease, whereas n-6 fatty acids prevent or reduce the severity. In contrast, in both T-cell and antibody-mediated auto-immune disease the desaturated and elongated metabolites of linoleic acid are protective. Suppression of autoantibody and T lymphocyte proliferation, apoptosis of autoreactive lymphocytes, and reduced pro-inflammatory cytokine production by high-dose fish oils are all likely mechanisms by which n-3 fatty acids ameliorate autoimmune disease. However, these could be undesirable long-term effects of high-dose fish oil which may compromise host immunity. The protective mechanism(s) of n-6 fatty acids in T-cell- mediated autoimmune disease are less clear, but may include dihomo-gamma-linolenic acid- and arachidonic acid-sensitive immunoregulatory circuits such as Th1 responses, TGF beta 1-mediated effects and Th3-like responses. It is often claimed that n-6 fatty acids promote autoimmune and inflammatory disease based on results obtained with linoleic acid only. It should be appreciated that linoleic acid does not reflect the functions of dihomo-gamma-linolenic and arachidonic acid, and that the endogenous rate of conversion of linoleic to arachidonic acid is slow (Hassam et al. 1975, 1977; Phylactos et al. 1994; Harbige et al. 1995). In addition to effects of dietary fatty acids on immunoregulation, inflammation as a consequence of immune activation in autoimmune disease may also be an important mechanism of action whereby dietary fatty acids modulate disease activity. In conclusion, regulation of gene expression, signal transduction pathways, production of eicosanoids and cytokines, and the action of antioxidant enzymes are all mechanisms by which dietary n-6 and n-3 fatty acids may exert effects on the immune system and autoimmune disease. Probably the most significant of these mechanisms in relation to our current understanding of immunoregulation and inflammation would appear to be via fatty acid effects on cytokines. The amount, type and balance of dietary fatty acids and associated antioxidant nutrients appear to impact on the immune system to produce immune-deviation or immunosuppressive effects, and to reduce immune-mediated inflammation which will in turn affect the susceptibility to, or severity of, autoimmune disease.

Animals↗
PubMed2005

[Association between serum markers for celiac and thyroid autoimmune diseases].

Celiac disease (CD) is an autoimmune disease of the small bowel characterized by a strong genetic association with HLA - DQ2 and DQ8. Gluten is the etiological factor and the tissue enzyme transglutaminase (TGase) is its autoantigen. CD is associated with several autoimmune diseases such as type 1 diabetes, systemic lupus erythematous, rheumatoid arthritis, Sjögrens syndrome and autoimmune thyroid diseases. The aim of this study was to investigate the occurrence of serum IgA anti-endomysial and anti-human TGase antibodies in individuals with positive anti-thyroid antibody (ATA). The concordance between these two tests was also evaluated. Anti-endomysial antibodies were positive in 10 out of 456 (2.2%) and anti-human TGase were positive in 14 of 454 (3.1%) individuals with positive ATA. In control subjects they were positive in 1 of 197 (0.5%) and 2 of 198 (1%) for anti-endomysial and anti-human tissue TGase antibodies, respectively. The odds ratio (OR) for the anti-endomysial antibodies was 4.42 and for the anti-human TGase 3.12 in individuals with ATA when compared with controls. An elevated concordance index (k= 0.84) was observed between anti-endomisyal antibodies and anti-human TGase. We conclude that the determination of anti-TGase antibodies is a good test for DC screening.

Adolescent↗
PubMed1994

[New approaches to the regulation of autoimmune disease].

Recent advancement in immunology has revealed that autoimmune diseases occur when T lymphocytes become activated on recognizing a self-antigen linked to the autologous class II molecule of the major histocompatibility complex (MHC). The resulting complex of antigen, MHC, and T cell receptor could be a target for treatment of autoimmune disease. This approach is now being studied in animal models. Experimental autoimmune uveoretinitis is a T cell mediated autoimmune disease directed against retinal proteins and has been studied as a model for human uveitis. In Lewis rats, uveitogenic peptides and uveitogenic T cell receptor families have been detected. It is a first step toward developing specific immunotherapy. This paper describes a general outline of the steps of T cell activation and ways of suppression of autoimmune diseases by the modulation of these steps, especially in experimental autoimmune uveoretinitis.

Amino Acid Sequence↗
PubMed2000

Autoimmune disease in first-degree relatives of patients with multiple sclerosis. A UK survey.

Previous studies examining an association with other autoimmune diseases have suggested the existence of a generalized autoimmune diathesis in patients with multiple sclerosis. We investigated the prevalence of autoimmune disease in first-degree relatives of probands with multiple sclerosis using a case-control method. The results show an excess of autoimmune disease within these families, but no significant association was seen with non-autoimmune diseases. The higher risk in multiplex than simplex families suggests an effect of genetic loading. While the increase in risk applies to each autoimmune disease, autoimmune thyroid disease (and Graves' disease in particular) contributes disproportionately to the excess risk. There was no increase in autoimmune disease within patients with multiple sclerosis themselves when compared with the index controls or population data. We conclude that autoimmune disease is more common in first-degree relatives of patients with multiple sclerosis and hypothesize that common genetic susceptibility factors for autoimmunity co-exist with additional disease specific genetic or environmental factors, which determine clinical phenotype in the individual.

Adolescent↗
PubMed2025

Causal effect of three autoimmune diseases on brain functional networks and cerebrospinal fluid metabolites to underlie the pathogenesis of autoimmune psychosis: a two-sample mendelian randomization analysis.

BACKGROUND: Autoimmune diseases such as Systemic Lupus Erythematosus (SLE), Sj&#xf6;gren's Syndrome (SS), and Hashimoto's Thyroiditis (HT) frequently exhibit neuropsychiatric manifestations, including cognitive impairment, depression, anxiety, and so on, yet the exact pathogenesis underlying this association remain incompletely understood. Dysfunction of brain resting-state functional networks and cerebrospinal fluid (CSF) metabolite disturbances have been widely reported in psychiatric disorders. However, the application of resting-state functional magnetic resonance imaging (rsfMRI) and CSF metabolomics in the diagnosis and monitoring of autoimmune psychosis is still limited. METHODS: A two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationships between three autoimmune diseases (SLE, SS, and HT, n&#x2009;=&#x2009;14,267 to 402,090 individuals) and 191 rsfMRI phenotypes (n&#x2009;=&#x2009;47,276 individuals), as well as 338 CSF metabolites. The genome-wide association study (GWAS) of three autoimmune diseases was used as the exposure, whereas rsfMRI phenotypes and 338 CSF metabolites were treated as the outcome. Inverse variance weighted (IVW) with P value&#x2009;<&#x2009;0.05 was regarded as the primary approach for calculating causal estimates. Additionally, the false discovery rate (FDR)-adjusted P value (PFDR)&#x2009;<&#x2009;0.05 was utilized to account for multiple testing. MR Egger method, weighted median method, simple mode method and weighted mode method were used for sensitive analysis. RESULTS: Our analyses identified 5 causal relationships between SLE and the 191 rsfMRI phenotypes, 48 between SS and the 191 rsfMRI phenotypes, and 4 between HT and the 191 rsfMRI phenotypes. Additionally, we found 8 causal relationships between HT and CSF metabolites. Furthermore, all three diseases were significantly associated with the temporal lobe and triple networks (default mode network (DMN), salience network (SN), and central executive network (CEN)), which are the core brain regions and functional networks for cognition. Following FDR correction, 6 causal relationships between SS and the 191 rsfMRI phenotypes were further validated. CONCLUSIONS: Our study pinpoints important brain functional networks and CSF metabolites potentially implicated in the pathogenesis of psychiatric disorders associated with autoimmune diseases and highlights critical brain regions for the development of novel therapeutics.

Humans↗
PubMed1992

Contemporary concepts of autoimmunity and autoimmune diseases.

No single theory or mechanism can explain the phenomenon of autoimmunity and autoimmune diseases. Not all autoimmune responses are harmful or "forbidden." Considerable research has indicated that autoimmune response may be normal and important in the regulation of the immune system. Autoimmunity may play a role in a wide range of clinical states including physiological clearance of dead cells, and cell components, aging, response to viral and microbial infections, and generalized immunological diseases. There are many factors involved in autoimmunity including genetic, hormonal, immunological, and environmental factors. The susceptibility to autoimmune diseases is multifactorial and polygenic. There is a definite association of the autoimmune diseases with MHC alleles. Also, non-MHC genes are involved in disease susceptibility. Numerous mechanisms of autoimmunity have been discussed. There may be an alteration with dysregulation of the immune system with defective generation of normal suppressor mechanisms or an altered neuroendocrine regulation. The altered immune system will make the host more susceptible to autoimmune disease. Autoimmune reactions can occur in a host with a normal immune system. Some examples are as follows: 1. Infection or damage to host target organ with release or alteration of autoantigen 2. Molecular mimicry or cross-reactivity between virus or bacteria and host autoantigens 3. Abnormal expression of MHC molecules by antigen-presenting cells in target cells resulting in activation of autoreactive T-cells. 4. Drug administration

Autoantigens↗
PubMed1992

Murine models of autoimmune disease.

Animal models of autoimmunity are used to identify important immunologic factors and pathways involved in the different autoimmune diseases. Identification of the role of cytokines and development of new disease models have led to new possibilities for treatment.

Animals↗
PubMed1990

Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease.

BALB/c athymic nu/nu mice spontaneously developed organ-specific (gastritis, thyroiditis, oophoritis, or orchitis) and systemic (arteritis, glomerulonephritis, and polyarthritis) autoimmune diseases when transplanted with neonatal BALB/c thymuses. Transplantation of thymuses from adult BALB/c mice was far less effective in inducing histologically evident organ-specific autoimmune disease in nu/nu mice. Autoimmune disease developed, however, when adult thymuses were irradiated at a T cell-depleting dose before transplantation. Engrafting newborn thymuses into BALB/c mice T cell depleted by thymectomy, irradiation, and bone marrow transplantation produced similar organ-specific autoimmune disease as well, but thymus engrafting into T cell-nondepleted BALB/c mice (i.e., mice thymectomized as adults, but not irradiated) did not, despite the fact that transplanted thymuses grew well in both groups of mice. The mice with organ-specific autoimmune disease produced autoantibodies specific for the respective organ components, such as gastric parietal cells, thyroglobulins, oocytes, or sperm. The thymus-transplanted nu/nu mice also had hypergammaglobulinemia and developed anti-DNA autoantibodies, rheumatoid factors, and immune complexes in the circulation. These results indicate that: (a) the thymus of a murine strain that does not develop spontaneous autoimmune disease can produce pathogenic self-reactive T cells that mediate organ-specific and/or systemic autoimmune diseases; and (b) such self-reactive T cells, especially those mediating organ-specific autoimmune disease, spontaneously expand and cause autoimmune disease when released to the T cell-deficient or -eliminated periphery.

Animals↗