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PubMed1986

Autoimmune disorders in diabetes.

The development of IDDM correlates with the presence of biologic markers pointing to the involvement of the immune system in the disease process. In addition to clinical observations of association of IDDM with other autoimmune disease and morphologic evidence of a mononuclear cell infiltration of the islets of Langerhans at the onset of the disease, anti-islet cell antibodies are detected in the serum of IDDM patients. Moreover, a strong genetic association with HL-A DR3 and DR4 identifies a genetic background compatible with autoimmune phenomena. Whether autoimmune phenomena are primary or secondary to an initial damage of the islets by infectious agents or other environmental factors is unknown. Whether or not the autoimmune response participates in the selective destruction of insulin-secreting cells has been a major issue in the past five years. The presence of T lymphocytes and anti-islet cell antibodies, which selectively inhibit or lyse insulin-secreting cells in vitro, strongly suggests that it may be the case. A definitive demonstration is difficult to provide in human IDDM. The development of animal models for IDDM has allowed useful insight into the pathogenetic mechanisms responsible for IDDM. In both the BB rat and the low-dose streptozotocin mouse model, the role of the immune system in the destruction of the islets of Langerhans is supported by the prevention of the disease by treatments interfering with the immune system. The BB rat develops a spontaneous autoimmune disease on a genetic background defined by the association with a major histocompatibility complex allele without any evidence for a role in initial damage of islets of a triggering infectious or chemical process. The low-dose streptozotocin model is an autoimmune IDDM secondary to the selective damage of islet cells by a toxin. The present scheme of an islet cell target and specific autoreactive T and B lymphocyte clones raises two major issues: what is the target antigen on islet cells and what is the role at the molecular level of class II major histocompatibility complex genes in susceptibility for IDDM? The first issue is presently being addressed in several laboratories using the hybridoma technology. The second issue is addressed at the biochemical level by studying restriction site polymorphism of major histocompatibility genes in susceptible individuals and IDDM patients, and at the functional level by studying the action of monoclonal antibodies to class II antigen on the development of IDDM in animal models. These steps are likely to be a prerequisite to antigen-specific immunotherapy in IDDM.

Animals↗

PubMed1985

Autoimmune mechanisms in inflammatory eye disease.

This paper summarises the principal immunopathological mechanisms which may underlie ocular inflammation and draws attention to how autoimmune reactions may be regulated by idiotypic networks of the immune system. The study of autoimmunity in inflammatory eye disease is illustrated by our current investigations of retinal vasculitis in man and of experimental autoimmune uveoretinitis in rodents where three lines of evidence indicate that immune complex formation may be a compensatory host response to the development of antiretinal autoimmunity. In discussing immunological implications of these results we suggest that retinal inflammation in antiretinal autoimmunity is limited by a protective anti-idiotypic antibody response and that retinal disease arises when this compensatory response is improperly balanced. The clinical implications of this reasoning include the identification of patients at risk of relapse of ocular disease and the development of therapeutic methods for restoring an imbalanced anti-idiotypic autoimmune response towards normality.

Animals↗

PubMed1985

Premature ovarian failure: its relationship to autoimmune disease.

Thirty-three patients with the diagnosis of chromosomally competent premature ovarian failure were reviewed for evidence of autoimmune disease. Thirty-nine percent of subjects had an associated autoimmune disorder, of which thyroid disease was the most common. One patient had vitiligo and one had adrenal insufficiency. A family history of autoimmune disease was elicited from 18% of subjects, all of whom proved to have an autoimmune disease themselves. From these findings, and a review of other studies, the authors conclude that an associated autoimmune disease, or other evidence of autoimmunity, is present in 30 to 50% of patients with premature ovarian failure.

Adolescent↗

PubMed1984

The role of vascular smooth muscle cells in experimental autoimmune vasculitis. I. The initiation of delayed type hypersensitivity angiitis.

The destruction of vascular smooth muscle cells (VSMCs) in autoimmune arteritis is a poorly understood phenomenon. For evaluation of the cellular interactions that may contribute to vasculitis, the immunobiology of VSMCs and lymphocytes was explored in vitro. Primary VSMC cultures were established, and the interaction of these cells (from normal or autoimmune mice) with lymphocytes was then assessed. Specifically, splenocytes from MRL/lpr or C3H mice were cocultivated with MRL/lpr or C3H VSMCs. Massive mononuclear cell clusters from normal and autoimmune mice enveloped MRL/lpr VSMCs, which culminated in the detachment of MRL/lpr VSMCs from the culture plate. In contrast, the interaction of SPs from either normal or autoimmune mice did not encompass or destroy normal VSMCs. Further investigation indicated that MRL/lpr, but not C3H, VSMCs spontaneously expressed Ia and released Il-1 like factor(s), which may be at least two mechanisms by which MRL/lpr VSMCs stimulate the in vitro mononuclear cell influx. As a result of these studies, a novel mechanism for the induction of mononuclear cell autoimmune vasculitis is proposed. VSMCs derived from autoimmune mice may stimulate a mononuclear inflammatory cell phlogistic response which culminates in VSMC autodestruction.

Animals↗

PubMed1983

[Clinical significance and pathogenesis of drug- or microbe-induced autoimmune hemolytic anemias].

Methyldopa and several other drugs, continuously taken over months or years, may induce autoimmunity in persons having a probably genetic predisposition. The autoimmunity is reversible after discontinuation of the drug. A number of infectious agents may lead to the same effect. The autoantibodies can react with different autologous targets, for instance red blood cells. This may occasionally cause an autoimmune haemolytic anaemia. The two pathogenetic cardinal points are discussed in the case of the methyldopa-induced autoimmune haemolytic anaemia: the induction of the process results very probably by inhibiting or blocking of the competent suppressor-T-lymphocytes, which normally prevent an autoantibody production, representing a form of chemical "contrasuppression". This has been demonstrated in cultures of peripheral human blood lymphocytes of patients on methyldopa therapy. The second pathogenetic cardinal point is the effect of the autoantibody after its binding to the drugs investigated up to now. Rarely it is pathogenic. This relation is exactly contrary to the idiopathic warm autoantibody anaemia and remains an unsolved problem. A reversible selective deficiency of suppressor-T-cells has also to be postulated for other autoimmune haemolytic anaemias and autoimmune diseases induced by drugs or infectious agents.

Adult↗

PubMed1983

CBA/N X-linked defect delays expression of the Y-linked accelerated autoimmune disease in BXSB mice.

BXSB male mice spontaneously develop progressive autoimmune disease characterized by high serum immunoglobulins, including anti-nuclear antibodies (ANA), enlarged spleen and lymph nodes, and diffuse proliferative glomerulonephritis. Females develop symptoms at a much slower rate. The mechanisms underlying the autoimmune disease and the nature of the Y-linked accelerating factor have not yet been elucidated. We found that the male progeny of the cross between the non-autoimmune strain CBA/Ca and BXSB (CBA/Ca X BXSB)F1 showed progressing signs of autoimmunity starting at 6 to 7 mo. In contrast, the male progeny that resulted from BXSB males crossed with immune-defective CBA/N females (Xid) were devoid of splenic B colonies, were nonresponsive to TNP-Ficoll, and were free of autoimmune disease for at least 10 mo. At 18 mo, some of the (CBA/N X BXSB)F1 mice developed weak antinuclear antibodies, but no spleen or lymph node enlargement was seen. The same mice had low anti-TNP Ficoll responses but did not produce B colonies in vitro. The role of the X chromosome in regulating expression of autoimmunity in young and old BXSB mice is discussed.

Aging↗

PubMed1982

The in vitro and in vivo induction of anti-double-stranded DNA antibodies in normal and autoimmune mice.

To determine whether the existence of anti-dsDNA producing lymphocyte clones is limited to autoimmune strains of mice, spleen cells derived from autoimmune mice (NZB, NZB X NZW F1, MRL) and from normal strains (BALB/c, DBA/2, C57BL/6, C3H/eb) were cultured with E. coli lipopolysaccharide (LPS). DNase-treated supernatants from these cultures were assayed for anti-dsDNA antibodies by employing a sensitive solid-phase radioimmunoassay with poly (dA-dT) as the antigen. All tested spleen cells secreted a small yet significant amount of anti-dsDNA upon stimulation with LPS. There was no difference in the amount or in the heavy chain type of anti-dsDNA secreted by cells from normal and autoimmune strain cells. Evidence of clonal expansion in unstimulated cells was observed only in cultures prepared from older autoimmune animals. Removal of T cells from the spleen cell preparations had no marked effect on the spontaneous or stimulated antibody secretion. Anti-dsDNA antibodies could also be induced in vivo by i.p. injection of LPS into young normal animals. Splenocytes from all tested strains spontaneously secreted anti-ssDNA and anti-TNP antibodies in culture, and these were present at relatively high levels in the serum of unstimulated animals. Stimulation with LPS increased secretion of anti-ssDNA and anti-TNP in all strains in vitro and in five of seven strains in vivo as well. It can be concluded that a) the existence of anti-dsDNA-producing clones is not limited to autoimmune strains, and b) these clones are expanded in old but not in young autoimmune mice. They are not expanded in normal mice at any age.

Aging↗

PubMed1994

[Autoimmune disorders in interferon therapy].

Interferons (IFNs) have immunomodulatory properties such as direct increase in the production of pathogen autoantibodies, enhanced cytotoxic T cell and B cell activities, inhibition of T suppressor cell function and induction of HLA class I antigen expression. These actions of IFN induce autoimmune disorders including autoimmune thyroiditis, hemolytic anemia and thrombocytopenia, SLE, rheumatoid arthritis and psoriasis, however, these autoimmune diseases except for autoimmune thyroiditis, are rare among side effects of IFN therapy. Most of the patients showing these autoimmune disorders during IFN treatment have predisposal immunological abnormalities such as positive ANA and antithyroidal autoantibodies. We described here autoimmune disorders during and after IFN treatment among 1023 cases with chronic active type C hepatitis. The cases with SLE, thrombocytopenic purpura, rheumatoid arthritis and psoriasis showed good prognosis after cessation of IFN administration.

Adult↗

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↗

PubMed1993

[Virus and autoimmunity with emphasis on liver diseases].

The dualism virus pathogenesis and autoimmune pathogenesis in liver disease is given up increasingly. A survey is given about the development of autoimmunity and virus induction of the autoimmune hepatitis. The hypothesis of virus induction of autoimmune hepatitis put forward by Storch 1975 (19) is unproven up to now, but the concept of virus-associated autoimmune hepatitis put forward by Storch 1980 (23) is acknowledged today. First of all, antibodies against endoplasmic reticulum (liver and kidney microsomes) type 1, liver ribosomes, and liver cell cytoplasm are regarded as markers of a hepatitis C virus-associated autoimmune hepatitis. At present it is unknown, if antibodies against the surface of tongue epithelium, basal cells of squamous epithelium, Golgi apparatus, and nerve cells are further suitable markers.

Autoantigens↗

PubMed1995

Stem cell transplantation for severe autoimmune diseases: new proposals but still unanswered questions.

An extensive series of experimental investigations has shown that both inherited and induced autoimmune diseases in laboratory animals may be transferred and, conversely, cured by stem cell transplantation. In man, the evidence is mainly anecdotal, originating both from the transmission of autoimmune conditions following allogeneic BMT from carrier donors to non-autoimmune recipients transplant-requiring diseases, and from the resolution of autoimmune diseases (mainly rheumatoid arthritis) of the recipients after allogeneic BMT from healthy donors. Will it be possible to cure severe autoimmune diseases with powerfully immunosuppressive conditioning regimens followed by the administration of hematopoietic stem cells? If the reconstitution of a naive immune system is necessary, allogeneic stem cells will be necessary, but the procedure is still saddled with its attending problems, with TRM in the foreground. When utilizing autologous stem cells in conjunction with TCD the patients' tolerance will be significantly better, but remissions are to be anticipated rather than cures. However, some special manipulations may be expected to ameliorate results in those selected autoimmune patients not or badly responding to conventional immunosuppressive therapy, for whom this type of treatment can be offered.

Autoimmune Diseases↗

PubMed1996

Molecular weights and isoelectric points of sperm antigens relevant to autoimmune infertility in men.

PURPOSE: We determined the molecular weights and isoelectric points of antigens in the uncapacitated and capacitated spermatozoa of fertile men binding to the serum immunoglobulin G (IgG) from 8 autoimmune infertile men and 8 fertile nonautoimmune men. MATERIALS AND METHODS: We used double fluorochrome cytotoxicity and immunobead binding assays to determine the sperm antibody status of the study subjects. 2-Dimensional gel electrophoresis and Western blot analysis were used to determine the molecular weights and isoelectric points of sperm antigens binding to serum IgG from these men. Amino acid sequencing of the digested peptides of chosen proteins was accomplished. Immune reactivity to the proteins in autoimmune infertile men was further verified. RESULTS: Serum IgG from fertile men failed to react significantly. Serum IgG from all autoimmune men (100%) showed significant binding to proteins with a molecular weight of 92 kDa. and isoelectric points of 3.5 to 4.0 in the capacitated spermatozoa. Six of 8 infertile men (75%) had serum IgG binding to capacitated sperm antigens with a molecular weight of 18 kDa. and isoelectric points of 4.5 to 5.2. Amino acid sequencing of peptides of the 92 kDa. protein matched complement component 1 (C1) inhibitor, with noted differences in the amino acid sequencing from the latter. The 18 kDa. protein matched calmodulin. We verified that serum IgG from autoimmune infertile men bound with C1 inhibitor and ascertained that the 92 kDa. protein in the spermatozoa was C1 inhibitor-like protein. CONCLUSIONS: Significant antibody responses to C1 inhibitor-like protein and calmodulin were noted in autoimmune men. Both of these proteins may be of testicular origin and these autoimmune responses may be highly relevant to infertility.

Amino Acid Sequence↗

PubMedDate not supplied

Autoimmune thyroid disease in systemic lupus erythematosus and Sjögren's syndrome.

Autoimmune thyroid disease is common in patients with either systemic lupus erythematosus (SLE) or Sjögren's syndrome (SS); however, whether the risk is greater than in well matched controls is not clear. Antinuclear antibodies are found in the sera of patients with autoimmune thyroid disease, but there is no evidence of autoantibodies binding antigens characteristic of SLE or SS. Autoantibodies to thyroid antigens and overt autoimmune thyroid disease are common in patients with SLE or SS. However, in SLE patients there is little or no increased risk of autoimmune thyroid disease compared to an age and sex matched population. Patients with SS are likely to be at increased risk of thyroid disease, but those with autoimmune thyroid disease are not at special risk of SS. This difference can be explained if SS is considered to be an autoimmune epitheliitis that targets polarized epithelia, including the thyroid.

Autoantibodies↗

PubMed1996

Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation.

Autologous stem cell transplantation with or without in vitro lymphocyte depletion has been suggested as a new treatment option for severe autoimmune diseases. We describe five patients with autoimmune diseases (CREST syndrome, myasthenia gravis and Hashimoto's thyroiditis, systemic lupus erythematosus, atopic dermatitis, and rheumatoid arthritis) who underwent autologous bone marrow (n = 1) or peripheral blood progenitor cell (n = 4) transplantation with unmanipulated grafts as treatment for the autoimmune disease in one case or as treatment for a malignant disorder with a concomitant autoimmune disorder in four cases. In all patients serological and clinical signs of the autoimmune disease recurred early or persisted. These observations should be regarded as a cautionary note concerning the efficacy of high-dose therapy followed by transplantation of unmanipulated autologous stem cells for treatment of severe autoimmune diseases.

Adult↗

PubMedDate not supplied

Autoimmune hepatitis.

Autoimmune hepatitis is an inflammatory liver disease in which the immune system is believed to orchestrate an immune attack onto the liver cell. Current knowledge suggests that both T helper 1 (TH1) and TH2 programmes are involved in the generation of the liver damage. Release of TH2 cytokines leads to the production of autoantibodies to the hepatocyte membrane that recruit killer cells. TH1 cytokines induce macrophage activation which contributes to hepatocyte destruction. Patients commonly possess the "autoimmune" HLA A1/B8/DR3 haplotype and a silent gene at the C4A locus with consequent partial deficiency of the complement component C4. Two main types of autoimmune hepatitis are recognised according to the presence of circulating non-organ specific autoantibodies. Patients with smooth muscle antibody and/or antinuclear antibody may be adults or children, while patients with antiliver kidney microsomal type 1 (LKM1) antibody are usually children or very young adults. In both types there is a preponderance of females. LKM1 antibody is also present in a proportion of adult patients, mainly male, with chronic hepatitis C virus infection. This observation originally led to the suggestion that hepatitis C virus may be the cause of this form of autoimmune hepatitis, but several studies have shown that the epitopes target of the LKM1 antibody in autoimmune hepatitis and chronic hepatitis C virus infection differ. Although autoimmune hepatitis responds satisfactorily to immunosuppression in the short term, progression to cirrhosis is frequent. It is hoped that ongoing research will provide a better understanding of the pathogenic mechanisms of liver damage leading to a more effective and specific mode of treatment.

Autoantibodies↗

PubMed1997

[Recent advances in animal models of autoimmune disease].

Various autoimmune diseases can be induced in normal animals by simply manipulating the thymus/T cells. For example, elimination of CD25+CD4+ T cells, which constitute about 10% of peripheral CD4+ T cells of normal mice, leads to the development of various organ-specific autoimmune diseases, such as thyroiditis, gastritis, adrenalitis, insulitis, sialoadenitis, oophoritis, or orchitis. Reconstitution of CD25+CD4+ T cells prevents the autoimmune development. Elimination/reduction of CD25+CD4+ T cells induced by genetical manipulation of T-cell ontogeny or caused by environmental agents, such as virus infection, also causes similar autoimmune diseases in normal mice. These newly developed animal models of autoimmune disease will be useful for elucidating the mechanism of immunologic self-tolerance and pathogenetic mechanism of autoimmune disease.

Animals↗

PubMed1997

Organ-specific autoantibodies in coeliac disease: do they represent an epiphenomenon or the expression of associated autoimmune disorders?

BACKGROUND AND AIMS: The occurrence of autoimmune disorders and organ-specific autoantibodies has been reported in coeliac disease. We assessed the prevalence of organ-specific autoantibodies in coeliac patients and evaluated whether their finding is an expression of associated autoimmune diseases. METHODS: Sera from 70 coeliac disease patients were tested for thyroid microsomal, gastric parietal cell, adrenal cortex and pancreatic islet cell antibodies by indirect immunofluorescence on O blood group human tissues. RESULTS: Eighteen coeliacs (26%) were positive for at least one of the autoantibodies studied; thyroid microsomal antibodies showed a higher prevalence (21%) than parietal cell (11%), adrenal cortex (4%) and islet cell antibodies (3%). In 15 (21%) of the 70 coeliacs studied an association with autoimmune diseases was found, including insulin dependent diabetes mellitus (6 cases), autoimmune hepatitis (3 cases), hypothyroidism (4 cases), thyrotoxicosis (1 case) and dermatomyositis (1 case). One or more organ-specific autoantibodies were positive in 12 (80%) of the 15 coeliacs with autoimmune disorders in comparison with their positivity in 6 (11%) of the 55 coeliacs without autoimmune diseases (p < 0.0001). CONCLUSIONS: The finding of organ-specific autoantibodies in coeliac patients discloses the coexistence of a wide spectrum of immunological diseases.

Adolescent↗

PubMed1997

Advances in basic concepts of autoimmune disease.

Both practical and conceptual considerations of immunologic tolerance have permitted a better understanding of how the body escapes autoimmunity and the resulting tissue damage. Such studies have led to our understanding of the role of different arms of the immune response in the induction and progression of autoimmune disease in humans. Cytokines play important roles in determining whether an autoimmune state will be induced and whether it will progress and the nature of tissue damage. Once an autoimmune state is induced, the selective expansion of the-T-cell subsets may determine if and how the autoimmune state will progress. As in response to foreign antigens such as pathogens, CD4+ T-cell responses to autoantigen, resulting in disease, may be polarized to the Th1 or Th2 subsets. Why one CD4+ T-cell subset response acts as an inhibitor of disease while the other plays a regulatory role is an important area to investigate for clues in the regulation of autoimmune responses once they are initiated.

Animals↗