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At least 235 records · Page 13Linked to original sources

PubMed1989

Combined treatment of autoimmune MRL/Mp-lpr/lpr mice with cholera toxin plus irradiation. Combined treatment of autoimmune MRL/l mice.

MRL/Mp-lpr/lpr (MRL/1) mice spontaneously develop autoimmune diseases like systemic lupus erythematosus (SLE) from 2 months of age, accompanied by massive lymphadenopathy. Such mice of 2 months of age were treated with 1 microgram cholera toxin (CT) every 7 days and/or with 400 rad of one-shot 60Co irradiation. CT treatment alone markedly improved nephritis as evaluated by proteinuria and moderately suppressed lymphadenopathy and anti-DNA antibody production, while irradiation alone prominently improved lymphadenopathy but showed little effect on both nephritis and anti-DNA antibody production. On the other hand, when mice were treated with the combination of CT plus irradiation, autoimmune nephritis as well as anti-DNA production and lymphadenopathy were almost completely inhibited. Taken together, each agent exerts the improvement effect at the different points from each other in an abnormal immunological circuit displayed in MRL/1 mice. This kind of combined treatment may be applicable to the clinical use for autoimmune diseases.

Animals↗

PubMed1999

Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans.

Human exposure to certain compounds or therapeutic drugs can result in the development of an autoimmune syndrome. Mercury (Hg) induced autoimmunity is one of the few animal models in which administration of a chemical induces a specific loss of tolerance to self-antigens. After receiving subtoxic doses of Hg or other heavy metals, susceptible mouse strains rapidly develop highly specific antibodies to nucleolar antigens. In addition, these animals display a general activation of the immune system, especially pronounced for the Th2 subset and a transient glomerulonephritis with immunoglobulin deposits. Like many human autoimmune diseases, this syndrome is associated with the expression of susceptible major histocompatibility complex (MHC) class II genes. In this article, we review the essential features of this model, and we discuss the putative mechanisms by which Hg creates such a severe immune dysfunction.

Animals↗

PubMed1996

Autoimmune interstitial nephritis and hepatitis in polyglandular autoimmune syndrome.

A 6-year-old female with polyglandular autoimmune syndrome type I, chronic active hepatitis, and renal failure is described. The renal biopsy demonstrated advanced tubulointerstitial disease with antibodies directed against tubular basement membranes. The patient's serum contained circulating antibodies directed against both renal and hepatic parenchyma. Renal disease culminating in renal failure and anti-tubular basement membrane disease have not been previously reported in association with polyglandular autoimmune disease. We describe for the first time a patient with polyglandular autoimmune syndrome, chronic active hepatitis, circulating antibodies directed against both renal and hepatic parenchyma, and primary tubulointerstitial disease culminating in renal failure.

Child↗

PubMed1993

New approaches to the study of T cell autoimmunity in multiple sclerosis. Meeting report on the 2nd Workshop on T cell Autoimmunity in MS, Perugia, Italy, 26-28 November, 1992.

This report discusses some of the papers presented during the 2nd T Cell Autoimmunity in MS Workshop held in Perugia on November 26-28, 1992. The 'trait d'union' of the meeting was the awareness that recent studies have failed to uncover clear-cut differences in T cell reactivity to autoantigens between patients with multiple sclerosis and healthy individuals. Hence, new strategies have been proposed to try to distinguish between 'pathological' autoimmunity in patients and 'natural' autoimmunity in healthy individuals. Furthermore, the studies have been extended to new potential autoantigens (myelin constituents other than myelin basic protein, superantigens, heat shock proteins) and new susceptibility genes such as those coding for transport-associated proteins (Tap-1 and Tap-2).

Autoimmune Diseases↗

PubMedDate not supplied

Relationship between the synthesis of autoimmune antibodies and the formation of clusters of B, T and APC cells during the syngeneic mixed lymphocyte reaction in BALB/c and NZB mice: a technique for isolation of the spleen autoimmune compartment of non-immunized pathogen-free mice.

Cells from the spleens of non-immunized mice were cultured in horizontal tubes, rotating very slowly around their long axis. Under these conditions, the flux speed gradient of the cell suspension near the tube walls greatly increased the chances of cells coming into contact with one another. Mixed clusters of B, T and APC cells were soon found adhering firmly to the walls of the tube; cluster formation leveled off after about 3 h. The clustered cells were easily separated from those remaining in suspension and constituted a particular cell compartment comprising a maximum of 20-30% of the total. B cells from this compartment, cultured in complete medium for 48 h, almost exclusively produced IgM antibodies. Antibodies reacting with self antigens were so numerous in the culture medium that it is likely all IgM were self antibodies. That the clusters obtained under these conditions constituted a compartment of autoimmune cells is supported by previous work which showed that 20-30% of spleen cells secrete IgM antibodies almost exclusively. Cluster formation as a function of age was compared in NZB mice which are used as a model of lupus erythematosus, and in BALB/c mice which never manifest self-immune pathology. The number of cells found in clusters per whole spleen increased exponentially with age in NZB mice and linearly in BALB/c mice. The production of autoimmune antibodies as a function of age also increased exponentially for NZB mice and linearly in BALB/c mice, which provides further striking support for the hypothesis that the clusters formed constitute the autoimmune comportment.

Aging↗

PubMed2004

Interferon induced Autoimmune Thyroid Disease (AITD): a model for human autoimmunity.

Interferon (IFN) alpha treatment for various conditions has been associated with thyroid autoimmunity. The incidence of interferon induced thyroid autoimmunity has been reported to range from 2.5% to 42%, possibly depending upon dose and duration of medical therapy and patient characteristics. It is not known whether IFN-alpha initiates autoimmune thyroid disease (AITD) or simply exacerbates AITD in individuals with subclinical AITD.

Animals↗

PubMed2004

Autoimmune polyglandular syndrome type 1 and the autoimmune regulator.

The autoimmune polyglandular syndrome type I (APSI) is an auto-somal recessive disorder that is characterized by chronic mucocutaneous candidiasis, multiple autoimmune endocrinopathies, and ectodermal dystrophies. The gene that is responsible for APSI has been identified as autoimmune regulator (AIRE). More than 50 different mutations have been discovered in patients who have APSI and the defects include nonsense and missense mutations, small insertions and deletions that lead to frameshift, and splice site mutations. The 545-amino acid protein that is encoded by AIRE contains several structural motifs that are suggestive of a transcriptional regulator. We provide an overview of the clinical and genetic features ofAPSI as well as the structure and functions of the AIRE protein.

Humans↗

PubMed2005

Enhanced expression of netrin-1 protein in the sciatic nerves of Lewis rats with experimental autoimmune neuritis: possible role of the netrin-1/DCC binding pathway in an autoimmune PNS disorder.

Netrin-1 is a chemotropic factor that plays an important role as a survival factor in the adult nervous system. To investigate whether netrin-1 is involved in autoimmune injury of the peripheral nervous system (PNS), the temporal expression of netrin-1 protein was analyzed in the sciatic nerves of Lewis rats with experimental autoimmune neuritis (EAN). Western blot analysis revealed a significant increase in the level of netrin-1 protein in the sciatic nerves of rats on days 11 to 24 post-immunization (p.i.) compared to controls; netrin-1 expression declined by day 30 p.i. Immunohistochemistry revealed that netrin-1 protein was expressed weakly in Schwann cells and vessels in the sciatic nerves of normal and CFA-immunized control rats. In the sciatic nerves of EAN-affected rats, netrin-1 immunoreactivity was increased mainly in the cell membrane and extracellular matrix of OX42-positive macrophages and S100-positive Schwann cells at the peak and recovery phases of EAN. Moreover, the putative netrin-1 receptor, deleted in colorectal cancer (DCC), was expressed mainly in axons, some macrophages, and Schwann cells in EAN-affected sciatic nerves, although the level of protein expression did not change significantly over the course of EAN. We suggest that a significant increase in netrin-1 expression contributes to host cell survival and axon regeneration to counter autoimmune injury and inflammation, which may play a role in recovery from EAN-induced paralysis.

Animals↗

PubMed1994

Familial autoimmune enteropathy with circulating anti-bullous pemphigoid antibodies and chronic autoimmune hepatitis.

In a family of four children (two boys and two girls), the two brothers had severe, protracted watery diarrhea beginning at 2 and 3 weeks of life, respectively. Duodenal mucosa in both patients showed total villous atrophy and severe inflammatory infiltration of the entire bowel. The first patient also had lymphoid cell infiltration of the pancreas and died at 6 weeks of age. The second boy is alive at 2 years of age and is immunocompetent, but still receives total parenteral nutrition. Indirect immunofluorescence studies revealed circulating antibodies to enterocytes, smooth muscle, thyroid, and islet cells. Bullous pemphigoid antibodies (230 and 180 kd), specific for hemidesmosomal proteins and usually associated with a subepidermal blistering skin disease, were detected by direct and indirect immunofluorescence studies and by Western immunoblot. A diagnosis of autoimmune hepatitis was made, based on evidence of chronic active hepatitis and circulating anti-smooth muscle antibody. Immunosuppressive treatments induced partial clinical remission of the diarrhea but no resolution of the small bowel injury. At 16 months of age, remission of the diarrhea occurred, but persistent autoimmune hepatitis led us to maintain treatment with prednisone and azathioprine, and later with cyclosporine. In this child, as in other patients with autoimmune disease, the link between autoantibodies and organ damage remains uncertain but immunosuppressive treatment is indicated.

Autoantibodies↗

PubMed1999

Gender- and androgen-related influence on the expression of proto-oncogene and apoptotic factor mRNAs in lacrimal glands of autoimmune and non-autoimmune mice.

Our previous studies have shown that the mRNA levels of c-myb, c-myc, bcl-2 and p53 are higher, and partial Fas antigen (i.e. exons 1-2) lower, in lacrimal tissues of female, as compared to male, MRL/lpr mice, which are a model of Sjögren's syndrome. We have also found that this gender-related difference in bcl-2 and c-myb expression appears to be due to the influence of androgens. To extend these findings, we sought to determine: first, whether these gender- and/or hormone-associated variations in mRNA content are unique to MRL/lpr mice, or are also present in lacrimal glands of other murine strains, including autoimmune NZB/NZW F1 (F1) and non-obese diabetic (NOD), as well as non-autoimmune C3H/HeJ (C3H) and BALB/c, mice; and second, whether the levels of these apoptotic factor mRNAs are altered in lacrimal tissues of mice (i.e. testicular feminized (Tfm) with dysfunctional androgen receptors, as compared to glandular amounts in their 'normal' controls (i.e. Tabby). Lacrimal tissues were obtained from adult mice, which were either untreated or treated with placebo or testosterone for 21 days. Glands were processed for the analysis of proto-oncogene mRNAs by RT-PCR (at exponential phase of amplification) and data were standardized to the corresponding levels of beta-actin mRNA. Our results demonstrate that Fas antigen, Fas ligand, c-myb, c-myc, bcl-2, Bax and p53 mRNAs are present in lacrimal tissues of F1, NOD, C3H, BALB/c, Tabby and Tfm mice. The relative levels of Fas antigen mRNA are consistently higher in glands of males, whereas amounts of bcl-2 mRNA are greater in tissues of F1, C3H and BALB/c females. Testosterone administration induced a significant increase in the lacrimal gland content of Bax mRNA, but a striking decrease in the lacrimal tissue level of bcl-2 mRNA in F1 and C3H mice. Lacrimal glands of Tfm mice contained elevated amounts of bcl-2 mRNA, as compared to values in tissues of their Tabby controls. In summary, our findings show that fundamental gender-related differences exist in the expression of genes associated with programmed cell death in lacrimal glands of autoimmune and normal mice. In addition, some of these differences may be due, at least in part, to the effect of androgens.

Androgens↗

PubMed2000

CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity?

For most autoimmune disorders, the pattern of inheritance is very complex. The major histocompatibility complex (MHC) gene complex has been implicated as the major genetic component in the predisposition to these diseases but other genes are likely to be involved. Based on function and experimental data, the gene encoding cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. In this review, we critically evaluate the evidence for pathogenetical involvement of CTLA-4 in the different autoimmune diseases with focus on the possible role of genetic variation of the CTLA4 locus.

Abatacept↗

PubMed1992

Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. International Kidney Biopsy Registry of Cyclosporine in Autoimmune Diseases.

BACKGROUND: Cyclosporine is an immunosuppressive drug that is used to treat patients with autoimmune disease as well as patients who have received allografts. The drug can cause renal damage, but the incidence of and risk factors for nephropathy in patients treated with cyclosporine for autoimmune or inflammatory diseases are not known. METHODS: We analyzed data from renal biopsies performed in 192 patients (129 adults and 63 children) who had been treated with cyclosporine for insulin-dependent diabetes mellitus of recent onset, uveitis, psoriasis, Sjögren's syndrome, or polychondritis. The mean (+/- SD) initial dose of cyclosporine was 8.2 +/- 2.8 mg per kilogram of body weight per day, and the duration of treatment was 4 to 39 months (median, 13). RESULTS: Forty-one patients (37 adults and 4 children) had cyclosporine-induced nephropathy, defined as at least moderate focal interstitial fibrosis with tubular atrophy, arteriolar alterations, or both. As compared with patients in whom nephropathy did not develop, these patients received a larger initial dose of cyclosporine (9.3 +/- 2.8 vs. 8.0 +/- 2.8 mg per kilogram per day), had a larger maximal increase in the serum creatinine concentration above base-line values (101 +/- 77 percent vs. 50 +/- 33 percent), and were older (31 +/- 13 vs. 23 +/- 12 years). These three variables were shown by multivariate logistic-regression analysis to be significant risk factors. The duration of the elevation in the serum creatinine concentration and the occurrence of elevated blood pressure were not additional risk factors. CONCLUSIONS: Nephropathy is an important potential effect of cyclosporine therapy. The risk of its development in patients with autoimmune diseases who are treated with cyclosporine can be minimized by allowing a dose no higher than 5 mg per kilogram per day and avoiding increases in serum creatinine of more than 30 percent above the patient's base-line value.

Adolescent↗

PubMed1987

Exercise induced augmentation of cellular and humoral autoimmunity associated with increased cardiac dilatation in experimental autoimmune myocarditis.

To determine the effects of exercise in experimental autoimmune myocarditis, guinea pigs immunised with heterologous heart protein (rat heart), Freund's complete adjuvant, and pertussis vaccine (treated group) were exercised on a treadmill for a total of 11 weeks and compared with non-exercise treated animals. In vivo heart rates and pressures, in vitro left ventricular pressure-volume relations, myocardial histology, circulating antiheart antibody, and in vitro lymphocyte stimulation were determined. Exercise resulted in increased cardiac dilatation in treated animals as assessed by in vitro left ventricular pressure-volume relations compared with non-exercise treated animals (at 8 mmHg 1.41(0.17) ml.kg-1 vs 1.20(0.17) ml.kg-1 respectively, p less than 0.005). Exercise also resulted in increased concentrations of circulating antiheart antibody as assessed by radioimmunoassay (0.14(0.04) microgram vs 0.10(0.03) microgram respectively, p = 0.01), and increased lymphocyte activation to specific antigen (stimulation index 3.7(0.07) vs 2.4(1.0) respectively, p less than 0.001). Despite the associated augmentation of autoimmunity with cardiac dilatation, there were no differences in the histopathological findings between the exercised treated and the non-exercised treated animals either qualitatively or quantitatively (number of inflammatory cell microaggregates). This finding suggests that, although the immune system is important in experimental autoimmune myocarditis, the amount of inflammation and necrosis does not appear to correlate with the degree of left ventricular dilatation and presumed dysfunction.

Animals↗

PubMed1991

Tolerance and suppressor mechanisms in experimental autoimmune encephalomyelitis: implications for immunotherapy of human autoimmune diseases.

Recent advances in understanding antigen recognition at the level of the trimolecular complex have provided new approaches for selective immunotherapy. Many of these approaches have been applied successfully to the animal model experimental autoimmune encephalomyelitis, and some are being tested in the human disease multiple sclerosis. In addition, new approaches utilizing nonspecific modulation of immune function are being explored in animals and humans. Immunospecific therapy in autoimmune diseases will ultimately be based on understanding how the normal immune system maintains unresponsiveness to self and how this state of self-tolerance is broken. Strategies for specific immune intervention in human diseases based on components of the trimolecular complex will have to take into account the polymorphism of the major histocompatibility complex in humans and the degree of heterogeneity among autoimmune T cells that react with an autoantigen.

Adjuvants, Immunologic↗

PubMed1986

Membrane surface properties of lymphocytes of normal (DBA/2) and autoimmune (NZB/NZW)F1 mice: effects of L-canavanine and a proposed mechanism for diet-induced autoimmune disease.

Partitioning cells in a dextran polyethylene glycol aqueous two-phase system (countercurrent distribution, CCD) is a sensitive method for learning about cell surface membrane properties and for subfractionating cell populations. In this study, we subjected lymphocytes from normal DBA/2 mice and autoimmune F1 New Zealand black/New Zealand white [NZB/NZW)F1) mice to countercurrent distribution and found that T cells partition to the right and B cells partition to the left of the CCD curve. We found no difference between the CCD patterns of normal and autoimmune mice. When the murine lymphocytes were exposed to a cationic dietary amino acid (L-canavanine) in vitro, L-canavanine selectively affected the CCD pattern of autoimmune B cells, reflecting an alteration in surface membrane properties. We separated these lymphocytes with altered surface membrane properties by CCD. Impaired B-cell immune responses associated with L-canavanine were isolated to this lymphocyte fraction. This study provides the first evidence that alterations in the charged surface membrane properties are associated with abnormal (auto) immune response.

Animals↗

PubMed1993

Autoimmune diseases in humans, e.g. autoimmune rheumatic diseases.

In spite of increasing evidence that viruses and especially retroviruses could act as etiologic factors in autoimmune and especially autoimmune rheumatic diseases, clear-cut evidence for an involvement of these agents is still missing. Findings, which, for example, indirectly support the hypothesis that retroviruses might play a part, are the demonstration of antibodies to the gp24 in SLE and Sjögren's patients as well as the description of retroviral antigens in the inflamed synovium of rheumatoid arthritis patients. Furthermore, evidence comes from animal models that viruses, such as the Visna or Caprine arthritis encephalitis virus, induced chronic inflammatory diseases in sheep and goats. More recently, a mouse model for rheumatoid arthritis and Sjögren's syndrome was reported in mice transgenic for HTLV-1tax. It is hoped that, especially from the experimental animal models, the possible role of retroviruses as etiological factors in autoimmune rheumatic diseases can be clarified.

Animals↗

PubMed2004

Experimental autoimmune diabetes: a new tool to study mechanisms and consequences of insulin-specific autoimmunity.

(Prepro)insulin is considered a central antigenic determinant in diabetic autoimmunity. Insulin has been used to modify diabetes development in NOD mice and prediabetic individuals. We have recently shown that (prepro)insulin can adversely promote diabetes development in murine type 1 diabetes. Based on these findings we have developed experimental autoimmune diabetes (EAD), a new mouse model characterized by (1) CD4(+)/CD8(+) insulitis, induced by (2) (prepro)insulin DNA vaccination, leading to (3) beta cell damage and insulin deficiency in (4) RIP-B7.1 transgenic mice (H-2(b)). EAD develops rapidly in 60-95% of mice after intramuscular, but not intradermal ("gene gun"), vaccination; and DNA plasmids expressing insulin or the insulin analogues glargine, aspart, and lispro are equally potent to induce EAD. Similar to NOD mice, diabetes is adoptively transferred into syngeneic recipients by spleen cell transplantation in a dose-dependent fashion. We have devised a two-stage concept of EAD in which T cell activation and expansion is driven by in vivo autoantigen expression, followed by islet damage that requires beta cell expression of costimulatory B7.1 for disease manifestation. Taken together, EAD is a novel, genetically defined animal model of type 1 diabetes suitable to analyze mechanisms and consequences of insulin-specific T cell autoimmunity.

Adoptive Transfer↗

PubMed2000

Novel mutations of the autoimmune regulator gene in two siblings with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the first multiple autoimmune disease that has been shown to be caused by mutations of a single gene named autoimmune regulator (AIRE). Fourteen different mutations of the AIRE gene have been identified in 61 patients from 55 families with APECED. However, there has been no report documenting AIRE gene mutations in the Asian population. We report on 2 siblings with variable manifestations of APECED who were born to a Japanese mother and a Korean father. The 11yr-old girl had intractable thrush and ungual candidiasis, hypoparathyroidism, and occipital alopecia. The 9-yr-old boy had mild ungual candidiasis alone. Direct sequencing revealed novel frameshift mutations of the AIRE gene: an insertion of a cytosine at nucleotide 29635 at the exon 10 (29635insC), which should lead to a premature termination at the codon 371, producing a truncated protein missing the second plant homeodomain-type zinc finger motif and the third LXXLL motif, and a deletion of a guanine at nucleotide 33031 at the exon 13 (33031delG), which should result in a premature termination at the codon 520, yielding a truncated protein missing the third LXXLL motif. The mother was heterozygous for 29635insC, and the father was heterozygous for 33031delG. The frameshift mutations were undetected in 40 alleles of 20 Japanese control subjects. The results imply that the C-terminus of AIRE protein including the third LXXLL motif plays a critical role in the development of APECED, and that the phenotypic spectrum can vary between siblings with the same mutations.

Child↗