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PubMed2000

Differential cytokine and chemokine production characterizes experimental autoimmune meningitis and experimental autoimmune encephalomyelitis.

After primary immunization with myelin/oligodendrocyte glycoprotein, CD28(-/-) mice developed experimental autoimmune meningitis (EAM) rather than experimental autoimmune encephalomyelitis (EAE). Cytokine and chemokine production in EAE and EAM were compared to understand the differences in disease phenotype. T cells from the central nervous system lesions of mice with either EAE or EAM expressed intracellular TNF-alpha. Splenic T cells from mice with EAM produced TNF-alpha and IL-6 but no IL-2. Conversely, EAE-derived splenic T cells produced TNF-alpha and IL-2 but no IL-6. Altered T cell differentiation in EAM was not due to a Th1 to Th2 shift, because equivalent amounts of T cell IFN-gamma mRNA were produced in both diseases. Neutrophils also produced inflammatory mediators such as TNF-alpha and IL-6 in EAM. Autocrine production of MIP-2 mRNA was observed in neutrophils from mice with EAM but not EAE. Therefore, distinct patterns of cytokines and chemokines distinguish EAE and EAM.

Amino Acid Sequence↗

PubMed1982

Genetic factors predisposing to autoimmune diseases. Autoimmune hemolytic anemia, chronic thrombocytopenic purpura, and systemic lupus erythematosus.

Genetic factors predisposing to autoimmune diseases were investigated in 10 families having more than one affected member. Seventy relatives and 23 spouses from two large kindreds (one in whom the proband had autoimmune hemolytic anemia and the other immune thrombocytopenic purpura) were examined for immunologically mediated disorders, autoantibodies, immunoglobulin abnormalities, and HLA genotypes. Significant differences between relatives and spouses were found for immune diseases (21 percent versus 0 percent; p = 0.02), antinuclear antibody titer of 1:80 or more (18 percent versus 0 percent; p = 0.04), single-strand DNA antibodies (18 percent versus 0 percent; p = 0.04), high-titer antinuclear antibody or antibodies to single-strand DNA or both (33 percent versus 0 percent; p = 0.001), and the combined frequencies of immune diseases and serologic abnormalities (44 percent versus 4 percent; p = 0.0004). Similar frequencies were found in 41 relatives from eight families in whom the proband had SLE. Segregation analyses using these abnormalities as genetic traits were most compatible with a Mendelian dominant model. Impressive odds (100:1) against linkage to HLA were calculated.

Adolescent↗

PubMed1991

TH2 cells in systemic autoimmunity: insights from allogeneic diseases and chemically-induced autoimmunity.

Systemic autoimmune diseases can be induced experimentally in rodents by graft-versus-host or host-versus-graft reactions and by chemicals such as HgCl2, gold salts and D-penicillamine. These models share several features, such as productions of anti-nuclear antibodies, immune glomerulonephritis, MHC class II hyperexpression on B cells, hyper-IgE, increased IL-4 activity and impairment of IL-2 production. This profile of cytokines suggests a central role for TH2-type cells in their pathogenesis. Here, Michel Goldman and colleagues review the data supporting this hypothesis and discuss the possible molecular bases for T-cell activation in chemically-induced systemic autoimmunity.

Animals↗

PubMed1990

Immunosuppression by gramicidin S of experimental autoimmune uveoretinitis, pinealitis and autoimmune encephalomyelitis.

Using an in vitro lymphocyte proliferation assay we screened several cyclic peptide antibiotics (bacitracin, oleandomycin, capreomycin, colistin, virginiamycin, and gramicidin S) for their immunosuppressive activity. Gramicidin S (GrS) was found to inhibit [3H]-thymidine incorporation into concanavalin A-stimulated and E coli lipopolysaccharide-stimulated lymphocytes. In vivo studies, experimental autoimmune uveoretinitis (EAU) and pinealitis were induced in female Lewis rats by immunization with bovine S-antigen and experimental autoimmune encephalomyelitis (EAE) were induced by immunization of rats with rat brain homogenates. GrS suppressed the onset of these inflammatory diseases at nontoxic concentrations. Evidence was obtained that GrS inhibits [3H]-thymidine incorporation into lymphocytes by preventing transport of the compound across the membrane. Since GrS binds to various cell membranes, GrS would suppress the proliferation of not only lymphocytes but also of other immune cells by modifying cell membrane properties. The present study indicates that a search for compounds which cause proper cell membrane modification should be a worthwhile strategy for development of immunosuppressive drugs.

Amino Acid Sequence↗

PubMed2001

Age-related prevalence of platelet-associated immunoglobulins G in nonthrombocytopenic patients with autoimmune thyroid disease and autoimmune polyglandular syndrome.

OBJECTIVE: The prevalence of platelet-associated IgG (paIgG) in nonthrombocytopenic patients with autoimmune thyroid disease (AITD) alone or associated with autoimmune polyglandular syndrome (APS) has been studied. SUBJECTS: A total of 164 individuals were enrolled in this study: 81 patients with AITD alone, 33 patients with APS, and 50 healthy controls. RESULTS: The presence of paIgG was recorded in 41 of 81 patients with AITD (51%) as compared with 2 of 50 control subjects (4%, p < 0.0001). The prevalence of paIgG in patients with APS was higher even when compared with patients with AITD alone (25/33, 76%; p = 0.02). The presence of paIgG was not related to the functional thyroid parameters. The prevalence of paIgG was higher in the older than in the younger patients (75 vs. 47%, p = 0.0037). CONCLUSIONS: The results indicate that the prevalence of paIgG in patients with AITD is higher than previously thought, namely in elderly patients and in patients with APS, and not related to the thyroid function.

Adult↗

PubMed1995

Epstein-Barr virus-induced autoimmune responses. II. Immunoglobulin G autoantibodies to mimicking and nonmimicking epitopes. Presence in autoimmune disease.

During infectious mononucleosis, IgM autoantibodies are generated to a protein, p542, which contains a glycine-rich 28-mer epitope cross-reactive with the Epstein-Barr nuclear antigen-1 through Epstein-Barr nuclear antigen-1's glycine/alanine repeat. In normal individuals it is uncommon to find IgG anti-p542, but among patients with progressive systemic sclerosis, systemic lupus erythematosus, and ulcerative colitis high IgG anti-p542 (> 3 SD above the mean of normal 20-50 yr controls) occurred frequently. Lesser elevations occurred in Sjögren's syndrome, rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease, but none with chronic hepatitis B infection. The reactive epitopes on p542 were mapped with deletion mutants, which indicated that the glycine-rich 28-mer was the major antigenic determinant, with lesser antibody responses to other epitopes. We conclude that normally there is an inability to generate IgG autoantibodies to the cross-reactive (mimicking) epitope of the p542 host protein, but that this inability is overcome in a proportion of patients with autoimmune disease. We conclude also that non-cross-reactive autoepitopes exist on p542 protein, to which IgG autoantibodies can commonly be formed in autoimmune disorders. The mechanisms responsible for the latter must involve different mechanisms than those responsible for autoantibodies to the mimicking epitope.

Adolescent↗

PubMed1991

Cardiac muscle cell damage through autoimmune mechanism--can cardiac proteins provoke autoimmune myocarditis?

In this paper, the ability of human cardiac myosin to provoke autoimmune myocarditis was investigated. Myosin fractions were immunized into A.SW. mice, Lewis rats or Hartley guinea pigs. All of the immunized rats displayed overt symptoms of myocarditis and, in a few cases, died from it. The hearts of these rats were enlarged and discolored. Histologically, the muscles of the heart were characterized by remarkable cell infiltration, extensive myofiber necrosis and the appearance of polynuclear giant cells. Neither mice nor guinea pigs showed such disease profile. In this novel experimental model, the disease state was transferable by T lymphocytes. Thus, cardiac myosin was shown to provoke muscle cell damage through a T cell mediated autoimmune process.

Animals↗

PubMed2006

Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses.

Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system. Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a possible new strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP), a well-known immunosuppressive neuropeptide. Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), in a MS-related rodent model system. VIP suppressed EAE neuropathology by reducing central nervous system inflammation, including the regulation of a wide spectrum of inflammatory mediators, and by selectively blocking encephalitogenic T-cell reactivity. Importantly, VIP treatment was therapeutically effective in established EAE and prevented the recurrence of the disease. Consequently, VIP represents a novel multistep therapeutic approach for the future treatment of human MS.

Animals↗

PubMed2002

IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination.

Experimental autoimmune encephalomyelitis (EAE) serves as a model for multiple sclerosis and is considered a CD4(+), Th1 cell-mediated autoimmune disease. IL-12 is a heterodimeric cytokine, composed of a p40 and a p35 subunit, which is thought to play an important role in the development of Th1 cells and can exacerbate EAE. We induced EAE with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (MOG(35-55)) in C57BL/6 mice and found that while IL-12p40-deficient (-/-) mice are resistant to EAE, IL-12p35(-/-) mice are susceptible. Typical spinal cord mononuclear cell infiltration and demyelination were observed in wild-type and IL-12p35(-/-) mice, whereas IL-12p40(-/-) mice had normal spinal cords. A Th1-type response to MOG(35-55) was observed in the draining lymph node and the spleen of wild-type mice. A weaker MOG(35-55)-specific Th1 response was observed in IL-12p35(-/-) mice, with lower production of IFN-gamma. By contrast, a Th2-type response to MOG(35-55) correlated with disease resistance in IL-12p40(-/-) mice. Production of TNF-alpha by microglia, CNS-infiltrating macrophages, and CD4(+) T cells was detected in wild-type and IL-12p35(-/-), but not in IL-12p40(-/-), mice. In addition, NO production was higher in IL-12p35(-/-) and wild-type mice than in IL-12p40(-/-) mice. These data demonstrate a redundancy of the IL-12 system in the induction of EAE and suggest that p40-related heterodimers, such as the recently cloned IL-23 (p40p19), may play an important role in disease pathogenesis.

Animals↗

PubMedDate not supplied

Estrogen in autoimmunity: expression of estrogen receptors in thymic and autoimmune T cells.

OBJECTIVE: To identify the targets of estrogen in immune system lymphocytes and to examine gender differences in autoimmunity. DESIGN: RNA samples from purified lymphocyte subsets were analyzed for the presence of mRNA for estrogen receptor alpha and beta (ER alpha and ER beta). Groups of male, female, and testicular-feminized mice were compared for autoantibody production. SUBJECTS: Autoimmune-prone lpr (Fas-deficient), testicular-feminized (Tfm, androgen receptor-deficient) and wild-type mice were studied. METHOD: Lymphocyte subsets were purified by fluorescence-activated cell sorting (FACS) and RNA was assessed for the presence of estrogen receptor sequences using specific oligonucleotide primers and the reverse transcription-polymerase chain reaction (RT-PCR). Spontaneous and induced antibody production in mice was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ER alpha was expressed in all lymphocyte subsets examined. ER beta was expressed at low levels in thymic CD4/CD8- T cells in wild-type mice and at high levels in the peripheral CD4-/CD8- T cells in lpr mice. Both spontaneous and induced autoantibody production was higher in female lpr mice than in male lpr mice. CONCLUSIONS: The presence of ERs in lymphocytes indicates that estrogen may affect immune cells during their development and mature function. The selective expression of ER beta may help explain some of the physiological effects of estrogen and its pharmacologic analogues and may lead to means to direct estrogen analogues to such cells. Such effects may be explored in lpr mice, given the enhanced capacity of female lpr mice for autoantibody production.

Androgen-Insensitivity Syndrome↗

PubMed1991

[Fibrosing alveolitis in a 7-year-old girl with autoimmune hemolytic anemia and autoimmune hepatitis].

A Coombs-positive haemolytic anaemia with proof of heat autoagglutinins and autoantibodies against cell nuclei was diagnosed in a girl, now 7 1/2 years of age, in the sixth month of her life as a sequel to jaundice. Shortly afterwards liver biopsy yielded a confirmed diagnosis of giant cell hepatitis. The signs of the disease receded under treatment with decortin and imurek. An attempt to discontinue the medication at 5 1/2 years of age resulted in a histologically confirmed recurrence of autoimmune hepatitis. When the patient was 5 years old, the x-ray revealed a mainly interstitial pneumonia; at 6 years of age, bronchiectases in the region of the left lower lobe were confirmed by bronchography. Resection of the lower lobe was performed after occurrence of atelectasis. Histopathological findings confirmed fibrotic alveolitis associated with giant cells. Based on the overall clinical course and the histological and immunological findings, autoimmune etiology of fibrotic alveolitis must be discussed. Progression of the disease could be avoided during the past 6 months by intensifying the immunosuppressive prednisolone therapy.

Anemia, Hemolytic, Autoimmune↗

PubMed1993

TH2 activated cells prevent experimental autoimmune uveoretinitis, a TH1-dependent autoimmune disease.

Mercuric chloride (HgCl2) injections protect (Lewis x Brown-Norway) F1 (F1) rats against experimental autoimmune uveoretinitis (EAU) induced by immunization with the retinal S antigen (S-Ag); in contrast HgCl2-injected F1 rats develop EAU following transfer of lymph node (LN) cells from rats immunized with S-Ag alone. In the present study we demonstrate that the ability of LN cells from rats protected against EAU to transfer the disease into naive F1 rats was considerably reduced. These LN cells neither produced interleukin (IL)-2 nor (interferon (IFN)-gamma but exhibited mRNA for IL-4. In contrast, LN cells from diseased rats easily transferred EAU into naive F1 rats, produced significant IL-2 and IFN-gamma levels but barely exhibited mRNA for IL-4. Furthermore protected rats predominantly produced IgG1 anti-S-Ag antibodies, while diseased rats produced IgG2b anti-S-Ag antibodies and the increase in expression of MHC class II molecules on B cells was higher in protected rats than in diseased rats. These data suggest that (1) to exert a protective effect, HgCl2 must act at an early stage of differentiation of precursors of S-Ag specific T cells, and (2) this effect is related to the preferential activation of TH2 cells to the detriment of uveitogenic TH1 cells. Finally, these results indicate that activation of TH2 cells protect from a TH1-dependent autoimmune disease.

Animals↗

PubMed1996

Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis.

Overlapping features between primary sclerosing cholangitis (PSC and autoimmune hepatitis (AIH) have previously been noted. To assess systematically similarities between these disorders, we have evaluated 114 PSC patients (36 women; 78 men), all confirmed by endoscopic retrograde cholangiography (ERC), according to a scoring system proposed by The International Autoimmune Hepatitis Group for the diagnosis of AIH. The scoring system attributes positive or negative scores to the parameters sex, ratio of elevation of serum levels of alkaline phosphatase (ALP) vs. aminotransferase, serum levels of immunoglobulins and autoantibodies, viral markers, history of drug and alcohol intake, genetic factors, liver histology, and response to therapy. Two of the PSC patients (2%) obtained scores above 15 before treatment, satisfying the diagnostic criterion of "definite" AIH. Thirty-eight patients (33%) scored between 10 and 15 points and could be classified as "probable" AIH. The serum level of immunoglobulin G (IgG) was elevated in 68 patients (61% of 111 cases tested), and positive titers of antinuclear antibodies (ANA) or smooth muscle antibodies (SMA) were detected in 24 patients (22% of 111 cases tested). Thirty-five of the PSC patients (33% of 105 evaluable biopsy specimens) obtained positive scores for histological features similar to those of AIH, but the total score for histology was in the negative range in 72 patients (69%) because of the presence of biliary changes. The frequent finding of high scores in PSC patients underlines the similarities PSC may have with AIH. A modification of the scoring system, in particular by increasing the negative score for histological biliary changes, would improve its potential to discriminate between AIH and PSC.

Adolescent↗

PubMed1999

Cloning of Aire, the mouse homologue of the autoimmune regulator (AIRE) gene responsible for autoimmune polyglandular syndrome type 1 (ASP1).

The human autoimmune regulator gene (AIRE), responsible for autoimmune polyglandular syndrome Type 1 (APS1), has recently been identified by positional cloning. Here we report the cloning of Aire, the mouse homologue of AIRE, and the characterization of its genomic structure. The complete Aire gene is contained in 14 exons and encodes a protein of 552 amino acids. The coding region shares 77% nucleotide homology and 71% protein homology with human AIRE. As in its human homologue, Aire contains two PHD-type zinc-finger motifs, suggesting that the Aire protein may act as a transcription regulator.

Amino Acid Sequence↗

PubMed2000

Autoimmune reactivity of sera to hepatocyte plasma membrane in type 1 autoimmune hepatitis.

Type 1 autoimmune hepatitis (AIH-1) is an organ-specific autoimmune liver disease for which no tissue-specific autoantigen has yet been identified. We examined the reactivity by sensitive immunoblotting with enhanced chemiluminescence (IB-ECL) of 43 sera from patients with AIH-1 and 182 sera from patients with other diseases on hepatocyte plasma membrane derived from rat or human liver (RHPM, HHPM) and separated by aqueous two-phase partition. The sera studied were from patients with AIH-1, primary biliary cirrhosis, chronic viral hepatitis, and systemic lupus erythematosus (SLE); and from normal subjects. Specificity of reactivity by IB-ECL was sought: (i) by testing sera on human or rat liver membrane; (ii) by testing sera on liver or kidney membrane; (iii) by serial titration of reactive sera; and (iv) by testing reactive sera from AIH-1 before and after successful treatment with prednisolone. The results were that in AIH-1 there were multiple reactive components which were not species-specific, since they were detected with both RHPM and HHPM, but were mostly tissue-specific for liver. There was no significant correlation between antinuclear antibodies (ANA) titer and the frequencies of sera reactivities against RHPM. Most of these reactive components were demonstrable at a lesser frequency in other liver diseases and in SLE. There was a striking decrease in reactivity by IB-ECL of AIH-1 sera with liver membrane after clinical remission, further suggesting that differences between AIH-1 and other inflammatory liver diseases and SLE are predominantly quantitative rather than qualitative. However, our study did point to candidate liver membrane antigens with molecular sizes of 136, 116, 81, and 49 kDa, additional to components previously described by others. The molecular identification of these prominent reactants with AIH-1 sera could prove informative for ascertaining pathogenesis.

Adult↗

PubMed2006

Type 1 autoimmune hepatitis in Taiwan: diagnosis using the revised criteria of the International Autoimmune Hepatitis Group.

Autoimmune hepatitis (AIH) is rare in Asian countries compared to the West, and an exceptionally low prevalence was noted previously in Taiwan. Using the revised criteria of the IAIHG, 48 cases of AIH patients were diagnosed. All patients were consecutively diagnosed over a period of 5 years. Detailed medical histories including disease onset, hepatitis B and C, alcohol, drugs, blood transfusion, and family history of autoimmune disease were recorded. Clinical manifestations, result of steroid therapy, outcome, and survival rate were investigated and analyzed. Clinical data on AIH patients with cirrhosis and without cirrhosis were compared and analyzed for their outcome. The statistical methods used were Fisher's exact test, Wilcoxon rank sum test, and Kaplan-Meier curve. Forty-eight patients were diagnosed as AIH type 1, with a median age of 58 years and a female:male ratio of 37:11. The most common clinical features at presentation were fatigue, jaundice, and anorexia. Ninety-eight percent of patients were ANA positive, and most of the patients showed elevated values of AST, ALT, serum globulin, and bilirubin. A substantial proportion of patients presented with poor liver function at entry and 35% of patients had liver cirrhosis, with relatively prolonged PT (P=0.001) and poorer outcome (P=0.005) compared to the noncirrhotics. As a whole there was a favorable treatment response and the overall survival rate was 85%. We conclude that the incidence of AIH in Taiwan is much higher than previously presumed and AIH type 1 is the predominant type of the disease. Although a substantial proportion of AIH patients presented with poor hepatic function at entry, as a whole there was a favorable clinical outcome.

Adult↗

PubMed2003

Experimental autoimmune encephalomyelitis: cytokines, effector T cells, and antigen-presenting cells in a prototypical Th1-mediated autoimmune disease.

Experimental autoimmune encephalomyelitis (EAE) is widely depicted as the prototypical CD4+ Th1-mediated autoimmune disease. Microglia and perivascular macrophages are believed to act as antigen-presenting cells during the effector phase of EAE. In this article, recent data that challenge these conceptions are reviewed. Several recent studies have shown that myelin-reactive CD8+ T cells can mediate inflammatory demyelination. Furthermore, dendritic-like cells have been detected in EAE lesions and implicated in encephalitogenic T-cell activation. Although Th1 polarizing monokines, such as interleukin-12 (IL-12) and possibly IL-23, are critical for the manifestation of EAE, individual Th1 effector cytokines were found to be dispensible.

Animals↗

PubMedDate not supplied

Anti-idiotypic immunity and autoimmunity: III. Investigations in human autoimmune thyroiditis.

We have recently shown that autoantibodies to thyroglobulin in from rats with spontaneous autoimmune thyroiditis share idiotypic determinants and can be characterized using heterologous anti-idiotypic antibodies. We have also shown that cross-reacting idiotypic determinants are present on autoantibodies to rat thyroglobulin from rats with experimentally induced autoimmune thyroiditis as well as on antibodies to rat thyroglobulin from animals of various strains and species. In the present paper we report that anti-idiotypic antibodies have been obtained in rabbits immunized with purified human autoantibodies against thyroglobulin. We also confirm the finding that both human and rat autoantibodies to thyroglobulin partially cross-react with heterologous thyroglobulin.

Animals↗