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PubMed1980

Splenic immunoglobulin-secreting cells and their regulation in autoimmune mice.

We have investigated in vitro the magnitude, nature, and regulation of spontaneous and mitogen-induced Ig secretion by splenic lymphocytes from several autoimmune murine strains (NZB, NZB X W, MRL/l BXSB) and appropriate, normal mice. All autoimmune strains had increased numbers of mature splenic B lymphocytes, which secreted and/or contained Ig, compared to age-matched normal strains. In NZB and NZB X W mice, the high frequency of mature B cells was apparent early in life, whereas in MRL/l and BXSB mice it was first noted shortly before the clinical onset of disease. Spleen cells from young autoimmune mice of all four strains secreted predominantly IgM, but with aging and the appearance of disease, the cells switched to IgG secretion predominantly. In contrast, spleen cells from normal mice were predominantly IgM, but with aging and the appearance of disease, the cells switched to IgG secretion predominantly. In contrast, spleen cells from normal mice were predominantly IgM secretors throughout the animals' lives. Approximately 15% of the total Ig-secreting cells in older NZB, NZB X W, and MRL mice were committed to secretion of anti-ssDNA antibodies. In both autoimmune and normal spleen cells, the B-cell population alone contained fewer secreting cells than the total lymphocyte population, indicating that T cells were required to achieve maximal levels of plaque-forming cells. Spleen cells of NZB and NZB X W mice had a greater response to lipopolysaccharide (LPS) than other autoimmune and normal strains. Responsiveness to LPS, as measured by the frequency of induced Ig-secreting cells, was considerably diminished with age and onset of disease in all autoimmune but not in normal strains. LPS-induced Ig secretion by B cells of autoimmune and normal mice was subject to regulation by splenic T cells. No significant differences were observed between concanavalin-A (Con A) stimulated spleen cells from young and older autoimmune mice and normal control strains in effectively suppressing spontaneous and LPS-induced Ig secretion. Moreover, B cells from autoimmune mice and from normal strains were equally receptive to Con A-induced suppressor signals. T cells from young and older NZB and BXSB mice added to a standard number of B cells from syngeneic young mice provided equal help in enhancing LPS-induced Ig secretion, and this help in turn was equivalent to that provided by T cells from normal mice of the same H-2 haplotype. The exception was the MRL/l strain; T cells from older animals provided considerably more help than T cells from young MRL/l or T cells from young and older H-2-compatible normal mice.

Animals↗

PubMed1993

An autoimmune disease with multiple molecular targets abrogated by the transgenic expression of a single autoantigen in the thymus.

Many autoimmune diseases are characterized by autoantibody reactivities to multiple cellular antigens. Autoantigens are commonly defined as targets of the autoimmune B cell response, but the role, if any, of these autoantigens in T cell-mediated autoimmune diseases is generally unknown. Murine experimental autoimmune gastritis is a CD4+ T cell-mediated organ-specific autoimmune disease induced by neonatal thymectomy of BALB/c mice. The murine disease is similar to human autoimmune gastritis and pernicious anemia, and is characterized by parietal and chief cell loss, submucosal mononuclear cell infiltrates, and autoantibodies to the alpha and beta subunits of the gastric H/K ATPase. However, the specificity of T cells that cause the disease is not known. To examine the role of the H/K ATPase in this T cell-mediated disease, transgenic mice were generated that express the beta subunit of the H/K ATPase under the control of the major histocompatibility complex class II I-Ek alpha promoter. We show that transgenic expression of the gastric H/K ATPase beta subunit specifically prevents the onset of autoimmune gastritis after neonatal thymectomy. In addition, thymocyte transfer experiments suggest that tolerance of pathogenic autoreactive T cells is induced within the thymus of the transgenic mice. We conclude that the beta subunit of the gastric H/K ATPase is a major T cell target in autoimmune gastritis and that thymic expression of a single autoantigen can abrogate an autoimmune response to multiple autoantigens.

Animals↗

PubMed1995

Mechanisms of autoimmune disease in the testis and ovary.

This article reviews recent research on autoimmune diseases of the testis and ovary based on two experimental approaches for induction of autoimmune diseases of the gonads (immunization with testis or ovary antigen, usually with adjuvant, and deliberate alteration of the immune system in normal animals, without injecting antigen or adjuvant). It has been found that the local testicular immunoregulatory environment partially impedes autoimmune responses to ontogenic testis antigens and regulatory T cells usually control pathogenic T cells that are found in the normal peripheral immune system. If the clonal balance of these CD4+ T cell subsets is tipped in favour of pathogenic T cells, autoimmune diseases of the gonads could ensue. Loss of regulatory T cells may occur through aberrant T cell development, or oophoritogenic T cells can be activated by non-ovarian peptides that crossreact with self peptides at the level of the T cell receptor. The inflammatory CD4 (Th1) T cell mechanism has been established to be a critical pathway for autoimmune orchitis and autoimmune oophoritis; tumour necrosis factor has been shown to be required for amplification of the pathogenic T cell response. Histopathology has suggested tissue locations wherein pathogenic T cells encounter testicular and ovarian target antigens. Antibodies bind to both testicular and ovarian target antigens during the development of autoimmune orchitis and autoimmune oophoritis, but the precise role of the antibodies has not been determined. Resolution of this role may influence the clarification of the mechanism whereby autoantibody may access ejaculated human spermatozoa to cause infertility and the future of contraceptive vaccine development based on ovarian antigens. A novel mechanism of autoantibody induction and an immunogenetic approach to autoimmune oophoritis and orchitis, based on molecular linkage analysis of inbred mice, are also reviewed.

Animals↗

PubMed2002

Objective evidence of decreased salivary function in patients with autoimmune thyroiditis (chronic thyroiditis, Hashimoto's thyroiditis).

Impaired salivary flow is found in Sjögren's syndrome, which is a common, chronic, autoimmune, inflammatory connective tissue disease, mainly affecting the exocrine glands. Histopathologically, lymphocytic infiltrations of the salivary glands are found in Sjögren's syndrome that are similar to those of the thyroid gland in autoimmune thyroiditis (chronic thyroiditis, Hashimoto's thyroiditis). To test this hypothesis by Daniels et al ., salivary function was measured by quantitative salivary scintigraphy in autoimmune thyroiditis patients, as well as in age- and sex-matched controls. Forty patients, each with a history of autoimmune thyroiditis of over 10 years, and 61 healthy controls were enrolled in the study. All of the 40 autoimmune thyroiditis patients had good blood sugar control. None presented autonomic neuropathy. They were separated into two subgroups: patient group 1, 20 patients with xerostomia; patient group 2, 20 patients without xerostomia. Two control groups of healthy subjects were included for comparison: control group 1, 36 subjects without xerostomia; control group 2, 25 subjects with xerostomia. After intravenous injection of 5 mCi (99m)Tc-pertechnetate, sequential images at 1 min per frame were acquired for 30 min. The first and 15th minute uptake ratios (URs) were calculated from the tracer uptakes in the four major salivary glands relative to the background regions of interest (ROIs). Saliva excretion was stimulated by one tablet of 200 mg ascorbic acid given orally 15 min after injection of the tracer. The maximal excretion ratios (ERs) of the four major salivary glands after sialagogue stimulation were calculated. Impaired salivary function, represented by significantly decreased UR and ER values, in autoimmune thyroiditis patients with xerostomia was demonstrated in this study. Significantly poorer salivary function was found in autoimmune thyroiditis patients with xerostomia, when compared with autoimmune thyroiditis patients without xerostomia and healthy controls with or without xerostomia, via objective and quantitative salivary scintigraphy. However, a larger series of autoimmune thyroiditis patients is necessary to confirm our findings.

Adult↗

PubMed1998

Autoimmune thyroid diseases and coeliac disease.

BACKGROUND: Coeliac disease may be associated with a wide variety of diseases of known or suspected immunological aetiology. OBJECTIVE: To screen for both (a) the prevalence of coeliac disease in adults with autoimmune thyroid diseases, and (b) thyroid impairment among adults with coeliac disease, as compared to sex- and age-matched controls. DESIGN: Prospective cohort study. SETTING: University teaching hospital. PATIENTS: A total of 152 consecutive adults with autoimmune thyroid diseases, 185 consecutive coeliac disease patients (53 newly diagnosed and 132 already on a gluten-free diet) and 170 sex- and age-matched controls. METHODS: Screening for coeliac disease was done by means of IgA anti-endomysium antibodies, detected by indirect immunofluorescence on monkey oesophagus. Patients with positive sera underwent duodenal biopsy for diagnostic confirmation. Thyroid function was assessed by measuring the levels of serum thyroid-stimulating hormone, free T3, free T4, thyroperoxidase and thyroid microsome antibodies. Autoimmune thyroid diseases were classified according to the American Thyroid Association guidelines. RESULTS: Anti-endomysium antibodies were positive in five of 152 autoimmune thyroid disease patients (3.3%) and coeliac disease was histologically confirmed in all: this prevalence is 10-fold higher than expected. Only one patient presented with gastrointestinal complaints, but iron deficiency was found in three and alterations at bone mineralometry in all. The overall prevalence of autoimmune thyroid diseases was significantly higher (38/185, 20.5%) in coeliac patients than in controls (19/170, 11.2%). The prevalence of both hypo- and hyperthyroidism was not different from that of controls, while the prevalence of autoimmune thyroid disease with euthyroidism was 13% in patients and 4.7% in controls. CONCLUSIONS: The association of coeliac disease with autoimmune thyroid disease is not surprising as they share common immunopathogenetic mechanisms. It is advisable to screen autoimmune thyroid disease patients for coeliac disease as there is an increased risk for gluten intolerance. In contrast, thyroid function assessment in coeliac disease patients is probably less justified, although the need for a strict clinical follow-up of those patients with euthyroidism and autoimmune thyroid disease, who could develop overt thyroid impairment, remains an open question.

Adolescent↗

PubMed1999

Autoimmune liver disease in patients with neoplastic diseases.

BACKGROUND: Development of de novo autoimmune liver disease has not been well documented in patients with malignant diseases. METHODS/RESULTS: In this paper we report on a series of six patients with neoplastic disorders who acquired liver disease with autoimmune features. Five patients had suffered from haematological neoplasms and one from colonic cancer. In two patients, liver disease was detected at the time of presentation with malignancy. In the remaining four, all of whom were successfully treated for malignancies, features of liver disease presented at intervals 24-72 months after the cancer diagnosis. Twelve liver specimens (11 biopsies and one hepatectomy specimen) were obtained at time intervals of 1-76 months after initial presentation of neoplastic disease. Biopsies from three patients showed features of hepatitis (one acute, one sub-acute, one chronic). Two patients had histological features suggestive of an overlap syndrome (one autoimmune hepatitis/primary biliary cirrhosis, one autoimmune hepatitis/primary sclerosing cholangitis). The sixth patient had features of autoimmune cholangiopathy. All but one responded well to steroid therapy with complete clinical and biochemical remission obtained 4 weeks to 8 months after steroid introduction. We discuss briefly possible aetiologies of autoimmune liver disease in these patients. CONCLUSIONS: Autoimmune liver disease may be precipitated by therapy for neoplastic disease or malignant disease itself. The unusually heterogeneous clinicopathological findings in this group as well as the response to treatment support the concept of a wide spectrum of manifestations of autoimmune liver disease. The results may also suggest that autoimmune liver disease may be possibly added to the list of paraneoplastic syndromes. Further prospective studies are required to confirm a causal association and to determine whether the mechanisms involved are disease- or treatment-related.

Adult↗

PubMed2003

The utility of positron emission tomography in the evaluation of autoimmune hearing loss.

OBJECTIVE: To evaluate positron emission tomography as an imaging tool in the diagnosis, evaluation, and management of autoimmune inner ear disease. BACKGROUND: Autoimmune inner ear disease is a form of cochleovestibular disease associated with variable hearing loss and vertigo for which no reliable diagnostic tests are available. METHODS: Pilot study of 10 patients with autoimmune inner ear disease and 5 sex-matched and age-matched control subjects without any history of autoimmune inner ear disease, who underwent limited positron emission tomography of the inner ear. Five patients with new or active autoimmune inner ear disease underwent serial positron emission tomography before and after 4 to 6 weeks of a high-dose tapering course of prednisone. The subjects had cranial magnetic resonance imagining, audiometric and vestibular studies, and heat-shock protein (HSP-70) measurements. Reading of the positron emission tomography scans was blinded. RESULTS: Positron emission tomography was normal in 4 of 5 normal control subjects and abnormal in 1 with normal audiometric and vestibular studies and positive HSP-70. Of patients with established and stable autoimmune inner ear disease, 4 of 5 had no positron emission tomography abnormalities and negative HSP-70, and the one with abnormal positron emission tomography shortly thereafter manifested clinically active disease. Of the 5 patients with active autoimmune inner ear disease monitored serially, 4 had an initial abnormal positron emission tomography in at least one ear, which became normal in all but 1 patient after therapy. HSP-70 correlated with disease activity. Only 1 patient with clinically active autoimmune inner ear disease had a normal positron emission tomography before and after therapy (the HSP-70 was positive before therapy and negative after the therapy). CONCLUSIONS: Positron emission tomography, especially when combined with HSP-70 determination, may be a useful technique for assessing disease in patients with autoimmune inner ear disease.

Adult↗

PubMed1987

Spectrum and frequency of autoimmune derangements in lymphoproliferative disorders: analysis of 637 cases and comparison with myeloproliferative diseases.

The records of 637 patients with lymphoproliferative disorders and 346 patients with myeloproliferative disorders were retrospectively analysed for the presence of additional autoimmune derangements. The frequency of autoimmune perturbations in lymphoproliferative diseases (51 cases; 8.0%) was significantly higher than in myeloproliferative diseases (six cases; 1.7%; P less than 0.0001). Rheumatic disorders, autoallergic haematological manifestations and other organ-specific autoimmune derangements were responsible for about one third each of the observed disturbances. Autoimmune diseases which preceded the onset of malignancy, occurred in lymphoproliferative and myeloproliferative disorders with a comparable frequency without significant differences between individual subgroups of lymphoproliferative diseases. In contrast, autoimmune complications developing in the course of the neoplastic disease were significantly more frequent in lymphoproliferative (4.9%) than in myeloproliferative disorders (0.3%; P less than 0.0005). Here marked differences were observed between individual lymphoma entities, the rate of concomitant autoimmune derangements ranging from zero to over 15%. With the exception of centroblastic-centrocytic lymphoma which in no case was associated with secondary autoimmune complications, the proportion of patients with autoimmune perturbations increased with improving prognosis of the lymphoproliferative diseases. Possible pathogenetic mechanisms involved in the manifestation of autoimmune complications in malignant lymphomas are discussed.

Autoimmune Diseases↗

PubMed1992

Thyroid autoimmunity and hypothyroidism during long-term treatment with recombinant interferon-alpha.

Forty-five patients with myeloproliferative or myelodysplastic syndromes, treated with recombinant interferon-alpha (rIFN-alpha) for a minimum of 1 up to 4 years, were examined for the occurrence of thyroid autoimmunity. During treatment, the rate of thyroid autoimmunity rose to more than 20%. The decrease in severity and frequency of thyroid autoimmunity after withdrawal of IFN shows that this is a potentially reversible side effect. The key determinant for the manifestation of this IFN-related autoimmune phenomenon seems to be a predisposition for autoimmunity, since patients with initially detectable thyroid antibodies are prone to exacerbations of thyroid autoimmunity. Concurrent with thyroid autoimmunity, hypothyroidism occurred but did not correlate with the levels of thyroid antibodies, although severe hypothyroidism in two patients was accompanied by increased levels of thyroid antibodies. This investigation shows that thyroid autoimmunity and consecutively hypothyroidism must be expected in certain patients treated with rIFN-alpha during long periods. Furthermore, it may be assumed that IFN-alpha does not induce the development of autoimmunity, but rather enhances the levels of pre-existent thyroid antibodies.

Adult↗

PubMed1999

Prevalence of GBV-C/HGV-RNA, virus genotypes, and anti-E2 antibodies in autoimmune hepatitis.

OBJECTIVE: We investigated the prevalence of hepatitis G-RNA (GBV-C/HGV-RNA), a recently cloned new flavivirus, and of antibodies to the envelope 2 antigen (anti-E2), a marker of past infection, in patients with autoimmune hepatitis, and compared it with the prevalence in patients with chronic viral hepatitis and healthy control individuals. METHODS: Sera of 63 patients with autoimmune hepatitis were studied for the presence of GBV-C/HGV-RNA by reverse-transcription polymerase chain reaction and for anti-E2 by enzyme-linked immunosorbent assay. GBV-C/HGV genotypes were determined by genome sequencing. RESULTS: Patients with autoimmune hepatitis had a similar high prevalence of GBV-C/HGV-RNA and anti-E2 antibodies as patients with chronic viral hepatitis B or C. GBV-C/HGV-RNA was found significantly more often in patients with autoimmune hepatitis (11%, p = 0.045), hepatitis B (16%, p = 0.004), or hepatitis C (21%, p = 0.001) than in healthy controls (2%). The prevalence of anti-E2 antibodies in patients with autoimmune hepatitis was not different from healthy controls (17% vs 13%, NS). The various subtypes of autoimmune hepatitis had similar prevalence rates of GBV-C/HGV-RNA as patients with liver-kidney microsomal antibody-positive hepatitis C. All of our anti-E2+ (GBV-C/HGV-RNA-) patients were positive for anti-smooth-muscle antibody, whereas only 29% of GBV-C/HGV-RNA+ (anti-E2-) patients were positive (p = 0.025). All seven of the GBV-C/HGV-RNA+ patients with autoimmune hepatitis had genotype 2a, which is also the most prevalent genotype in our region. CONCLUSION: The prevalence of GBV-C/HGV-RNA is significantly increased in patients with autoimmune hepatitis, compared with healthy controls, and is similar to the increased prevalence seen in chronic hepatitis B or C patients. Anti-E2 positivity was associated with antibodies against smooth-muscle antigen in all cases. All GBV-C/HGV+ autoimmune hepatitis patients were infected with genotype 2a.

Adult↗

PubMed2001

Cardiac myosin autoimmunity in acute Chagas' heart disease.

Infection with Trypanosoma cruzi, the agent of Chagas' disease, may induce antibodies and T cells reactive with self antigens (autoimmunity). Because autoimmunity is generally thought to develop during the chronic phase of infection, one hypothesis is that autoimmunity develops only after long-term, low-level stimulation of self-reactive cells. However, preliminary reports suggest that autoimmunity may begin during acute T. cruzi infection. The goal of the present study was to investigate whether cardiac autoimmunity could be observed during acute T. cruzi infection. A/J mice infected with the Brazil strain of T. cruzi for 21 days developed severe myocarditis, accompanied by humoral and cellular autoimmunity. Specifically, T. cruzi infection induced immunoglobulin G (IgG) autoantibodies and delayed type hypersensitivity (DTH) to cardiac myosin. This autoimmunity resembles that which develops in A/J mice immunized with myosin in complete Freund's adjuvant in that myosin-specific antibodies and DTH responses both develop by 21 days postinfection or postimmunization. While the levels of myosin IgG in T. cruzi-infected mice were slightly lower than those in myosin-immunized mice, the magnitude of myosin DTH in the two groups was statistically equivalent. In contrast, C57BL/6 mice, which are resistant to myosin-induced myocarditis and its associated autoimmunity, developed undetectable or low levels of myosin IgG and did not exhibit myosin DTH or myocarditis upon T. cruzi infection. Therefore, humoral and cellular cardiac autoimmunity can develop during acute T. cruzi infection in the genetically susceptible host.

Animals↗

PubMed2006

High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?

BACKGROUND: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. METHODS: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. RESULTS: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a "probable autoimmune hepatitis" (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). CONCLUSIONS: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.

Aged↗

PubMed2006

Association of schizophrenia and autoimmune diseases: linkage of Danish national registers.

OBJECTIVE: Individuals with schizophrenia and their relatives tend to have either higher or lower than expected prevalences of autoimmune disorders, especially rheumatoid arthritis, celiac disease, autoimmune thyroid diseases, and type 1 diabetes. The purpose of the study was to estimate the association of schizophrenia with these disorders as well as a range of other autoimmune diseases in a single large epidemiologic study. METHOD: The Danish Psychiatric Register, the National Patient Register, and a register with socioeconomic information were linked to form a data file that included all 7,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their parents along with a sample of matched comparison subjects and their parents. The data linkage required that the autoimmune disease occur before the diagnosis of schizophrenia. RESULTS: A history of any autoimmune disease was associated with a 45% increase in risk for schizophrenia. Nine autoimmune disorders had higher prevalence rates among patients with schizophrenia than among comparison subjects (crude incidence rate ratios ranging from 1.9 to 12.5), and 12 autoimmune diseases had higher prevalence rates among parents of schizophrenia patients than among parents of comparison subjects (adjusted incidence rate ratios ranging from 1.3 to 3.8). Thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial cystitis, and Sjögren's syndrome had higher prevalence rates among patients with schizophrenia than among comparison subjects and also among family members of schizophrenia patients than among family members of comparison subjects. CONCLUSIONS: Schizophrenia is associated with a larger range of autoimmune diseases than heretofore suspected. Future research on comorbidity has the potential to advance understanding of pathogenesis of both psychiatric and autoimmune disorders.

Age of Onset↗

PubMed2004

Autoimmunity, infertility and assisted reproductive technologies.

Despite strongly held opinions, a trustworthy scientific basis for most statements about autoimmunity, autoimmune diseases and assisted reproductive technologies (ART) does not exist. It is not likely that autoimmunity causes infertility, nor that patients with autoimmune diseases are unusually infertile. When carefully monitored in selected patients, ART does not appear to harm patients who have pre-existing autoimmune diseases, but the ovarian hyperstimulation syndrome and multiple gestation pregnancies impart independent risks. Stable autoimmune diseases without major organ damage probably do not affect the outcomes of ART pregnancies. Children born of ART pregnancies are apparently normal at birth, whether or not the genetic or birth mother has autoimmune disease, but long-term follow-up is not available. Male fertility is probably not altered by autoimmune disease. Fiscal, ethical and moral issues related to ART in patients with autoimmune diseases are beyond the scope of this discussion but remain important.

Autoimmune Diseases↗

PubMed2003

Antipituitary antibodies in adults with apparently idiopathic growth hormone deficiency and in adults with autoimmune endocrine diseases.

The role of antipituitary antibodies (APA) in autoimmune pituitary diseases still needs to be clarified. The aim of this study was 2-fold: first, to investigate the presence of APA in adults with idiopathic or acquired GH deficiency (GHD) and in adults with autoimmune endocrine diseases; and second, to evaluate whether in autoimmune endocrine patients APA titer is correlated to the pituitary function and particularly to GH secretion. We studied 12 adults with isolated and apparently idiopathic GHD who were treated with recombinant GH in childhood (group 1a), 14 patients with adult GHD secondary to surgery for pituitary and parasellar tumors (group 1b), and 180 patients with organ-specific autoimmune diseases (group 2). APA were evaluated by indirect immunofluorescence. In all APA-positive patients and in 20 APA-negative patients of group 2, GH secretion was investigated by testing its response to insulin-induced hypoglycemia (insulin tolerance test) and, when impaired, also to arginine. APA were found (at high titers) in 4 of 12 patients of group 1a (33.3%) but were absent in all patients in group 1b. APA were also found in 40 of 180 patients of group 2 (22.2%), 35 of them at low titers (group 2a) and 5 at high titers (group 2b). Twenty of the 140 autoimmune endocrine APA-negative patients studied (group 2c) and all APA-positive patients at low titers (group 2a) had normal pituitary function. Conversely, all APA-positive patients at high titers (groups 1a and 2b) had a severe isolated GHD. An inverse correlation between APA titers and GH peak serum response to insulin tolerance test in autoimmune endocrine patients was observed. Our results suggest that APA, when detected at high titers, may be considered a good diagnostic tool to highlight the possible occurrence of GHD in adults with autoimmune endocrine diseases. Moreover, they may indicate an autoimmune pituitary involvement in adults with apparently idiopathic GHD, suggesting that the prevalence of autoimmune GHD is much higher than that so far considered.

Adult↗

PubMed2005

Elevated serum interferon-gamma-inducible chemokine-10/CXC chemokine ligand-10 in autoimmune primary adrenal insufficiency and in vitro expression in human adrenal cells primary cultures after stimulation with proinflammatory cytokines.

Chemokines are a large family of cytokines involved in the pathogenesis of inflammatory and autoimmune diseases. Among CXC chemokines, CXC chemokine ligand 10 (CXCL10) has been identified to play an important role in several endocrinological autoimmune diseases, such as Hashimoto's thyroiditis, Graves' disease, and type 1 diabetes mellitus. Although the mechanisms leading to glandular autoimmune process may be at least in part shared by different endocrine organs, the role of CXCL10 in autoimmune adrenal insufficiency is unknown. The aim of this study was to evaluate the role of CXCL10 in Addison's disease (AD). Serum CXCL10 levels were assayed in 64 patients with clinically evident autoimmune AD, 20 patients with autoimmune subclinical AD, nine patients with nonautoimmune AD, and 48 healthy volunteers. Clinically evident and subclinical AD, but not nonautoimmune AD patients, showed a significant increase in serum CXCL10 levels compared with healthy subjects: 119.9 pg/ml (range, 39.8-427.6) and 124.0 pg/ml (range, 37.0-384.7) vs. 75.6 pg/ml (range, 22.4-164.0; P < 0.001 for both groups). Comparable serum CXCL10 levels were found between patients with an isolated form of AD and patients with other autoimmune conditions associated with AD, suggesting a specific influence of the adrenal autoimmune process in determining elevated CXCL10 concentrations in such patients. No relationship was found between serum CXCL10 levels and anti-21-hydroxylase or adrenal cortex autoantibody titers or between CXCL10 levels and duration of disease. The role of CXCL10 in the adrenal gland was also evaluated in vitro in human zona fasciculata cells (hZFC). CXCL10, although not basally detected in cultured hZFC, was strongly induced by interferon-gamma and synergistically increased by TNF-alpha addition. Hydrocortisone or ACTH alone had no effect on CXCL10 secretion in hZFC, but they both significantly inhibited cytokine-induced CXCL10 secretion. Taken together, these data suggest a potential role of hZFC, through the production of CXCL10, in regulating the recruitment of specific subsets of activated lymphocytes in autoimmune AD.

Addison Disease↗

PubMed2002

Mercury-induced autoimmunity in mice.

We have studied the effect of gender, genetics, and toxicokinetics on immune parameters in mercury-induced autoimmunity in mice. Data strongly suggest that the mechanism for mercury-induced autoimmunity involves modification of the autoantigen fibrillarin by mercury followed by a T-cell-dependent immune response driven by the modified fibrillarin. Mice with different H-2 haplotypes were treated with (203)HgCl(2) in a dose of 0.5-16 mg Hg/L drinking water for 10 weeks. Whole-body accumulation and renal accumulation of mercury were assessed. Serum antinuclear antibodies were used to evaluate the autoimmune response, and serum immunoglobulin E (IgE) to study effects on T-helper cells of type 2. Strains with a susceptible H-2 haplotype developed autoantibodies to the nucleolar protein fibrillarin (AFA) in a dose-dependent pattern within 2 weeks. The substantially lower whole-body and organ mercury level needed to induce AFA in the susceptible A.SW strain compared with the H-2 congenic B10.S strain demonstrates that genetic factors outside the H-2 region modify the autoimmune response. Mouse strains without the susceptible haplotype did not develop any autoimmune reaction irrespective of dose and organ deposition of mercury. In susceptible mouse strains, males and females had different thresholds for induction of autoimmune reactions. In susceptible strains, serum IgE increased dose dependently and reached a maximum after 1-2.5 weeks. A susceptible H-2 haplotype is therefore a prerequisite for the autoimmune response. Mercury exposure will modulate the response, qualitatively through the existence of dose-related thresholds for autoimmune response and quantitatively as increasing doses cause increasing autoimmune response. Further, gender and non-H-2 genes modulate both the induction and subsequent development of AFA. Induction of IgE seems not to be mechanistically linked to the AFA response.

Animals↗

PubMed1999

Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity.

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL/lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl(2)-induced exacerbation of autoimmunity. Such genetic predisposition may have to be considered when assessing the immunotoxicity of xenobiotics. Additional comparative studies using autoimmune-prone and nonautoimmune mice strains with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations susceptible to autoimmune diseases.

Animals↗