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PubMed2004

Autoimmune thyroiditis and anti-thyroid antibodies in primary Sjogren's syndrome: a case-control study.

OBJECTIVE: To determine the frequency of antithyroid antibodies and the presence of autoimmune thyroiditis among patients with primary Sjögren's syndrome. DESIGN: A case-control study. METHODS: 53 consecutive patients with primary Sjögren's syndrome, 30 with rheumatoid arthritis, 12 with secondary Sjögren's syndrome associated with rheumatoid arthritis, 17 with autoimmune thyroiditis, and 53 apparently healthy controls were studied for anti-TG and anti-TPO antibodies as well as serum thyroid hormones and TSH levels. RESULTS: The overall frequencies of thyroid antibodies were 6/53 (11%) in primary Sjögren's syndrome, 2/30 (7%) in rheumatoid arthritis, 2/12 (17%) in secondary Sjögren's syndrome, 4/53 (8%) in healthy controls, and 16/17 (94%) in autoimmune thyroiditis. There was no difference in the frequency of the thyroid antibodies among the groups if patients with autoimmune thyroiditis were excluded (p = 0.415 for anti-TPO; p = 0.275 for anti-TG; p = 0.696 for either anti-TG and/or anti-TPO). Only two patients with primary Sjogren's syndrome had clinical hypothyroidism associated with autoimmune thyroiditis. CONCLUSIONS: In this Turkish population, no association between primary Sjögren's syndrome and autoimmune thyroiditis was found.

Adult↗

PubMed2005

Development of additional autoimmune diseases in a population of patients with primary Sjögren's syndrome.

BACKGROUND: To investigate whether patients with primary Sjögren's syndrome (pSS) have an increased tendency to develop other autoimmune diseases. METHODS: A retrospective case note review was carried out on 114 patients in whom a diagnosis of pSS had been made in a department of rheumatology from 1979 onwards. The year of diagnosis of pSS was recorded, plus the diagnosis and year of diagnosis of any other identified autoimmune disease. RESULTS: Of the 114 patients with pSS, seven (6%) were male and 107 (94%) female. Mean age at diagnosis of pSS was 53 years (range 21 to 83). Patients were followed up for an average of 10.5 years (range 0 to 23). Thirty eight patients (33.3%) were diagnosed as having another autoimmune disease, while nine (7.9%) had two or more. Thirteen additional autoimmune diseases were identified. Twenty five diagnoses (51.0%) were made before the diagnosis of pSS, three (6.1%) within the same year, and 21 (42.9%) after the diagnosis. Hypothyroidism was the most common autoimmune disease (n = 16). CONCLUSIONS: Although pSS is a relatively benign condition, affected individuals have an increased tendency to develop additional autoimmune diseases. Patients with pSS should be monitored on a regular basis for such diseases.

Adult↗

PubMed1978

Autoimmunity in juvenile diabetics and their families.

Pancreatic islet cell, thyroid, and gastric antibodies were studied in 116 young insulin-dependent diabetics and 257 relatives. Seventy-four per cent of the diabetics studied within three months of diagnosis had islet-cell antibodies but only 20% of those studied three years or more after diagnosis. Persistence of these antibodies was associated with a high prevalence of thyrogastric autoimmunity, which suggests that some cases have an aetiology similar to that of "polyendocrine" autoimmune disease. Retinopathy or nephropathy, or both, was present in 10 diabetics, who were all members of "autoimmune" families, in which one or more members had organ-specific antibodies. Nine of the 10 healthy relatives with islet-cell antibodies and all families with more than one diabetic were also in this autoimmune group. These data suggest that an autoimmune factor may contribute to juvenile diabetes and that such autoimmune diabetes has a tendency to run in families and may be more likely to cause complications.

Adolescent↗

PubMed1990

Soluble interleukin 2 receptors in autoimmune chronic active hepatitis.

Children with uncontrolled autoimmune chronic active hepatitis have increased numbers of activated T lymphocytes expressing interleukin 2 receptors (IL2R). A soluble form of IL2R has recently been described whose proposed role is to downregulate T cell activation by competing for interleukin 2. We investigated whether a deficiency of soluble IL2R could account for the high concentrations of IL2R positive T lymphocytes in autoimmune chronic active hepatitis. Soluble IL2R was measured by enzyme-linked immunosorbent assay in the serum of 16 children with autoimmune chronic active hepatitis, eight with chronic liver disease due to hepatitis B virus infection, seven with Wilson's disease, nine with alpha 1 antitrypsin deficiency, and 15 healthy age matched controls. Soluble IL2R concentration was significantly higher in patients with autoimmune chronic active hepatitis than in healthy controls (mean (SEM) 475 (75) U/ml, 145 (8) U/ml respectively, p less than 0.01). Eleven patients who had active disease had significantly higher soluble IL2R concentrations (590 (89) U/ml) than the five cases with inactive disease (220 (36) U/ml, p less than 0.01). No difference was found between the controls and the patients with chronic liver disease due to hepatitis B infection, Wilson's disease, and alpha 1 antitrypsin deficiency. Percentages and absolute numbers of surface IL2R positive T cells as detected by immunofluorescence were significantly higher in the patients with autoimmune chronic active hepatitis (11.8% (1); 274/microliters (31)) than in controls (0.2% (0.1); 5/microliters (2), p less than 0.001), the highest values being found in those with uncontrolled disease. A significantly positive correlation was observed between concentrations of soluble IL2R and the percentage of T cells expressing IL2 receptors (r=0.67, p<0.001). These results indicate that the high levels of IL2R positive T lymphocytes characteristic of autoimmune chronic active hepatitis are not due to a deficiency of soluble IL2 receptors.

Adolescent↗

PubMed1995

Heterogeneity of liver/kidney microsomal antibody type 1 in autoimmune hepatitis and hepatitis C virus related liver disease.

Liver/kidney microsomal antibody type 1 (LKM-1), the serological marker of a subset of autoimmune hepatitis, is also present in a proportion of patients with hepatitis C virus (HCV) related chronic liver disease. To characterise further this autoreactivity and to evaluate whether an autoantibody giving an identical immunofluorescence staining, and detected in two different clinical conditions, involves the same antigenic target(s), sera from autoimmune and HCV infected patients were tested with native, recombinant, and synthetic antigens. Sixty five sera were selected on the basis of the typical immunofluorescence pattern: 50 patients had serological markers of HCV infection, the remaining 15 suffered from autoimmune hepatitis. The reactivity of each serum with rat and human microsomal fractions, full length human recombinant CYP2D6, and two synthetic peptides spanning the amino acid regions 257-269 and 373-398 of CYP2D6 was systematically investigated by immunoblotting. Fourteen (93%) sera from autoimmune hepatitis patients and 39 (78%) from HCV infected patients reacted with rat and/or human microsomal polypeptides of 39 kD, 50 kD, 58 kD, and 66 kD in different associations, the 50 kD band being the most frequently observed. Reactivity to CYP2D6 and its amino acid sequence 257-269 was significantly more common in autoimmune hepatitis than in HCV infected patients (p < 0.001 and p < 0.0003, respectively). LKM-1 reactivity is directed against heterogeneous and not entirely defined autoantigens. The main target in autoimmune sera is CYP2D6 and its 257-269 amino acid region, while sera from patients with HCV infection are more likely to recognise other microsomal targets, the molecular identity of which is currently unknown.

Adolescent↗

PubMed2004

Growth factors associated with gastric mucosal hypertrophy in autoimmune gastritis.

A prominent pathological feature of murine autoimmune gastritis is a pronounced mucosal hypertrophy. Here, we examined factors that may be responsible for inducing this hypertrophy. Because gastrin is known to be both an inducer of gastric mucosal cell proliferation and is elevated in autoimmune gastritis, mice deficient in gastrin were thymectomised at day 3 and assessed for autoimmune gastritis. Gastrin-deficient mice showed all the characteristic features of murine autoimmune gastritis, including gastric unit hypertrophy due to hyperproliferation and accumulation of immature epithelial cells, decreases in the number of zymogenic and parietal cells, and autoantibodies to the gastric H+/K+-ATPase. Hence, gastrin is not required for either the establishment of chronic gastritis or development of the typical pathological features of this disease. We also examined mRNA levels of a number of gastric mucosal growth factors in RNA samples from mice with hypertrophic autoimmune gastritis. Members of the Reg family, RegIIIbeta and RegIIIgamma, were greatly elevated in mice with hypertrophic gastritis, whereas RegI and amphiregulin (an EGF receptor ligand) were more modestly and/or inconsistently induced. These data demonstrate that induction of gastric mitogenic factors, such as members of the Reg family, can be achieved in inflammatory situations by gastrin-independent pathways. Members of the Reg family, in particular RegIIIbeta and RegIIIgamma, are good candidates to be involved in inducing the mucosal hyperproliferation in autoimmune gastritis. These findings are likely to be of relevance to other gastric inflammatory conditions.

Amphiregulin↗

PubMed2001

Coeliac disease in patients with autoimmune thyroiditis.

BACKGROUND AND AIMS: The close association between coeliac disease and autoimmunity prompted us to perform an antibody screening for gluten-sensitive enteropathy in patients with autoimmune thyroid dysfunction. METHODS: Sera from 220 patients with autoimmune thyroiditis, 50 euthyroid subjects with thyroid nodules and 250 blood donors were tested for IgA anti-tissue transglutaminase (anti-tTG) and antiendomysial antibodies (EmA). RESULTS: IgA anti-tTG was positive in 7 patients with autoimmune thyroiditis, whereas IgA EmA was found only in 6 of them. Duodenal biopsy confirmed coeliac disease diagnosis disclosing marked and mild villous atrophy in 6 and 1 of them, respectively. All but 2 of the 7 coeliacs did not show any sign of malabsorption. All euthyroid controls were negative for IgA antibodies, whereas 1 blood donor, positive for both IgA anti-tTG and EmA, was found to be coeliac. The prevalence of coeliac disease in patients with autoimmune thyroiditis (3.2%) was significantly higher than that found in blood donors (0.4%) (p = 0.022, Fisher's exact test). CONCLUSIONS: Antibody screening for coeliac disease should be included in the work-up of patients with autoimmune thyroiditis. Either IgA anti-tTG or EmA may be used, even though the former seems to be slightly more sensitive than the latter.

Adolescent↗

PubMed2004

Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes.

The ability of autoreactive T cells to provoke autoimmune disease is well documented. The finding that immunization with attenuated autoreactive T cells (T cell vaccination, or TCV) can induce T cell-dependent inhibition of autoimmune responses has opened the possibility that regulatory T cells may be harnessed to inhibit autoimmune disease. Progress in the clinical application of TCV, however, has been slow, in part because the underlying mechanism has remained clouded in uncertainty. We have investigated the molecular basis of TCV-induced disease resistance in two murine models of autoimmunity: herpes simplex virus-1 (KOS strain)-induced herpes stromal keratitis and murine autoimmune diabetes in non-obese diabetic (NOD) mice. We find that the therapeutic effects of TCV depend on activation of suppressive CD8 cells that specifically recognize Qa-1-bound peptides expressed by autoreactive CD4 cells. We clarify the molecular interaction between Qa-1 and self peptides that generates biologically active ligands capable of both inducing suppressive CD8 cells and targeting them to autoreactive CD4 cells. These studies suggest that vaccination with peptide-pulsed cells bearing the human equivalent of murine Qa-1 (HLA-E) may represent a convenient and effective clinical approach to cellular therapy of autoimmune disease.

Animals↗

PubMed2002

Primary biliary cirrhosis and autoimmune cholangitis are not associated with coeliac disease in Crete.

BACKGROUND: An increased prevalence of coeliac disease in patients with primary biliary cirrhosis has been recently reported. However, in other studies the association has not been confirmed. There have been no formal attempts to systematically evaluate patients with autoimmune cholangitis for coeliac disease. METHODS: Sera from 62 patients with primary biliary cirrhosis, 17 with autoimmune cholangitis and 100 blood donors were screened for anti-gliadin, anti-endomysial, anti-reticulin, and IgA class antibodies to guinea pig liver-derived tissue transglutaminase. Eighteen untreated coeliacs served as methodological controls. Analyses were performed by using the chi2 and Fischer's exact tests. RESULTS: Anti-gliadin antibodies were detected in 21% of patients with primary biliary cirrhosis, 35% of patients with autoimmune cholangitis, and 3% of controls (p < 0.001). IgA class gliadin antibodies positivity was more pronounced in patients with Scheuer's stage III-IV disease (p < 0.05). Anti-transglutaminase antibodies were detected in 10% and in 18% of patients with primary biliary cirrhosis and autoimmune cholangitis respectively (p < 0.001). Anti-reticulin and anti-endomysial antibodies were negative in all patients. Duodenal biopsies were performed in 59% and 71% of patients with primary biliary cirrhosis and autoimmune cholangitis respectively, tested positive for at least one antibody class. No histological features of coeliac disease were found. CONCLUSIONS: We were unable to demonstrate an increased risk of coeliac disease in patients with primary biliary cirrhosis and autoimmune cholangitis. Our results confirm the previously reported high prevalence of false-positive anti-gliadin and guinea pig liver-derived anti-tissue transglutaminase antibodies in patients with chronic liver disease.

Adult↗

PubMed1998

Production of pathogenic antibodies: cognate interactions between autoimmune T and B cells.

A select population of autoimmune T-helper (T(H)) cells drive the production of pathogenic anti-DNA autoantibodies in SLE. These T(H) cells recognize nucleosomal peptides that are processed and presented by the anti-DNA B cells that they help. The critical peptide epitopes for the T(H) cells reside in the core histones of the nucleosome particle. Remarkably, the nucleosomal peptide epitopes do not obey the rule of MHC-restriction; they can be promiscuously presented and recognized in the context of diverse MHC alleles. Such promiscuous antigens, called pantigens, are also recognized by autoimmune T cells, in a degenerate fashion, and this promiscuous recognition is conferred by the lupus TCR alpha chains. High-affinity interactions between the lupus TCRs and MHC-nucleosomal peptide complex due to reciprocally charged residues probably overcome the requirement for MHC restriction. These studies open up the possibility of developing 'universally' tolerogenic epitopes for therapy of lupus in humans despite their diversity of HLA alleles. The results also have profound implications regarding the selection of autoimmune T cells in the lupus-prone thymus and their expansion in the periphery. Furthermore, the T(H) cells, as well as B cells of lupus, have a regulatory defect causing markedly increased and prolonged expression of CD40 ligand (CD40L), which mediates abnormal co-stimulatory signals to autoimmune B cells, sustaining the production of pathogenic autoantibodies. These observations suggest a new paradigm for B cell hyperactivity in lupus and provide alternative targets for immunotherapy. Indeed, giving only three injections of anti-CD40L antibody in a one-week period to mice with manifest lupus selectively blocks the pathogenic autoimmune response and delays the development of lupus nephritis by one year (equivalent to three decades in humans). Thus, possession of promiscuous, high-affinity receptors and prolonged expression of CD40L by lupus T cells probably lowers activation threshold, leading to an autoimmune response against nucleosomes derived from apoptotic cells that are normally ignored by the immune system.

Animals↗

PubMed2005

Functional genomics in early autoimmunity.

The molecular mechanisms initiating the autoimmune process in type 1 diabetes mellitus (T1DM) remain unknown, and studies aiming to address this question have been compromised by the difficulty of predicting the disease at an early age both in humans and in animal models. An additional hindrance in selecting individuals at an early age has been the complex genetic inheritance of autoimmune diabetes, implicating not only several genes but also environmental factors. We have previously demonstrated the predictive value of insulin autoantibodies (IAAs) at an early age, between three to five weeks in the NOD mouse. Animals positive for early appearance of IAAs (E-IAAs) develop autoimmune diabetes earlier. We showed a correlation between the presence of IAAs in the mothers during pregnancy, E-IAAs in the litters, and the early appearance of T1DM. NOD mice, E-IAA-positive, within litters from IAA-positive mothers during pregnancy, develop diabetes earlier and at a much greater rate than animals that are IAA-negative and from IAA-negative mothers. The molecular mechanisms responsible for this early autoimmune subphenotype were addressed by a global approach to differential gene expression analysis in the pancreatic lymph nodes (PaLNs). Although the data analysis is currently in progress, gene expression signatures were observed that are characteristic for PaLNs with regard to the presence or absence of IAAs. Overall, these data are consistent with the hypothesis of an early environmental influence from the autoimmune maternal environment on the genetic predisposition of the offspring, characterized by specific gene signatures leading to autoimmune disease.

Animals↗

PubMed2005

Human and nonhuman primate lentiviral infection and autoimmunity.

The goal of this communication is to summarize the following-the types of autoimmune responses that have been characterized in human HIV-1 infection; the potential mechanisms that were initially thought to be the basis for such autoimmune responses; the prevalence and incidence of conventional autoimmune diseases with HIV-1 infection; the spectrum of autoimmune disorders following the institution of HAART and its associated mechanisms; the role of such autoimmunity in SIV-infected nonhuman primates; and the molecular basis for autoimmune responses, such as the role of exosomes in lentiviral disease.

Animals↗

PubMed2004

Differential expression of nonislet autoimmunity: comparison of Korean and U.S. patients with type 1 diabetes.

Type 1 diabetes (T1D) is frequently associated with other autoimmune diseases. The occurrence of common features of autoimmune diseases and the coassociation of multiple autoimmune diseases in the same individual or family support the notion that there may be common genetic factors. We previously reported that immunogenetic markers of T1D were similar in Korean and U.S. families. We hypothesized that nonislet autoimmunity might be expressed in a similar manner in Korean as well as in Caucasian patients and correlated with the DRB1-DQB1 haplotypes. Twenty-five percent of Korean patients with T1D (32/128) had antithyroid autoantibodies (ATA+), whereas eight percent of age-matched controls were ATA+ [OR = 3.7 (95% CI:1.0-12.0), P < 0.05]. Twenty-three percent (84/369) of age-matched T1D patients from the U.S. had ATA (not statistically different from that in Koreans). None of the Korean patients nor the family members were positive for 21-hydroxylase (21OH) or transglutaminase autoantibodies (TG). In contrast, in U.S. patients, nine T1D patients (2.4%) were 21OH+ (not statistically different from that in Koreans) and 39 T1D patients (10.6%) were TG+ [OR = 30.7 (95% CI: 4.6-111), P < 10(-4) vs. Korean patients]. Nonislet autoimmunity is prevalent in Korean and U.S. patients with T1D and their family members, but specific forms of autoimmunity differ even after matching for their HLA haplotypes. Individuals with T1D and their relatives frequently develop a panel of autoantibodies, perhaps due to other common susceptibility genes that are shared among first-degree relatives.

Adolescent↗

PubMed2001

Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care.

Postpartum thyroiditis is a syndrome of transient or permanent thyroid dysfunction occurring in the first year after delivery and based on an autoimmune inflammation of the thyroid. The prevalence ranges from 5-7%. We discuss the role of antibodies (especially thyroid peroxidase antibodies), complement, activated T cells, and apoptosis in the outbreak of postpartum thyroiditis. Postpartum thyroiditis is conceptualized as an acute phase of autoimmune thyroid destruction in the context of an existing and ongoing process of thyroid autosensitization. From pregnancy an enhanced state of immune tolerance ensues. A rebound reaction to this pregnancy-associated immune suppression after delivery explains the aggravation of autoimmune syndromes in the puerperal period, e.g., the occurrence of clinically overt postpartum thyroiditis. Low thyroid reserve due to autoimmune thyroiditis is increasingly recognized as a serious health problem. 1) Thyroid autoimmunity increases the probability of spontaneous fetal loss. 2) Thyroid failure due to autoimmune thyroiditis-often mild and subclinical-can lead to permanent and significant impairment in neuropsychological performance of the offspring. 3) Evidence is emerging that as women age subclinical hypothyroidism-as a sequel of postpartum thyroiditis-predisposes them to cardiovascular disease. Hence, postpartum thyroiditis is no longer considered a mild and transient disorder. Screening is considered.

Adult↗

PubMed2004

Adrenal sensitivity to adrenocorticotropin 1-24 is reduced in patients with autoimmune polyglandular syndrome.

Autoimmune polyglandular syndromes are fairly common diseases that are classified into four constellations based on the clinical clustering of the various component diseases. In types 1, 2, and 4, primary adrenal insufficiency due to an autoimmune process is usually present, but its diagnosis is often delayed because it is difficult to detect in a subclinical phase. It is widely accepted that the classical dose of 250 microg ACTH(1-24) is supramaximal, whereas 0.06 microg has been shown to be one of the lowest ACTH doses that is able to stimulate adrenal secretion in normal young subjects. The aim of this study was to clarify the sensitivity and maximal secretory response of the adrenal gland to ACTH in a group of patients with at least two autoimmune diseases, without clinical signs and symptoms of overt or subclinical hypocortisolism. Cortisol (F), aldosterone (A), and dehydroepiandrosterone (DHEA) responses to the sequential administration of very low and supramaximal ACTH(1-24) doses [0.06 microg followed by 250 microg ACTH(1-24) i.v. at 0 and +60 min] were studied in 18 patients with at least two autoimmune diseases (AP; age, 20-40 yr; body mass index, 22-26 kg/m(2)). The results in the patients were compared with the results recorded in 12 normal age-matched control subjects (CS; age, 22-34 yr; body mass index, 20-25 kg/m(2)). At baseline, ACTH levels in AP were within the normal range but higher (P < 0.05) than in CS, whereas F, A, DHEA, urinary-free F, and plasma renin activity were similar in both groups. F, A, and DHEA responses to ACTH were dose dependent in both groups. However, in AP, F, A, and DHEA levels showed no response to the 0.06- micro g ACTH dose, which, in turn, elicited clear responses (P < 0.01) in CS. On the other hand, F, A, and DHEA responses to 250 microg ACTH in AP were not different from those in CS. In conclusion, patients with autoimmune diseases who displayed a normal basal adrenal function showed a loss of F, A, and DHEA response to the very low ACTH dose, although they were normal responders to the high ACTH dose. These data are likely to indicate that a reduced sensitivity to ACTH in all adrenal zones occurs in patients with different types of autoimmune disease.

Adrenal Cortex Function Tests↗

PubMed2006

Clinical review: Type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow.

CONTEXT: The aim of this review was to explore the pathogenic and clinical spectrum of type 1 diabetes, which includes a form of adult onset autoimmune diabetes usually referred to as latent autoimmune diabetes in adults (LADA). We looked at this entire range of forms of autoimmune diabetes as a spectrum of genetic and nongenetic environmental influences, diabetes-associated immune responses, and metabolic changes. EVIDENCE ACQUISITION: We assessed epidemiological, genetic, immunological, and clinical data from major articles on autoimmune diabetes, including LADA and type 1 diabetes, published since 1992. EVIDENCE SYNTHESIS: Data analysis of autoimmune diabetes indi-cates that type 1 diabetes and LADA occupy different poles of the same spectrum. CONCLUSION: Evidence is presented that LADA represents one end of a rainbow encompassing type 1 diabetes. The clinical nature and management of autoimmune diabetes poses important therapeutic questions regarding conventional therapy for hyperglycemia as well as therapy aiming to protect residual beta-cell function. Limiting loss of endogenous insulin secretion using immunomodulation could be valuable, not only for LADA but also for type 1 diabetes.

Autoimmune Diseases↗

PubMed2007

Analysis of the Fc receptor-like-3 (FCRL3) locus in Caucasians with autoimmune disorders suggests a complex pattern of disease association.

CONTEXT: A four-marker haplotype in the 5' region of the Fc receptor-like 3 gene (markers FCRL3_3 to FCRL3_6) has been identified recently as contributing to rheumatoid arthritis (RA) susceptibility in the Japanese population. The promoter FCRL3_3*C allele also showed significant association with autoimmune thyroid disease and systemic lupus erythematosus. These findings raise the possibility that this locus may influence autoimmune disease susceptibility across many populations. PATIENTS AND DESIGN: We analyzed the same four 5' FCRL3 single nucleotide polymorphism markers, together with three additional exonic single nucleotide polymorphisms in the FCRL3 gene, in cohorts of white Caucasians with Graves' disease (n = 625), type 1 diabetes (n = 279), autoimmune Addison's disease (AAD; n = 200), and RA (n = 769). Healthy controls from the United Kingdom (n = 490) and New Zealand (n = 593) were used. RESULTS: Six of the seven FCRL3 markers showed association with AAD (P = 0.005-0.0001), with maximum evidence at the FCRL3_3*T allele [P([corrected]) = 0.0008; odds ratio (OR), 1.61; 5-95% confidence intervals (CIs), 1.26-2.05]. The most common seven-marker FCRL3 haplotype (TGGGAAA) was also found to be significantly associated with AAD (P([corrected]) = 1.1 x 10(-4); OR, 1.71; 5-95% CIs, 1.33-2.18). There was nominal evidence for allelic association at the marker FCRL3_8 in Graves' disease (OR, 1.50; 5-95% CIs, 1.06-2.13) and at FCRL3_9 with RA (OR, 1.25; 5-95% CIs, 1.01-1.54). CONCLUSIONS: The FCRL3 haplotype that is associated with AAD in Caucasians appears to be protective for autoimmune diseases in the Japanese population, demonstrating that this haplotype is unlikely to contain a single primary etiological allele for autoimmunity. Our observations suggest that the susceptibility to autoimmunity at the FCRL3 locus is more complex than initially thought and may extend either side of the currently associated region to include the adjacent FCRL2 gene.

Adult↗

PubMed1996

Identification of 3 beta-hydroxysteroid dehydrogenase as a novel target of steroid cell autoantibodies: association of autoantibodies with endocrine autoimmune disease.

Autoantibodies directed against steroid hormone-producing cells (SCA) detectable by immunofluorescence are typically found in a small proportion of patients with premature ovarian failure (POF) as well as in other endocrine autoimmune diseases. The SCA pattern stains cells in the outer zones of the adrenal cortex, ovary, and testis. To identify the molecular target of SCA, an adrenal complementary DNA expression library was screened using SCA-positive serum, and the steroid enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) was identified. Only 1 of 48 (2%) patients with idiopathic POF, not pre-selected for the presence of other autoimmune diseases, had SCA by immunofluorescence, whereas 10 of 48 (21%) had anti-3 beta HSD autoantibodies detectable by immunoblot using recombinant human enzyme compared with 6 of 115 (5%) control subjects (P = 0.002). Absorption of SCA-positive serum with recombinant human 3 beta HSD abolished the immunofluorescence pattern. We also examined the prevalence of anti-3 beta HSD autoantibodies in other endocrine autoimmune diseases. Two of 112 (2%) diabetic patients, but none of the thyroid or Addisonian patients, had SCA by immunofluorescence. Twenty-six (23%) diabetic subjects (P < 0.001 vs. controls), 3 of 18 thyroid patients (P > 0.05 vs. controls), and none of 4 Addisonian patients had anti-3 beta HSD autoantibodies. 3 beta HSD is the first steroid cell autoantigen defined at the molecular level to be associated with idiopathic POF occurring in the absence of other polyglandular diseases. Autoantibodies to 3 beta HSD in patients with other organ-specific autoimmune diseases indicate that the enzyme behaves as a typical target of polyendocrine autoimmunity. Anti-3 beta HSD autoantibodies in patients with POF may provide a marker of those subjects whose ovarian failure is autoimmune in origin and, as recent studies suggest, may be salvageable with glucocorticoid treatment.

3-Hydroxysteroid Dehydrogenases↗