Autoimmune Endocrine Diseases Research Articles

Primary Sjögren's syndrome: the challenge for classification of disease manifestations

A new model for classifying the clinical disease manifestations of primary Sjögren's syndrome is introduced. Three "exocrine' and four "nonexocrine' subgroups of disease manifestations are defined. Accordingly, "surface exocrine disease' includes the diagnostic features from eyes, mouth, and the manifestations from the upper airways, skin and genital tract. Involvement of the excretory parenchyma of the lungs, hepatobiliary system, pancreas, gastrointestinal tract and kidneys is designated "internal organ exocrine disease'. We suggest "monoclonal B lymphocyte disease' to be an exocrine disease manifestation because it originates mostly from the immunoinflammatory foci of the autoimmune exocrinopathy. The nonexocrine manifestations are subgrouped into "inflammatory vascular disease'. "noninflammatory vascular disease', "mediator-induced disease' and "autoimmune endocrine disease'.

High frequency of endocrine autoimmunity in patients with sarcoidosis

Autoimmune diseases and sarcoidosis may be related and, especially, the association between sarcoidosis and autoimmune thyroid disease has long been recognized. The frequency and type of endocrine autoimmunity was examined in a series of Swedish patients with sarcoidosis. Of all patients (N = 89) with documented sarcoidosis attending the Department of Pulmonary Medicine between January 1980 and December 1991, 78 patients (44 males and 34 females; median age at the time of the study 48 years. range 22-81 years) were examined at the Department of Endocrinology, Malmö University Hospital, in the present study. Fifteen patients (19.2%) had clinical or serological evidence of endocrine autoimmunity. Two patients had Addison's disease, both with polyglandular autoimmune (PGA) syndrome type II: evidence of thyroid autoimmunity was found in 13 patients, eight with clinical autoimmune thyroid disease (ATD) (two with Graves' disease and six with autoimmune thyroiditis), of whom two had PGA syndrome type III, and five with isolated positive thyroid serology; two patients had insulin-dependent diabetes mellitus and one had premature ovarian failure. The frequencies of Addison's disease, clinical ATD and PGA syndrome type II were significantly higher compared with the frequencies found in the general population. In conclusion, a high frequency of endocrine autoimmunity in patients with sarcoidosis, occurring in about 20% of the cases, was demonstrated. Thyroid autoimmunity and polyglandular autoimmune syndromes occurred most frequently. Complex immunological and genetic mechanisms might explain the association of sarcoidosis and endocrine autoimmune diseases.

Cytokines and the endocrine system. II. Roles in substrate metabolism, modulation of thyroidal and pancreatic endocrine cell functions and autoimmune endocrine diseases

Cytokines and the endocrine system. II. Roles in substrate metabolism, modulation of thyroidal and pancreatic endocrine cell functions and autoimmune endocrine diseases

Secretion of anterior pituitary hormones in patients with insulin-dependent diabetes mellitus and polyglandular autoimmune syndrome.

We extracted gammaglobulins from the serum of 10 patients with insulin-dependent diabetes mellitus (IDDM) to investigate their effect on anterior pituitary hormone secretion using cultures of rat anterior pituitary cells. Three of the 10 patients also had the polyglandular autoimmune syndrome (PGA) type III with an isolated failure of anterior pituitary hormone secretion. The gammaglobulin from each of the 3 patients with PGA and an isolated failure of secretion of adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH) or gonadotropin inhibited the secretion of ACTH, TSH or gonadotropin in cultures of rat anterior pituitary cells. The gammaglobulins obtained from the other 7 patients with IDDM also showed an inhibitory or stimulatory effect on anterior pituitary hormone secretion in vitro. We postulate that some patients with IDDM, especially those with other endocrine autoimmune diseases, may have substances in their gammaglobulin fraction that can affect the secretion of anterior pituitary hormones.

Classification of disease manifestations in primary Sjögren's syndrome: present status and a new proposal.

Establishing a model for classification of the clinical disease manifestations in primary Sjögren's syndrome is a challenge with important implications for handling individual patients and for describing and analyzing patient materials. Based on the pathobiology of primary SS we define three (1-3) "exocrine" and four (4-7) "nonexocrine" subgroups of disease manifestations. Accordingly, 1) "surface exocrine disease" includes the diagnostic features from eyes (keratoconjunctivitis sicca) and mouth (xerostomia), and the manifestations from upper airways (rhinitis sicca, xerotracheitis) and skin (xeroderma). Involvement of the excretory parenchyma of the lungs, hepatobiliary system, pancreas, intestinal tract and kidneys is designated 2) "internal organ exocrine disease". These manifestations are potentially severe, do not lead to subjective dryness, and none of them are diagnostic for the disease. We suggest 3) "monoclonal B-lymphocyte disease" (lymphoma) to be an exocrine disease manifestation because it originates mostly from the immunoinflammatory foci of the autoimmune exocrinopathy. The nonexocrine manifestations are subgrouped into: 4) "inflammatory vascular disease" (vasculitis and perivasculitis), 5) "noninflammatory vascular disease" (Raynaud), 6) "mediator-induced disease" (hematologic cytopenia, fever and fatigue) and 7) "autoimmune endocrine disease". Subdividing the seven subgroups leads to a third order of classification in which single and separate manifestations are placed. The descriptive and analytic power of the proposed model for classification of disease manifestations in primary Sjögren's syndrome should be evaluated in clinical studies.

Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease.

Because particular human leukocyte antigen (HLA) DQ alleles are the major predisposing factors for type 1 diabetes mellitus (IDDM), we investigated whether they are shared by other endocrine autoimmune diseases. We, therefore, analyzed the HLA DQ genotypes of 171 patients with IDDM, 271 with Graves' disease (GD), 65 with Hashimoto's thyroiditis, 51 with postpartum thyroiditis, 53 with Addison's disease (AD), and 271 healthy controls. HLA DQA1 and DQB1 alleles were defined by polymerase chain reaction and sequence-specific oligonucleotide hybridization as well as by single strand conformational polymorphism analysis. HLA DQA1*0501 was significantly more frequent in IDDM (60%), GD (65%), and AD (70%) than in controls (43%); DQA1*0301 was significantly more frequent only in IDDM (67% vs. 30% controls). The heterozygous state DQA1*0301/*0501 was found in 9% of controls and 35% of IDDM (relative risk, 5.6). An arginine at position 52 on either DQA1 allele was significantly more frequent in patients with IDDM (94%), GD (80%), and AD (89%) compared with controls (66%). HLA DQB1*0201 and DQB1*0302 were more frequent in IDDM patients (*0201, 62% vs. 36% in controls, *0302, 59% vs. 19% controls), whereas DQB1*0602 was less frequent in IDDM (4%) and GD (18% vs. 31% of controls). In conclusion, endocrine autoimmunity has a common immunogenetic background; susceptibility is conferred by DQA1*0501 as well as an arginine at position 52 of DQA1 alleles, and protection against IDDM and GD is conferred by DQB1*0602.

Tolerance induction as a therapeutic strategy for the control of autoimmune endocrine disease in mouse models.

This chapter aims to describe ways in which autoimmunity can be prevented or reversed and 'self-tolerance' re-established. To this end we have largely restricted our overview to the two main autoimmune disease models with which we are involved, i.e. IDDM in NOD mice and EAT in H-2k mice although, where appropriate and to demonstrate a particular point, other models are mentioned. The chapter has been divided into sections covering protection afforded by 1) transgenes, 2) autoantigen and 3) by reagents targetting T-cell surface molecules. Where established, the mechanism by which protection or tolerance is achieved is described but where, as in most cases, it is unknown the possibilities are discussed. Investigations using T-cell lines and clones and on islet regeneration which are currently being followed as part of a comprehensive approach to the study of autoimmunity are included as separate sections and their relevance discussed.

Autoimmune endocrine disease induced by recombinant interferon-alpha therapy for chronic active type C hepatitis.

To elucidate the role played by interferon-alpha (IFN alpha) in the pathogenesis of autoimmune endocrine disease, we determined the autoantibody status, thyroid function test results, hemoglobin-A1c levels, and clinical symptoms of 58 patients who received IFN alpha for treatment of chronic active type C hepatitis. Each patient was treated for 6 months with a total dose of 391 +/- 140 x 10(6) U (mean +/- SD). Thyroid microsomal and/or thyroglobulin antibodies newly appeared or were increased in titer in 6 patients, 2 of whom developed hypothyroidism during IFN alpha therapy. Neither islet cell antibodies nor insulin-dependent diabetes mellitus developed during IFN alpha therapy, although hemoglobin-A1c levels were increased in 2 patients. One patient became positive for antimitochondrial antibodies, and another patient with preexisting antimitochondrial antibodies also manifested deterioration in liver function test results. Parietal cell antibodies and smooth muscle cell antibodies were the most frequent newly developed antibodies in 7 patients. Adrenal medullary cell antibodies and nuclear antibodies newly developed in 2 and 1 patients, respectively. At least 1 of 8 autoantibodies newly appeared in 19 patients (32.8%) and hypothyroidism developed in 2 patients (3.4%) during IFN alpha therapy. On the other hand, in 19 age- and sex-matched patients who did not receive IFN alpha, no autoantibody appeared, and no autoimmune disease developed during a follow-up period of 3 months. These findings suggest that IFN alpha acts as an immunomodulatory agent, inducing autoantibody production and the development of autoimmune disease in susceptible patients. Special attention should be paid to the development of hypothyroidism during IFN alpha therapy.

Autoimmune endocrine disease induced by recombinant interferon-alpha therapy for chronic active type C hepatitis

Autoimmune endocrine disease induced by recombinant interferon-alpha therapy for chronic active type C hepatitis

Animal models of autoimmune endocrine disease and their uses in developing new methods of intervention

This review provides basic information concerning the major animal models in use for the study of autoimmune endocrine diseases (AEDs). Although several other models exist which parallel human AEDs such as autoimmune orchitis, most research in this area has centred on animal models of insulin-dependent diabetes mellitus (IDDM) and thyroiditis. These models, between them, appear to exhibit most of the disease manifestations of their human counterparts and thereby permit the study of possible methods of intervention in the disease process. While no one model represents a perfect correlation with the human disease it represents, common characteristics are recognizable between them. For instance, the central role of activated T cells in controlling the disease process. The chapter continues by examining the various ways in which models of autoimmunity, specifically IDDM and experimental allergic thyroiditis (EAT), have been used to investigate the possibility of preventing or arresting autoimmune destruction. Several different approaches are described that illustrate the variety of techniques that have proven both potentially, or in reality, effective and those that have proven less efficacious than first hoped.

Evidence for a retroviral trigger in Graves' disease.

An apparently high frequency of Graves' disease encountered in New Orleans, Louisiana, prompted an investigation for a possible infectious agent that might be triggering the disease in genetically susceptible individuals. We studied 40 patients with Graves' disease, and compared them to the following groups of controls: age and gender matched healthy subjects; patients with multinodular goiter (non-autoimmune thyroid controls); patients with chronic lymphocytic thyroiditis (autoimmune thyroid disease controls) and additional organ or tissue specific autoimmune controls exclusive of thyroid autoimmunity, including patients with Type I diabetes and other endocrine autoimmune complex disorders. Serum antibodies against a prototypic strain of a human intracisternal A-type retroviral particle type 1 (HIAP-1) were detected by a sensitive and specific immunoblotting assay. In 87.5% (35/40) of the Graves' disease patients there was a positive reaction against several HIAP-1-associated proteins, predominantly 97 Kd and 80 Kd, with only 5 showing no reactivity to any. In contrast, 2% (2/105) of sera from normal controls showed positive reactivity. Furthermore, only 10% (1/10) of sera from multinodular goiter control patients and 10% (1/10) of Hashimoto's patients showed reactivity (p < 0.0005). Sera from 3 of 20 (15%) of Type I diabetic patients none of whom had Graves' disease, showed reactivity but there was no reactivity in 9 other patients with one or more of the endocrine autoimmune complex disorders, including Addison's disease, vitiligo, myasthenia gravis and pernicious anemia. In addition we studied two individuals with Graves' disease from each of two families residing outside Louisiana, all of whom were positive for these antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Pregnancy and autoimmune endocrine disease

Pregnancy and autoimmune endocrine disease

Infections and autoimmune endocrine disease

The literature examined in this review points to the possible involvement of infectious agents in the pathogenesis of autoimmune endocrine diseases, primarily autoimmune thyroid disease and diabetes mellitus. Various mechanisms have been proposed to explain induction of autoimmunity by infection but it seems that three possibilities may be important in individuals susceptible to developing autoimmune disease: molecular mimicry (perhaps to retroviruses); polyclonal T cell activation (by an endogenous superantigen or an infecting organism); and MHC class II antigen induction. It seems reasonable that all three mechanisms operate together or separately in different individuals. Data continue to accumulate in favour of infectious agents being important initiators of autoimmune disease.

Western blot analysis of rat pituitary antigens recognized by human antipituitary antibodies.

Antipituitary antibodies have been reported to exist in sera of patients with autoimmune endocrine disorders. In order to investigate the pituitary antigens recognized by antipituitary antibodies, we studied the autoantigens in rat pituitary membrane and cytosolic fractions recognized by human antipituitary antibodies and anti-human pituitary hormone antibodies. Sera from 6 patients which showed positive antipituitary antibodies by immunofluorescence methods were studied. Each serum identified some proteins with 14.5, 22, 47, 49, 65, 84 and 97.5 kDa. Anti-GH antibodies and anti-PRL antibodies identified a positive band with 22 kDa, suggesting that anti-GH and anti-PRL antibodies may be present in patients' sera. These results indicate that Western blot analysis of rat pituitary antigens recognized by human antipituitary antibodies is a useful method to elucidate the pathophysiology of autoimmune endocrine disorders.

Autoimmunity to steroid-producing cells and familial polyendocrine autoimmunity

New insights into the autoimmune basis for Addison's disease have come from identification of at least three P450 cytochrome enzymes as autoantigens, each having distinct associations with Addison's disease as part of the APS type 1 or 2 syndrome. Enzymes are tissue-restricted proteins which are the frequent targets of autoimmunity in other organ-specific diseases (Editorial, 1992), and it seems likely that further P450 enzymes could be involved in the pathogenesis of other components of these syndromes. How adrenal damage is initiated remains unclear. Adrenal autoantibodies may have a pathogenic role, as yet obscure, or could arise secondary to T cell-mediated tissue damage, although it seems highly likely that the same autoantigen provokes cell-mediated and humoral autoimmunity. Sharing of autoantigens between ovary and adrenal glands, particularly the side-chain cleavage enzyme, is one explanation for the close association of ovarian failure and Addison's disease, but other, more common forms of ovarian autoimmune disease exist. Their further definition will come from identification of the autoantigens involved. By analogy with animal models, T cell-mediated injury is likely to be central to pathogenesis. The evidence for antibodies blocking hormone receptors in premature ovarian failure is meagre at present, but the availability of recombinant LH and FSH receptors should clarify this issue. HLA-DR3 is associated with almost all autoimmune endocrinopathies, and this is particularly striking in APS type 2. However, there is no such association with APS type 1; the most likely genetic candidate in this condition is at a locus controlling T cell development. Although the adrenal and ovarian autoimmune processes in APS type 1 and 2 may be distinct, the characterization of the gene involved in APS type 1 will have major implications for our understanding of autoimmune endocrine disease.

Autoimmune endocrinopathies: aspects of pathogenesis and the role of immune assays in investigation and management

It has been hypothesized over many years that the autoimmune endocrine diseases are each due to antigen-specific defects in suppressor (regulatory) T lymphocyte function. There is now increasing evidence in studies of autoimmune thyroid disease and insulin-dependent diabetes mellitus that suppressor cells are activated by irrelevant antigens but respond inadequately to specific relevant antigens. These inadequate responses are insufficient in themselves to precipitate the autoimmune disease; further insults from the environment increase the deficiencies in regulatory cell activity, adding to the genetically induced dysfunction, i.e., specific defects in antigen presentation. Diagnostic procedures for autoimmune endocrine diseases include tests of target cell function and the detection of various antibodies, which are becoming increasingly useful in prediction, diagnosis, and management of these diseases.

The role of tyrosinase in autoimmune vitiligo

Vitiligo is a common depigmenting skin disease, associated with certain autoimmune endocrinopathies, and autoantibodies to several antigens can be found in melanoma cells. We set out to identify the antigens. We examined 26 patients with vitiligo and associated endocrine disease. Of these, 18 patients (77%) and 8 immediate family members had autoantibodies specific for a 69 kDa protein in HTB-70 human melanoma cells that was not seen in control cells. The autoantibody-positive patient sera reacted with recombinant human tyrosinase expressed in Escherichia coli seen by western blots, as did antibodies raised in rabbits against hamster tyrosinase, but not to recombinant tyrosinase-related protein. Not one of 31 normal controls or 8 patients with alopecia or systemic lupus erythematosus had tyrosinase autoantibodies but a small proportion (12%) of 42 patients with autoimmune endocrine disease without a history of vitiligo had them. The results show that tyrosinase, an enzyme important in melanin formation, is a principal autoantigen of autoimmune vitiligo.

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease.

We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4-12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2-5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22-95). A "whole" or "mixed" pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell "selective" ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the "mixed" pattern in only three. None of this group had detectable 37 k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

The natural history of pre-Type 1 (insulin-dependent) diabetes mellitus in patients with autoimmune endocrine diseases

An 11-year prospective study was carried out in 180 non-diabetic patients with organ-specific autoimmune diseases to evaluate islet cell antibodies in predicting Type 1 (insulin-dependent) diabetes mellitus. Islet cell antibodies were characterised according to titres, persistence, complement-fixing ability, and pattern. During follow-up, 14 of 46 patients with islet cell antibodies persistently greater than 5 Juvenile Diabetes Foundation Units (JDF-U) (30.4%), none of 23 with islet cell antibodies between 2.5 and 5 JDF-U or fluctuating, and 3 of 109 without islet cell antibodies (2.7%), developed diabetes. The cumulative risk of developing diabetes was 70%, 0%, and 4%, respectively. All the patients who developed diabetes were females. Eight progressed to insulin-dependence acutely, four showed a transient period of non-insulin-dependence, while two were still insulin-free. No difference was found in titres of islet cell antibodies for the risk of diabetes. Complement-fixing islet cell antibodies enhanced the cumulative risk for the disease in patients with conventional islet cell antibodies at low-middle (> or = 2.5-40 JDF-U), but not at high (> or = 80 JDF-U) titres. Forty-two patients with islet cell antibodies were investigated for the whole or the selective pattern. In the presence of the whole pattern the cumulative risk for diabetes rose to 100%, while with the selective pattern it declined to 34%. The whole pattern was found in 83% of patients who developed Type 1 diabetes acutely. In patients with organ-specific autoimmune diseases, the whole islet cell antibody pattern greatly enhances the prediction for diabetes.

The natural history of pre-Type 1 (insulin-dependent) diabetes mellitus in patients with autoimmune endocrine diseases

The natural history of pre-Type 1 (insulin-dependent) diabetes mellitus in patients with autoimmune endocrine diseases