Polyglandular autoimmune syndrome, type 2

We have described two patients with Addison's disease and associated endocrinopathies, a condition termed polyglandular autoimmune (PGA) syndrome, type 2. One of our patients also had autoimmune hypothyroid disease, and the other had premature gonadal failure and Hashimoto's thyroiditis. This syndrome shows that glandular disorders tend to occur together. It has been suggested that an HLA-associated genetic predisposition coupled with environmental factors triggers an autoimmune process resulting in glandular hypofunction or hyperfunction. We stress the necessity for evaluation of every individual with idiopathic Addison's disease for associated endocrinopathies.     

Autoimmune polyglandular syndrome, type II

The combination of autoimmune adrenal insufficiency with autoimmune thyroid disease and/or type 1 autoimmune diabetes mellitus defines autoimmune polyglandular syndrome, type II. The conditions may occur in any order, and diagnosis is confounded by the nonspecific nature of the symptoms of adrenal insufficiency and hypothyroidism. The disorder is not common, but consequences can be life threatening when the diagnosis is overlooked. The conditions usually present in midlife, and women are affected more often than men. The cosyntropin test is recommended for diagnosing adrenal insufficiency, which must be present to diagnose this syndrome. Hormone therapy for each condition is similar to treatment that would be provided if the conditions occurred separately, except that treatment for adrenal insufficiency must be given before thyroid therapy is started when the conditions occur together.     

Autoimmune polyglandular syndromes

Autoimmune polyglandular syndromes are classified into three types. Type I occurs in childhood and is characterized by at least two of the following: chronic mucocutaneous candidosis, adrenal failure and hypoparathyroidism. There is also an association with chronic active hepatitis. Type II usually develops in adulthood and is characterized by adrenal failure plus hypothyroidism or diabetes mellitus, or both. Type III consists of thyroid disease and one other organ-specific autoimmune disorder. This classification has potential usefulness in patient management and family screening for autoimmune endocrine diseases.     

Novel presentation of autoimmune polyglandular syndrome II in a child with simultaneous Addison's disease,type 1 diabetes,and Hashimoto's thyroiditis: A case report

Providers should remain vigilant of autoimmune polyglandular syndrome type II in the context of persistent low blood sugar in type I diabetes. Correction of adrenal insufficiency is key for regulation of blood sugar and thyroid function.     

Celiac disease and autoimmune thyroid disease

Celiac disease (CD) or gluten sensitive enteropathy is relatively common in western populations with prevalence around 1%. With the recent availability of sensitive and specific serological testing, many patients who are either asymptomatic or have subtle symptoms can be shown to have CD. Patients with CD have modest increases in risks of malignancy and mortality compared to controls. The mortality among CD patients who comply poorly with a gluten-free diet is greater than in compliant patients. The pattern of presentation of CD has altered over the past three decades. Many cases are now detected in adulthood during investigation of problems as diverse as anemia, osteoporosis, autoimmune disorders, unexplained neurological syndromes, infertility and chronic hypertransaminasemia of uncertain cause. Among autoimmune disorders, increased prevalence of CD has been found in patients with autoimmune thyroid disease, type 1 diabetes mellitus, autoimmune liver diseases and inflammatory bowel disease. Prevalence of CD was noted to be 1% to 19% in patients with type 1 diabetes mellitus, 2% to 5% in autoimmune thyroid disorders and 3% to 7% in primary biliary cirrhosis in prospective studies. Conversely, there is also an increased prevalence of immune based disorders among patients with CD. The pathogenesis of co-existent autoimmune thyroid disease and CD is not known, but these conditions share similar HLA haplotypes and are associated with the gene encoding cytotoxic T-lymphocyte-associated antigen-4. Screening high risk patients for CD, such as those with autoimmune diseases, is a reasonable strategy given the increased prevalence. Treatment of CD with a gluten-free diet should reduce the recognized complications of this disease and provide benefits in both general health and perhaps life expectancy. It also improves glycemic control in patients with type 1 diabetes mellitus and enhances the absorption of medications for associated hypothyroidism and osteoporosis. It probably does not change the natural history of associated autoimmune disorders.     

Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci

Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor-ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.     

Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention

Type 1 diabetes is caused by the immune-mediated destruction of islet insulin-secreting beta-cells. This chronic destructive process is associated with both cellular and humoral immune changes in the peripheral blood that can be detected months or even years before the onset of clinical diabetes. Throughout this prediabetic period, metabolic changes, including altered glucose tolerance and reduced insulin secretion, deteriorate at variable rates and eventually result in clinical diabetes. A fraction of individuals with humoral immunological changes have clinical diabetes that initially is not insulin-requiring. The onset of diabetes in these patients is usually in adult life, and because their diabetes is at least initially not insulin-requiring, they appear clinically to be affected by type 2 diabetes. Such patients probably have the same disease process as patients with type 1 diabetes in that they have similar HLA genetic susceptibility as well as autoantibodies to islet antigens, low insulin secretion, and a higher rate of progression to insulin dependency. These patients are defined as being affected by an autoimmune type of diabetes not requiring insulin at diagnosis, which is also named latent autoimmune diabetes of the adult (LADA). Special attention should be paid to diagnose such patients because therapy may influence the speed of progression toward insulin dependency, and in this respect, efforts should be made to protect residual C-peptide secretion. LADA can serve as a model for designing new strategies for prevention of type 1 diabetes but also as a target group for prevention in its own right.     

POLYSEROSITIS AS A RARE COMPONENT OF POLYGLANDULAR AUTOIMMUNE SYNDROME TYPE II

Polyglandular autoimmune (PGA) syndromes (types I and II) may affect various endocrine and non-endocrine organs in the body. In the commoner PGA type II, primary adrenal insufficiency, autoimmune thyroid disease and type I diabetes mellitus are the most frequent manifestations. Serositis with pericardial or pleural involvement is not a well known component of the disease. Here, we report a 21-year-old man who first presented with a pleuropericardial effusion and Graves' disease, and who then developed type I diabetes mellitus.     

Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II

In autoimmune polyglandular syndromes (APS), several organ-specific autoimmune diseases are clustered. Although APS type I is caused by loss of central tolerance, the etiology of APS type II (APS-II) is currently unknown. However, in several murine models, depletion of CD4(+) CD25(+) regulatory T cells (T(regs)) causes a syndrome resembling human APS-II with multiple endocrinopathies. Therefore, we hypothesized that loss of active suppression in the periphery could be a hallmark of this syndrome. T(regs) from peripheral blood of APS-II, control patients with single autoimmune endocrinopathies, and normal healthy donors showed no differences in quantity (except for patients with isolated autoimmune diseases), in functionally important surface markers, or in apoptosis induced by growth factor withdrawal. Strikingly, APS-II T(regs) were defective in their suppressive capacity. The defect was persistent and not due to responder cell resistance. These data provide novel insights into the pathogenesis of APS-II and possibly human autoimmunity in general.     

Progressive autoimmune beta cell insufficiency: occurrence in the absence of high-risk HLA alleles DR3, DR4

In a prospective screening program for type I diabetes mellitus, we identified a unique family in which several members (mother and three siblings) expressed an unusual set of HLA-DR alleles (DR2+, DR3/4-) and were in different phases of immunologically mediated islet beta cell dysfunction. Immunologic and/or clinical manifestations of type I diabetes were absent in all siblings not sharing both HLA haplotypes in common with the proband. This article illustrates: the clinical utility of prospective family screening for predictive markers, such as islet cell antibodies, progressive autoimmune beta cell destruction can occur in the absence of the "high-risk" alleles HLA-DR3 and DR4, and HLA identity with the proband, rather than specific HLA alleles, i.e., presence of DR3, DR4 and absence of DR2, is an essential factor.     

Autoimmune polyglandular syndrome]

Among many etiologies for hypoparathyroidism, one of the inheritable forms of hypoparathyroidism, called as autoimmune polyglandular syndrome (APS), appears as a complex of hypofunction of several endocrine glands, candidiasis, pernicious anemia and vitiligo. Idiopathic hypoparathyroidism in APS typically presents by 20 years of age. Among the three most components of APS I, candidiasis is usually the first manifestation. Hypoparathyroidism almost invariably precedes the onset of Addison's disease. One should remember that Addison's disease can mask the presence of hypoparathyroidism and that glucocorticoid replacement therapy alone can cause hypocalcemic crisis.     

Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease.

Autoimmune polyendocrine syndrome type I (APS I) and idiopathic Addison's disease are both disorders with adrenal insufficiency but with differences in genetic background, clinical presentation, and extent of extraadrenal manifestations. In this study the major adrenal autoantigen identified with sera from patients with APS I was characterized by analyses using indirect immunofluorescence, Western blots of adrenal subcellular fractions and of recombinant proteins, immunoprecipitations of [35S]methionine-labeled lysates of a human steroid-producing cell line, and studies of enzymatic activity. Sera from patients with APS I, identifying cells in adrenal glands and testes involved in steroid synthesis, reacted in Western blots with a 53-kD antigen, which comigrated with the cytochrome P450 cholesterol side chain cleavage enzyme (SCC). The sera also immunoprecipitated this protein from lysates of radiolabeled adrenal cells. The enzymatic activity of SCC was inhibited by the APS I sera but not by control sera. Sera from patients with idiopathic Addison's disease did not react with the SCC. The results show that the autoimmune responses towards adrenal tissue in patients suffering from APS I and Addison's disease are remarkably selective and suggest that a determination of the antigen involved in a patient with autoimmune adrenal insufficiency will have diagnostic as well as prognostic implications.     

Disease association, origin, and clinical relevance of autoantibodies to the glycolytic enzyme enolase.

Serum autoantibodies to the glycolytic enzyme enolase have been reported in a diverse range of inflammatory, degenerative, and psychiatric disorders. Diseases in which these antibodies have been reported in high incidence include autoimmune polyglandular syndrome type 1 (80%, 35 of 44), primary (69%, 60 of 87), and secondary (58%, 14 of 24) membranous nephropathy, cancer-associated retinopathy (68.8%, 11 of 16), autoimmune hepatitis type 1 (60%, 12 of 20), mixed cryoglobulinemia with renal involvement (63.6%, seven of 11), cystoid macular edema (60%, six of 10), and endometriosis (50%, 21 of 41). In autoimmune polyglandular syndrome type 1 patients, all had chronic mucocutaneous candidiasis with demonstrated antibody reactivity to candida enolase, which is suggestive of cross reactivity or epitope mimicry. Formation of autoantibodies to enolase may be a normal process, with reported incidence in apparently healthy subjects ranging from 0% (zero of 91) to 11.7% (seven of 60). Nonetheless, we suggest that excessive production of these autoantibodies, which are generated as a consequence of uptake of enolase by antigen-presenting cells and subsequent B cell activation, can potentially initiate tissue injury as a result of immune complex deposition.     

Autoimmune thyroid disease induced by interferon therapy]

Interferon therapy, widely used in chronic viral hepatitis and in various malignant diseases, has been known to induce autoimmune phenomena, the most frequent being autoimmune thyroid disease. We have studied the human leukocyte antigen (HLA) in patients who developed autoimmune thyroid dysfunction after interferon-alpha therapy for chronic hepatitis C. Seventeen of 439 patients (3.9%) developed symptomatic autoimmune thyroid dysfunction after interferon-alpha therapy, including nine cases of hyperthyroidism and eight cases of hypothyroidism. The incidence of HLA-A2 in those patients was significantly higher than that in general population in Japan. The present results suggest that HLA-A2 is associated with interferon-alpha therapy-induced autoimmune thyroid dysfunction in patients with chronic hepatitis C.     

Latent Autoimmune Diabetes of Adults (LADA) Is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes

Latent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes–associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to 1) true autoimmune diabetes with a milder phenotype at older onset ages that initially appears similar to type 2 diabetes but later requires insulin, 2) a disease syndrome where the pathophysiologies of type 1 and type 2 diabetes are both present in each patient, or 3) a heterogeneous group resulting from difficulties in classification. Herein, we suggest that difficulties in classification are a major component resulting from defining LADA using a diagnostic test—islet autoantibody measurement—with imperfect specificity applied in low-prevalence populations. This yields a heterogeneous group of true positives (autoimmune type 1 diabetes) and false positives (nonautoimmune type 2 diabetes). For clinicians, this means that islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes: in an adult without clinical features of type 1 diabetes, it is likely that a single positive antibody will represent a false-positive result. This is in contrast to patients with features suggestive of type 1 diabetes, where false-positive results will be rare. For researchers, this means that current definitions of LADA are not appropriate for the study of autoimmune diabetes in later life. Approaches that increase test specificity, or prior likelihood of autoimmune diabetes, are needed to avoid inclusion of participants who have nonautoimmune (type 2) diabetes. Improved classification will allow improved assignment of prognosis and therapy as well as an improved cohort in which to analyze and better understand the detailed pathophysiological components acting at onset and during disease progression in late-onset autoimmune diabetes.     

The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice

IFN-beta, a type I IFN, is widely used for the treatment of MS. However, the mechanisms behind its therapeutic efficacy are not well understood. Using a murine model of MS, EAE, we demonstrate that the Th17-mediated development of autoimmune disease is constrained by Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta-dependent (TRIF-dependent) type I IFN production and its downstream signaling pathway. Mice with defects in TRIF or type I IFN receptor (IFNAR) developed more severe EAE. Notably, these mice exhibited marked CNS inflammation, as manifested by increased IL-17 production. In addition, IFNAR-dependent signaling events were essential for negatively regulating Th17 development. Finally, IFN-beta-mediated IL-27 production by innate immune cells was critical for the immunoregulatory role of IFN-beta in the CNS autoimmune disease. Together, our findings not only may provide a molecular mechanism for the clinical benefits of IFN-beta in MS but also demonstrate a regulatory role for type I IFN induction and its downstream signaling pathways in limiting Th17 development and autoimmune inflammation.     

The natural autoantibody repertoire and autoimmune disease.

The incidence of autoimmune diseases has shown a significant increase in developed countries during the last 40 years. The cause of this increase is still unknown, and reliable methods for the detection of individuals at risk of developing autoimmune disease are not available yet. To explore new methods for the diagnosis and monitoring of autoimmune disease, we have studied the repertoire of natural autoantibodies (NA) and its relationship with autoimmune disease using large arrays of defined antigens. NA are found in healthy humans and mice, apparently in the absence of immunization with their target antigens. We used knock-out mice to demonstrate that the repertoire of NA is influenced by factors not directly related to antigenic stimulation such as endogenous levels of histamine. By studying strains of mice known to differ in their susceptibility to autoimmune disease, we could conclude that the repertoire of NA reflects the susceptibility to develop autoimmune disease. The study of the human repertoire of NA required the development of bio-informatic tools to overcome the variation introduced by individual differences in the genetic background and immune history. We found that human NA are organized in clusters that can differentiate healthy subjects from patients with type 1 diabetes mellitus, type 2 diabetes mellitus or Beh?et's disease patients. The development of new tools to undertake large-scale NA analysis could also enhance our understanding of the immune system, and leave us in a better position to face the up-coming epidemics of autoimmune disorders.     

Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype.

Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers of anti-nuclear autoantibodies. This AH carries a single segment characterized by no C4A gene. This null allele does not code for a functional C4A protein that likely plays an anti-inflammatory role being specialized in the opsonization and immunoclearance processes. So, this genetic defect has been claimed to allow that an increased production of autoantibodies directed vs. cells that have undergone apoptosis and are not efficiently disposed because a reduced antigenic clearance. The results obtained in the present study fit very well with this hypothesis. In the AH carriers the simultaneous high setting of tumor necrosis factor (TNF)-alpha may supply the autoantigens (providing an excess of apoptotic cells) that drive the autoimmune response. In conclusion, the C4 defect associated to the increased spontaneous release of TNF-alpha, modifying a certain number of immunological parameter may be the most characterizing feature of the 8.1 AH. In the majority of individuals, an autoimmune response clinically relevant will develop only in the presence of other immunological abnormalities.     

HLA and disease association

The major histocompatibility complex (MHC) is a genetic system of over 70 known genes on the short arm of chromosome 6 and spans about 4 million base pairs of DNA. The high resolution typing of class I and class I MHC genes and the identification of other genes in the region have increased the definition of the genetic basis of immune responses and diseases of unknown etiology such as the autoimmune diseases. In this paper, I review the literature about HLA and migraine.