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PubMed2005

Disruption of immunological tolerance: role of AIRE gene in autoimmunity.

The mechanism underlying the generation of T and B autoreactive clones in autoimmune diseases is still unknown. Among genetic factors implicated in autoimmunity, Autoimmune Regulator gene (AIRE) is one of the candidates to better understand the complex scenario of autoimmune manifestations. AIRE mutations are responsible for the development of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) with monogenic autosomal recessive inheritance; it has been shown that AIRE regulates the negative selection of autoreactive T cells clones, driving the transcription of tissue-specific antigens in thymic epithelial cells. In various autoimmune manifestations correlated or not to APECED, AIRE variants act in a semidominant manner, leading to a reduction in AIRE protein amount per cell, and consequently to a marked decrease in ectopic proteins expression in the thymus. The co-occurrence of autoimmune diseases in the same individual has prompted several studies aimed to recognize shared patho-physiological mechanisms; in this scenario small reductions in function could explain the predisposition to autoimmunity in AIRE-heterozygous carriers of missense mutations; further studies to investigate whether the AIRE gene is involved in determining these autoimmune manifestations should be carried out.

Autoimmune Diseases↗
PubMed1997

[A rare case of juvenile diabetes mellitus associated with APECED (autoimmune poly-endocrinopathy, candidiasis and ectodermal dystrophy) with strong X-linked familial inheritance].

The polyglandular autoimmune syndromes (PGA) are well known and are distinguished into type I, type II and type III. PGAI, also called APECED (autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy), is an autosomal recessive disorder, appearing in childhood and typically characterized by hypoparathyroidism (unusual in PGAII and PGAIII) and adrenal insufficiency. In APECED, autoimmune destruction of the pancreatic beta cells with development of insulin-dependent type 1 diabetes is possible, but less frequent than in the other PGAs, especially PGAII. The pathogenesis of this unique autoimmune disease is unknown. No HLA association seems to exist and genetic studies have assigned the autosomal APECED locus to chromosome 21. The case of a 28-years-old female suggesting the diagnosis of APECED, is presented, characterized by psycho-somatic abnormal development, teeth alterations, post-puberal gonadal failure with dystrophic hypoplasia of external genitalia, previous vaginal candidiasis, a slowly developing juvenile brittle diabetes. Intestinal malabsorption induced by Giardia lamblia occurred (probably resulting, like candidiasis, from immunological anergy). A strong familiarity linked to female sex was noticed (the mother, a sister, the little nice and some maternal female cousins being affected) while the father and a brother were healthy. Diabetes seems to be characterized by early onset and severe complications. In this patient no organo-specific antibodies were detected and the only immunologic disorder was a small decrease of CD3 and CD4/CD8 ratio, both CD4 and CD8 being at the lower normal range. This patient (and her female maternal relatives) needs a long-term follow-up in order to evaluate the function of endocrine glands and to initiate early treatment for hormonal deficits, as well as to detect the non-endocrine components of disease.

Adult↗
PubMed2005

Polymorphisms at +49A/G and CT60 sites in the 3' UTR of the CTLA-4 gene and APECED-related AIRE gene mutations analysis in sporadic idiopathic hypoparathyroidism.

Autoimmune diseases such as Graves' disease and type 1 diabetes have been linked with +49A/G and CT60 single nucleotide polymorphisms (SNPs) in the 3' UTR of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene. Both these SNPs are functionally relevant and linked with T-lymphocyte activation. Hypoparathyroidism is seen in 70% of patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome (APECED). Although calcium sensing receptor autoantibodies (CaSRAb) and generalized activation of T lymphocytes are reported among patients with sporadic idiopathic hypoparathyroidism (SIH), CTLA-4 gene SNPs and APECED-related autoimmune regulator (AIRE) gene mutations have not been assessed in them. We studied lead CTLA-4 gene SNPs and APECED-related AIRE gene mutations in 73 patients with SIH and 114 healthy subjects. The CTLA-4 gene SNPs +49A/G in exon 1, CT60A/G in 3' UTR and -318C/T in the promoter region were genotyped by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) using BstEII, NcoI and MseI endonucleases, respectively. The APECED-related AIRE gene mutations, which is R257X (Finn-major) in exon 6, 4-bp insertion and 13-bp deletion in exon 8, and Iranian Jews population 'Y85C' mutation in exon 2, were studied by PCR-RFLP (Taq-I), PCR and nucleotide sequencing, respectively. CaSRAb were studied by immunoblotting. The frequencies of CTLA-4 A/A(49), A/G(49) and G/G(49) genotypes in the patients (47.9%, 38.4% and 13.7%) and controls (45.6%, 39.5% and 14.9%, respectively) and the frequencies of CT60 A/A, A/G, and G/G genotypes in the patient (42.4%, 37.0% and 20.6%) and the control (38.6%, 40.4% and 21.0%, respectively) groups were not significantly different. The frequencies of various haplotypes including genetic loci +49A/G and CT60 and frequencies of G alleles at these positions were comparable between patient and the control groups and its presence did not correlate with clinical and biochemical indices of the disease. None of the patients had APECED-related AIRE gene mutations. Lack of significant difference in the pattern of CTLA-4 A/G(49) and/or CT60A/G genotypes and absence of common APECED syndrome-related AIRE gene mutations among patients and controls suggest that these sites do not play a role in the development of the SIH.

3' Untranslated Regions↗
PubMed2003

Addisonian crisis precipitated by thyroxine therapy: a complication of type 2 autoimmune polyglandular syndrome.

Hypothyroidism is a common condition. Rarely, it may occur in combination with autoimmune failure of other endocrine glands (autoimmune polyendocrinopathy syndrome type 2, previously known as Schmidt's syndrome). In such cases, restoring normal thyroid function may precipitate adrenal failure. Clinicians should have a high index of suspicion for this condition in patients with Addison's disease, those with a family history of autoimmune endocrine gland failure, patients with one autoimmune endocrine disease who develop nonspecific or serious illness, and patients with type 1 diabetes mellitus whose insulin requirements drop without obvious explanation.

Addison Disease↗
PubMed1994

Case report: idiopathic hypoparathyroidism co-existing with celiac disease: immunologic studies.

Idiopathic hypoparathyroidism (IH) is often an isolated disorder in adults, but in children it is usually a component of the autoimmune polyendocrinopathy syndrome. The authors describe a patient diagnosed with isolated IH at age 57 and celiac disease at age 64. Testing of patients' serum show antibodies of the immunoglobulin A isotype against endomysium, reticulin, and gliadin antigens, as well as immunoglobulin G against gliadin. The circulating immunoglobulins reacted with bovine parathyroid tissue, specifically smooth muscle of the blood vessels and glandular cells, as detected by indirect immunofluorescence. Testing of celiac disease positive sera showed similar parathyroid reactivity. When the patient was placed on a gluten-free diet, endomysial, reticulin, and gliadin antibodies decreased to undetectable levels, which was parallel with disappearance of the parathyroid immunoreactivity. The gluten-free diet also produced severe hypercalcemia that responded to calcitriol withdrawal, and ultimately required a reduction by half of the original calcitriol dose. It is possible that in this case the same antibody or antibodies may have caused both hypoparathyroidism and celiac disease. We conclude that, as in the case of childhood-onset IH variants, patients with late-onset isolated IH should be monitored for additional endocrine and extra-endocrine autoimmune disorders.

Celiac Disease↗
PubMed1998

Secondary adrenal insufficiency associated with autoimmune disorders: a report of twenty-five cases.

OBJECTIVE: Addison's disease is frequently a component of autoimmune polyendocrinopathies while secondary adrenal insufficiency associated with autoimmune disorders is believed to be a rare event. We present a series of patients with secondary adrenal insufficiency coexisting with autoimmune diseases and/or antithyroid autoantibodies. DESIGN AND PATIENTS: Among a group of 102 patients with secondary adrenal failure of unknown origin diagnosed at the Department of Endocrinology of the Centre for Postgraduate Medical Education (Warsaw, Poland) we have identified a group with associated autoimmune disorders. Thyroid abnormalities occurred most frequently. Other diseases included insulin-dependent diabetes mellitus, pernicious anaemia, vitiligo, premature ovarian failure and autoimmune thrombocytopaenia. There were 23 women and one man aged 17-72 years at the time of investigation. Additionally, we included a woman with Addison's disease in whom the ACTH deficiency appeared 18 years after the onset of primary adrenal hypofunction. MEASUREMENTS: Pituitary-adrenal function tests comprised urinary excretion of 17-hydroxycorticosteroids in basal conditions and during a 2-day tetracosactrin test, plasma concentrations of ACTH and cortisol, and a 2-day metyrapone test (in eight cases). Thyroid function and immunity tests were: TSH, thyroxine, the antithyroglobulin, antimicrosomal and anti-peroxidase autoantibodies. Other endocrine studies included: serum LH, FSH and PRL. RESULTS: The 17-hydroxycorticosteroid values, both basally and during stimulation tests were consistent with a diagnosis of secondary adrenal insufficiency. Serum cortisol and plasma ACTH concentrations were low. In 14 patients primary hypothyroidism was confirmed by low T4 levels. In three patients subclinical primary hypothyroidism was revealed (elevated TSH levels). Three patients who had a past history of Graves' disease were euthyroid at the time of investigation. Twenty-three patients had antibodies against peroxidase. Most patients had gonadotrophins and PRL values within normal limits. CONCLUSIONS: The co-existence of autoimmune disorders with secondary adrenal insufficiency suggests an autoimmune aetiology for the ACTH deficiency.

Adolescent↗
PubMed2000

[Anti-neuronal antibodies and central nervous system diseases: contribution to diagnosis and pathophysiology].

Antibodies against antigens found in the central nervous system have been evidenced in several neurological diseases. The most well-known are associated with paraneoplastic neurological diseases (Anti-Hu, Yo, Ri amphiphysin, Tr, CV2 and Ta antibodies). Some of these antibodies are specific for certain types of cancer or neurological syndromes and are highly useful diagnostic tools for the clinician. They have contributed to the hypothesis that these paraneoplastic neurological syndromes involve autoimmune cross reactions between tumoral and nervous system antigens. They are however most unlikely pathogenic on their own. Anti voltage-dependent calcium channel antibodies associated with Lambert-Eaton syndrome which is paraneoplastic in only 60 p. 100 of the cases are also observed in cases of paraneoplastic cerebellar atrophy. Anti-GAD antibodies are seen in non-paraneoplastic stiff man syndrome and in certain progressive cerebellar atrophies. Antibodies reacting with different glutamate receptors are detected in different neurological diseases including Rasmussen's encephalitis. Finally, antibodies are described in diverse conditions such as amyotrophic lateral sclerosis, Sydeham chorea or Gilles de la Tourette syndrome. The significance of the antibodies observed outside the context of paraneoplastic syndromes is not well understood, but the anti-GAD antibodies associated with progressive cerebellar disorders and autoimmune polyendocrinopathies could be an expression of the autoimmune nature of certain neurological degenerative processes affecting the central nervous system.

Antibodies↗
PubMed2000

The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, caused by mutations in the autoimmune regulator (AIRE) gene, is an autosomal recessive autoimmune disease characterized by the breakdown of tolerance to organ-specific antigens. The 545 amino acid protein encoded by AIRE contains several structural motifs suggestive of a transcriptional regulator and bears similarity to cellular proteins involved in transcriptional control. We show here that AIRE fused to a heterologous DNA binding domain activates transcription from a reporter promoter, and the activation seen requires the full-length protein or more than one activation domain. At the structural level AIRE forms homodimers through the NH(2)-terminal domain, and molecular modeling for this domain suggests a four-helix bundle structure. In agreement, we show that the common transcriptional coactivator CREB-binding protein (CBP) interacts with AIRE in vitro and in yeast nuclei through the CH1 and CH3 conserved domains. We suggest that the transcriptional transactivation properties of AIRE together with its interaction with CBP might be important in its function as disease-causing mutations almost totally abolish the activation effect.

Amino Acid Sequence↗
PubMed1999

Localization of the APECED protein in distinct nuclear structures.

Autoimmune-polyendocrinopathy-candidiasis-ecto-dermaldystrophy (APECED) is the only systemic autoimmune disease with a monogenic background known so far revealing no association with the major histocompatibility complex region. We have recently isolated the gene defective in this syndrome and characterized several different mutations in individuals with the disorder. The novel gene, AIRE, contains a putative bipartite nuclear targeting signal predicting a nuclear location of the corresponding protein. The presence of two PHD-type zinc finger domains as well as the newly described putative DNA-binding domain, SAND, in the amino acid sequence of the APECED protein implies that it may be involved in the regulation of gene expression. Using transient expression of AIRE cDNA in mammalian cells we demonstrate here the nuclear location of the APECED protein. Immunohistochemical staining of transfected cells revealed that most of the recombinant 58 kDa APECED protein is present in the form of nuclear dots. By double immuno-fluorescence labelling we further show that these APECED-containing structures and the previously described PML nuclear bodies are largely non-overlapping. The AIRE protein was also visualized in multiple human tissues: a subset of the cells in thymus, in spleen and in lymph node showed nuclear staining with APECED antiserum. Immunofluorescence labelling of peripheral blood mononuclear leukocytes also revealed a nuclear body-like staining pattern in a fraction of these cells. These data from both in vitro and ex vivo systems, together with the predicted structural features of the APECED protein, suggest that this protein is most probably involved in the regulation of gene expression.

Animals↗
PubMed2004

Autoimmune enteropathy: molecular concepts.

PURPOSE OF REVIEW: Enteropathies causing temporary or permanent intestinal failure are a big diagnostic and therapeutic challenge for pediatric gastroenterologists. A now well-recognized and distinct entity is in the form of "autoimmune enteropathy (AIE)". Recent advances in the molecular workup of AIE gave first insight into the pathophysiology of AIE. In this review, we discuss new molecular concepts of AIE resulting in new diagnostic and therapeutic possibilities. RECENT FINDINGS: The identification of disease-causing mutations in the FOXP3 gene as a basic defect resulting in AIE points to a defect in regulatory T-cell homeostasis. FOXP3, primarily expressed by CD4+CD25+regulatory T cells, is a potent transcriptional suppressor and key modulator of T-cell functions. Nonfunctional FOXP3 leads to a tremendous hyperactivation of T cells, resulting in autoimmune aggression, such as seen in patients with immune dysregulation, polyendocrinopathy autoimmune enteropathy X-linked (IPEX) syndrome, a subgroup of AIE. There is recent evidence suggesting that a defect of regulatory factors other than FOXP3 might cause AIE. Anti-enterocyte autoantibodies, another main characteristic of AIE, seem to be of a secondary nature and can no more be considered as directly disease causing. SUMMARY: Based on the profound immune dysregulation, new treatment strategies emerged for AIE. The use of T-cell immunosuppressive drugs, such as tacrolimus combined to steroids, seems to be beneficial in some patients; however, long-term remission is not always possible. Bone marrow transplantation might be the treatment of choice in those patients who do not respond to immunosuppression; however, the first encouraging results remain to be confirmed since to date long-term outcome remains mixed.

Journal Article↗
PubMed2003

Life-threatening autoimmunity with diabetes: management with an insulin pump.

A 2-yr-old boy presented initially with type 1 diabetes (T1D). Over the next 9 yrs, he developed multiple autoimmune conditions including Evans' syndrome, alopecia, and autoimmune bowel disease. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) syndrome was considered, but no mutations were found in the autoimmune regulator-1 (AIRE-1) gene, making this diagnosis unlikely, and he did not fulfill the clinical criteria for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. We describe the challenges created by the combination of these diseases and how introduction of insulin pump therapy revolutionized his care.

Autoimmunity↗
PubMed1991

Parathyroiditis in the non-obese diabetic mouse--a new finding.

Autoimmune reactions to parathyroid cells have been observed in human autoimmune polyendocrinopathy, but such findings have not been described in animal models of polyendocrine autoimmunity. We report here three cases of lymphocytic infiltrations in 12 parathyroid glands identified in a total of 18 thyroid glands studied in the non-obese diabetic (NOD) mouse. The majority of parathyroid-infiltrating lymphocytes possessed the helper/inducer phenotype as defined by the L3T4 monoclonal antibody. Parathyroiditis was accompanied by lymphocytic thyroiditis only on one occasion, whereas in other cases of thyroiditis, lymphocytic infiltration of the parathyroid was undetectable. We conclude that parathyroiditis in the NOD mouse is part of the wide spectrum of autoimmunity observed in this animal model of diabetes.

Animals↗
PubMedDate not supplied

[Diabetes and autoimmune diseases. I].

An account is given of the clinical and serological associations between diabetes and autoimmune diseases, especially those between diabetes and antihyperoglobulin, antithyroid, anti-intrinsic factor, anticorticoadrenal cell, and anti-nucleic acid autoantibodies. Body fluid antipancreas autoimmunity is examined from various standpoints relating to antipancrease cell antibodies (ICA), autoantibodies against glucagon-secreting cells (ECA) and somatostatin-secreting cells (SCA), and anti-islet cell surface antibodies (McLaren and Lernmark antibodies). Particular attention is directed to ICAs, since these have supplied the background for the recent division of type I diabetes into Ia viral and Ib autoimmune. Stress is laid on both the soundness and the problems forming part of ICAs, since their actual pathogenetic role (cytoplasmic markers?) still has to be determined, even though their persistent and significant association with autoimmune polyendocrinopathies is certain.

Anemia, Pernicious↗
PubMed1989

[Polyendocrinopathy combined with primary pulmonary arterial hypertension].

We report the case of a woman who had premature menopause, adrenal insufficiency and hypothyroidism by peripheral gland lesion, all most probably due to an autoimmune disorder, and who subsequently developed primary pulmonary arterial hypertension. The causes of this hypertension are ill-defined, but an autoimmune origin has often been envisaged since primary pulmonary arterial hypertension is not unfrequently associated with connective tissue diseases. Its association with an autoimmune polyendocrinopathy has only been reported, to our knowledge, on four occasions; in all 4 cases the thyroid gland was involved, and a connective tissue disease was present in 3 of them. Our case, which includes adrenal insufficiency and premature menopause is, as far as we know, unique. The possible link between these various diseases is their autoimmune nature, in which case primary pulmonary arterial hypertension would belong to the category of organ-specific autoimmune diseases. Our case supports the hypothesis that a number of isolated primary pulmonary arterial hypertensions could be of autoimmune origin.

Autoimmune Diseases↗
PubMed2005

Genetic lesions in T-cell tolerance and thresholds for autoimmunity.

The cause of common organ-specific autoimmune diseases is poorly understood because of genetic and cellular complexity in humans and animals. Recent advances in the understanding of the mechanisms of the defects underlying autoimmune disease in autoimmune polyendocrinopathy syndrome type 1 and non-obese diabetic mice suggest that failures in central tolerance play a key role in predisposition towards organ-specific autoimmunity. The lessons from such rare monogenic autoimmune disorders and well-characterized polygenic traits demonstrate how subtle quantitative trait loci can result in large changes in the susceptibility to autoimmunity. These data allow us to propose a model relating efficiency of thymic deletion to T-cell tolerance and susceptibility to autoimmunity.

Animals↗
PubMed2006

Basic science for the clinician 37: Protecting against autoimmunity-tolerance: mechanisms of negative selection in the thymus.

As noted in previous articles in this series, tolerance, the ability of the immune system to differentiate self from nonself and leave the former alone, is a vital characteristic of a successful (and safe) immune system. With the detection of the molecule called aire (autoimmune regulator), the mechanism whereby autoreactive thymocytes encounter extrathymic proteins within the thymus and therefore are deleted, is now far better understood; aire was the subject of a prior article in this series. The absence of aire leads to autoimmune polyendocrinopathy, proof that aire is the center of an amazing "filtering" system. However, there are other mechanisms at work. Irregularities in expression of other proteins such as hypoxia-induced factor-1 (HIF-1) and CTLA4, have been implicated in autoimmune disease, the former in rheumatoid arthritis, the latter in autoimmune thyroid disease and lupus. Defects in intracellular factors involved in transcription of key apoptotic proteins have also been implicated in the escape of autoreactive thymocytes from the thymus, leading to autoimmune and lymphoproliferative syndromes as well. Changes in the proteins that oversee acetylation of histone lead to differential patterns of gene expression. At least 2 proteins involved in this process, HDAC and nur77, have been implicated in changes in survival of thymocytes. Yet again, there are multiple layers at work in the immune system; I have no idea how many more will be brought to light, which are phylogenetically most ancient or which will prove the most clinically relevant. For now, it is enough to bask in our new-found knowledge and know that the time from laboratory oddity, to animal model development, to therapeutic and/or diagnostic applications grows shorter each year since the molecular biologic revolution.

Antigens, CD↗
PubMed2006

Basic science for the clinician 36: protecting against autoimmunity: tolerance and aire, the immunologic shadow, and other mechanisms of negative selection in the thymus.

One of the miracles of immunology is tolerance, the ability of the immune system to differentiate self from nonself and leave the former alone. Autoreactive thymocytes (the cells that would otherwise differentiate into mature autoaggressive T cells) are deleted from the emerging immunologic repertoire within the thymus; only a very small proportion of thymocytes survive the thymus--perhaps 2% to 5% emerge to become mature T cells in the periphery, the rest dying to assure tolerance. This apparent wastage somehow works to the benefit of the developing animal and if the process works, all goes well for the maturing immune system. In some autoimmune syndromes, autoreactive thymocytes are not eliminated within the thymus by either clonal deletion or activation-induced cell death; these then emerge to wreak their havoc. However, how does this deletion happen? Recent research from a number of groups has (incredibly!) identified expression of nonthymic, nonlymphoid proteins within the thymus (casting of the "immunologic shadow of self"), and this is under the control of a single protein: AIRE (autoimmune regulator). By allowing autoreactive thymocytes to encounter a broad spectrum of proteins from extrathymic organs, aire allows deletion of these cells and the maintenance of tolerance. The absence of aire leads to autoimmune polyendocrinopathy, proof that aire is the center of an amazing "filtering" system. These and other molecular mechanisms underlying tolerance are explored in this and the next paper in this series.

Animals↗