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1.
Adv Exp Med Biol ; 1444: 19-32, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467970

RESUMO

One of the difficulties in studying the pathogenesis of autoimmune diseases is that the disease is multifactorial involving sex, age, MHC, environment, and some genetic factors. Because deficiency of Aire, a transcriptional regulator, is an autoimmune disease caused by a single gene abnormality, Aire is an ideal research target for approaching the enigma of autoimmunity, e.g., the mechanisms underlying Aire deficiency can be studied using genetically modified animals. Nevertheless, the exact mechanisms of the breakdown of self-tolerance due to Aire's dysfunction have not yet been fully clarified. This is due, at least in part, to the lack of information on the exact target genes controlled by Aire. State-of-the-art research infrastructures such as single-cell analysis are now in place to elucidate the essential function of Aire. The knowledge gained through the study of Aire-mediated tolerance should help our understanding of the pathogenesis of autoimmune disease in general.


Assuntos
Doenças Autoimunes , Poliendocrinopatias Autoimunes , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Autoimunidade/genética , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/metabolismo , Aprendizagem , Timo
2.
Adv Exp Med Biol ; 1444: 3-18, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467969

RESUMO

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic inborn error of autoimmunity that is caused by damaging germline variants in the AIRE gene and clinically manifests with multiple autoimmune diseases in patients. Studies on the function of the AIRE gene, discovered in 1997, have contributed to fundamental aspects of human immunology as they have been important in understanding the basic mechanism of immune balance between self and non-self. This chapter looks back to the discovery of the AIRE gene, reviews its main properties, and discusses the key findings of its function in the thymus. However, more recent autoantibody profilings in APECED patients have highlighted a gap in our knowledge of the disease pathology and point to the need to revisit the current paradigm of AIRE function. The chapter reviews these new findings in APECED patients, which potentially trigger new thoughts on the mechanism of immune tolerance.


Assuntos
Doenças Autoimunes , Poliendocrinopatias Autoimunes , Humanos , Autoimunidade/genética , Poliendocrinopatias Autoimunes/genética , Fatores de Transcrição/genética , Doenças Autoimunes/genética , Mutação
3.
Int J Mol Sci ; 25(5)2024 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-38473903

RESUMO

Autoimmune polyglandular syndromes (APS) are classified into four main categories, APS1-APS4. APS1 is caused by AIRE gene loss of function mutations, while the genetic background of the other APS remains to be clarified. Here, we investigated the potential association between AIRE gene promoter Single Nucleotide Polymorphisms (SNPs) and susceptibility to APS. We sequenced the AIRE gene promoter of 74 APS patients, also analyzing their clinical and autoantibody profile, and we further conducted molecular modeling studies on the identified SNPs. Overall, we found 6 SNPs (-230Y, -655R, -261M, -380S, -191M, -402S) of the AIRE promoter in patients' DNA. Interestingly, folding free energy calculations highlighted that all identified SNPs, except for -261M, modify the stability of the nucleic acid structure. A rather similar percentage of APS3 and APS4 patients had polymorphisms in the AIRE promoter. Conversely, there was no association between APS2 and AIRE promoter polymorphisms. Further AIRE promoter SNPs were found in 4 out of 5 patients with APS1 clinical diagnosis that did not harbor AIRE loss of function mutations. We hypothesize that AIRE promoter polymorphisms could contribute to APS predisposition, although this should be validated through genetic screening in larger patient cohorts and in vitro and in vivo functional studies.


Assuntos
Poliendocrinopatias Autoimunes , Humanos , Síndrome , Mutação , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
4.
Immunol Rev ; 322(1): 98-112, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38193358

RESUMO

Human autoantibodies (auto-Abs) neutralizing type I IFNs were first discovered in a woman with disseminated shingles and were described by Ion Gresser from 1981 to 1984. They have since been found in patients with diverse conditions and are even used as a diagnostic criterion in patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1). However, their apparent lack of association with viral diseases, including shingles, led to wide acceptance of the conclusion that they had no pathological consequences. This perception began to change in 2020, when they were found to underlie about 15% of cases of critical COVID-19 pneumonia. They have since been shown to underlie other severe viral diseases, including 5%, 20%, and 40% of cases of critical influenza pneumonia, critical MERS pneumonia, and West Nile virus encephalitis, respectively. They also seem to be associated with shingles in various settings. These auto-Abs are present in all age groups of the general population, but their frequency increases with age to reach at least 5% in the elderly. We estimate that at least 100 million people worldwide carry auto-Abs neutralizing type I IFNs. Here, we briefly review the history of the study of these auto-Abs, focusing particularly on their known causes and consequences.


Assuntos
COVID-19 , Herpes Zoster , Interferon Tipo I , Poliendocrinopatias Autoimunes , Feminino , Humanos , Idoso , Autoanticorpos
5.
Ophthalmic Genet ; 45(1): 59-62, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37017251

RESUMO

PURPOSE: Chronic keratoconjunctivitis is a rare presentation of autoimmune polyglandular syndrome type 1 (APS-1) during the first year of life. Herein, We report a case of a 10-month-old baby girl with chronic bilateral keratoconjunctivitis, corneal scarring and neovascularization that was treated initially with topical immunosuppressants. METHODS: Detailed ophthalmological assessment followed by molecular testing using whole exome sequencing. RESULTS: In addition to the severe chronic bilateral keratoconjunctivitis, corneal scarring and neovascularization, patient weight was found to be low than 10th percentile. Further genetic testing revealed autoimmune regulator (AIRE) gene variant that was only reported once in the literature confirming the diagnosis of APS-1. Further workup detected hypoparathyroidism that was treated with calcium supplementation. CONCLUSION: Our case represents the importance of multidisciplinary services and highlights the role of genetic testing in diagnosing such syndromic cases. We reviewed previous reports and found that available treatment for ocular involvement is usually nonsatisfactory; however, early detection and referral by ophthalmologists could result in treating previously undetected endocrine disorders that can be life threatening if left untreated.


Assuntos
Ceratoconjuntivite , Poliendocrinopatias Autoimunes , Feminino , Humanos , Lactente , Cicatriz , Mutação , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/genética , Arábia Saudita , Síndrome , Fatores de Transcrição/genética
6.
Intern Med ; 63(3): 425-431, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37344441

RESUMO

A 52-year-old Japanese woman developed type 1 diabetes mellitus (type 1 DM) at 41 years old. She became complicated with Hashimoto's disease and showed swelling of both submandibular glands, which was diagnosed as IgG4-related disease (IgG4-RD). This is a rare case of a Japanese patient with autoimmune polyglandular syndrome type 3A (APS-3A) coexisting with autoimmune thyroid disease (AITD) and type 1 DM complicated by IgG4-RD. Bilateral submandibular gland resection was successfully performed without steroid therapy. We discuss the possibility that the immunological pathogenic mechanisms of APS-3A and IgG4-RD are related.


Assuntos
Doenças Autoimunes , Diabetes Mellitus Tipo 1 , Doença de Hashimoto , Doença Relacionada a Imunoglobulina G4 , Poliendocrinopatias Autoimunes , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Doença Relacionada a Imunoglobulina G4/complicações , Doença Relacionada a Imunoglobulina G4/diagnóstico , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/diagnóstico , Doença de Hashimoto/complicações , Doença de Hashimoto/diagnóstico , Diabetes Mellitus Tipo 1/complicações , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico
7.
Reprod Sci ; 31(1): 1-16, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37500976

RESUMO

Autoimmune primary ovarian insufficiency (POI) is a devastating disease with limited clinical guidance. The objective of this systematic review was to identify treatments for autoimmune POI and analyze their efficacy. A comprehensive search of CINAHL, Cochrane, Embase, PubMed, Scopus, and Web of Science was performed from inception to April 2022. English language publications that evaluated women with autoimmune POI after a documented intervention were included. Animal models of autoimmune POI were also included. Risk of bias was assessed with the SYRCLE's risk of bias tool for animal studies or the NIH Quality Assessment Tool for Case Series as appropriate. Twenty-eight studies were included in this review, with 11 RCTs, 15 case reports, and 2 case series. Seventeen studies were in humans, and 11 were in animal models. No completed RCTs, cohort studies, or case-control studies were identified in humans. In observational human studies, corticosteroids were effective in select patients. In many case reports, adequate treatment of comorbid autoimmune conditions resulted in return of menses, hormonal normalization, or spontaneous pregnancy. In terms of assisted reproductive technologies, there was case report evidence for both in vitro fertilization (IVF) and in vitro maturation (IVM) in women wishing to conceive with their own oocytes. Ovulation induction, IVF, and IVM resulted in a total of 15 pregnancies and 14 live births. In animal models, there was additional evidence for stem cell therapies and treatments used in traditional Chinese medicine, although this research may not be generalizable to humans. Furthermore, litter size was not evaluated in any of the animal studies. Additional research is needed to establish the efficacy of current treatments for autoimmune POI with a controlled experimental design and larger sample size. Additionally, there is a critical need to develop novel therapies for this condition, as understanding of its pathophysiology and  available tools to modulate the immune response have progressed.


Assuntos
Doenças Autoimunes , Infertilidade Feminina , Ooforite , Poliendocrinopatias Autoimunes , Gravidez , Animais , Humanos , Feminino , Infertilidade Feminina/etiologia , Fertilização In Vitro/métodos , Poliendocrinopatias Autoimunes/complicações , Técnicas de Reprodução Assistida/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/complicações , Nascido Vivo , Taxa de Gravidez
8.
Immunogenetics ; 76(1): 69-74, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38030802

RESUMO

The immune regulator gene AIRE plays an essential role in the establishment of immune tolerance and the prevention of autoimmunity. This transcription factor plays a critical role in promoting self-tolerance in the thymus by regulating the expression of a large number of self-antigens that share the common feature of being tissue-restricted in their expression pattern in the periphery. Dysfunction of AIRE in humans causes a rare disease, autoimmune polyglandular syndrome type 1 (APS1), characterized by an autoimmune response against peripheral tissues, particularly endocrine tissues. Although a few dominant mutations have been described, the inactivation of AIRE is usually caused by recessive mutations. Recent data suggests that alterations in AIRE function contribute not only to APS1 but also to more common forms of autoimmune disease. Here, we present a previously unreported missense mutation (NM_000383.2:c.260 T > C) in exon 2 of the AIRE gene, predicted to cause the substitution (p.(Leu87Pro)) in the CARD domain of the AIRE protein. When inherited in conjunction with another dysfunctional AIRE allele, this mutation was associated with immune dysregulation in a pediatric patient. The presence of hypergammaglobulinemia, malabsorption syndrome, ectodermal dysplasia, mucocutaneous candidiasis, vitiligo, and hypothyroidism as well as the presence of multiple autoantibodies allowed us to confirm an APS1 diagnosis.


Assuntos
Mutação de Sentido Incorreto , Poliendocrinopatias Autoimunes , Criança , Humanos , Mutação , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/diagnóstico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Front Immunol ; 14: 1274672, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38077387

RESUMO

Background: Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients, including stiff person syndrome, cerebellar ataxia, refractory epilepsy, and limbic and extra limbic encephalitis. While there are few case reports and research on anti-GAD65 antibody-associated encephalitis in adults, such cases are extremely rare in pediatric cases. Methods: For the first time, we report a case of anti-GAD65-positive autoimmune encephalitis associated with autoimmune polyendocrine syndrome (APS) type II. We reviewed previously published pediatric cases of anti-GAD65 autoimmune encephalitis to discuss their clinical features, laboratory tests, imaging findings, EEG patterns, and prognosis. Case presentation: An 8-year-old, male child presented to the outpatient department after experiencing generalized convulsions for twenty days. The child was admitted for epilepsy and had received oral sodium valproate (500 mg/day) in another center, where investigations such as USG abdomen and MRI brain revealed no abnormalities, however, had abnormal EEG with diffuse mixed activity in the left anterior middle prefrontal temporal region. On the follow-up day, a repeat blood test showed a very low serum drug concentration of sodium valproate hence the dose was increased to 750 mg/day. Then, the child experienced adverse effects including increased sleep, thirst, and poor appetite, prompting the parents to discontinue the medication. A repeat MRI showed increased signals on FLAIR sequences in the right hippocampus hence admitted for further management. The child's past history included a diagnosis of hypothyroidism at the age of 4, and receiving levothyroxine 75 mcg once daily. His parents are healthy with no history of any similar neurological, autoimmune, or genetic diseases, but his uncle had a history of epilepsy. At presentation, he had uncontrolled blood glucose levels with elevated HbA1c levels. Additionally, the serum and CSF autoantibodies were positive against the anti-GAD65 antibody with the titer of 1:100 and 1:32 respectively. The patient was managed with a mixed type of insulin regimen and received first-line immunotherapy (intravenous immunoglobulin, IVIG) for five consecutive days, followed by oral prednisone and sodium valproate as an antiepileptic drug. Upon achieving a favorable clinical outcome, the patient was discharged with oral medications. Results: Among the 15 pediatric patients reported in this literature, nine presented with limbic encephalitis (LE), three with extralimbic encephalitis (ELE), and three with a combination of limbic and extralimbic encephalitis. Most of these cases exhibited T2-W FLAIR hyperintensities primarily localized to the temporal lobes in the early phase, progressing to hippocampal sclerosis/atrophy in the later phase on MRI. EEG commonly showed slow or spike waves on frontotemporal lobes with epileptic discharges. Prognostic factors varied among patients, with some experiencing persistent refractory seizures, type-1 diabetes mellitus (T1DM), persistent memory impairment, persistent disability requiring full assistance, and, in severe cases, death. Conclusion: Our findings suggest that anti-GAD65 antibody-positive autoimmune encephalitis patients may concurrently present with other APS. Our unique case presented with multiple endocrine syndromes and represents the first reported occurrence in children. Early diagnosis and timely initiation of immunotherapy are crucial for improving clinical symptoms and reducing the likelihood of relapses or permanent disabilities. Therefore, emphasis should be placed on prompt diagnosis and appropriate treatment implementation to achieve better patient outcomes.


Assuntos
Doenças Autoimunes do Sistema Nervoso , Encefalite , Epilepsia , Encefalite Límbica , Poliendocrinopatias Autoimunes , Adulto , Humanos , Masculino , Criança , Glutamato Descarboxilase , Encefalite Límbica/diagnóstico , Encefalite Límbica/tratamento farmacológico , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/tratamento farmacológico , Ácido Valproico , Encefalite/diagnóstico , Encefalite/tratamento farmacológico , Autoanticorpos , Imunoglobulinas Intravenosas
11.
J Clin Immunol ; 44(1): 5, 2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38112858

RESUMO

Autoimmune polyendocrine syndrome type-1 (APS-1) is caused by mono- or biallelic loss-of-function variants of the autoimmune regulator gene AIRE underlying early-onset multiorgan autoimmunity and the production of neutralizing autoantibodies against cytokines, accounting for mucosal candidiasis and viral diseases. Medical intervention is essential to prevent or attenuate autoimmune manifestations. Ruxolitinib is a JAK inhibitor approved for use in several autoimmune conditions. It is also used off-label to treat autoimmune manifestations of a growing range of inborn errors of immunity. We treated three APS-1 patients with ruxolitinib and followed them for at least 30 months. Tolerance was excellent, with no medical or biological adverse events. All three patients had remarkably positive responses to ruxolitinib for alopecia, nail dystrophy, keratitis, mucosal candidiasis, steroid-dependent autoimmune hepatitis, exocrine pancreatic insufficiency, renal potassium wasting, hypoparathyroidism, and diabetes insipidus. JAK inhibitors were therefore considered an effective treatment in three patients with APS-1. Our observations suggest that JAK/STAT pathways are involved in the pathogenesis of APS-1 autoimmune manifestations. They also suggest that JAK inhibitors should be tested in a broader range of APS-1 patients.


Assuntos
Candidíase , Inibidores de Janus Quinases , Poliendocrinopatias Autoimunes , Humanos , Poliendocrinopatias Autoimunes/tratamento farmacológico , Poliendocrinopatias Autoimunes/genética , Autoimunidade , Autoanticorpos
12.
Ter Arkh ; 95(10): 881-887, 2023 Nov 23.
Artigo em Russo | MEDLINE | ID: mdl-38159022

RESUMO

Autoimmune polyglandular syndromes (APS) are a heterogeneous group of clinical conditions characterized by functional impairment of multiple endocrine glands due to loss of central or peripheral immune tolerance. These syndromes are also often accompanied by autoimmune damage to non-endocrine organs. Taking into account the wide range of components and variants of the disease, APS is usually divided into a rare juvenile type (APS 1) and a more common adult type (APS 2-4). APS type 1 is caused by a monogenic mutation, while APS types 2-4 have a polygenic mode of inheritance. One subtype of adult APS (APS 3D) is characterized by a combination of autoimmune thyroid disease and autoimmune rheumatic disease. This review considers the available literature data on combinations that meet the above criteria. Many studies have noted a significantly higher prevalence of rheumatic diseases in patients with autoimmune thyroid disease compared with the control group. Also, as in a number of rheumatic diseases, a more frequent occurrence of autoimmune thyroiditis, primary hypothyroidism and Graves' disease was noted.


Assuntos
Doenças Autoimunes , Doença de Graves , Poliendocrinopatias Autoimunes , Doenças Reumáticas , Adulto , Humanos , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/epidemiologia , Poliendocrinopatias Autoimunes/genética , Doenças Autoimunes/complicações , Doença de Graves/complicações , Síndrome , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/genética , Doenças Reumáticas/complicações
13.
Sci Transl Med ; 15(727): eadg6822, 2023 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-38117899

RESUMO

Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Poliendocrinopatias Autoimunes , Humanos , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Linfócitos T Reguladores , Mutação/genética , Síndrome , Fatores de Transcrição Forkhead/genética , Receptores de Antígenos de Linfócitos T/genética
14.
Front Endocrinol (Lausanne) ; 14: 1236878, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37937054

RESUMO

Purpose: To characterize patients with APS type 4 among those affected by APS diagnosed and monitored at our local Reference Center for Autoimmune Polyglandular Syndromes. Methods: Monocentric observational retrospective study enrolling patients affected by APS diagnosed and monitored in a Reference Center. Clinical records were retrieved and analyzed. Results: 111 subjects (51 males) were affected by APS type 4, mean age at the onset was 23.1 ± 15.1 years. In 15 patients the diagnosis of APS was performed during the first clinical evaluation, in the other 96 after a latency of 11 years (range 1-46). The most frequent diseases were type I diabetes mellitus and celiac disease, equally distributed among sexes. Conclusions: The prevalence of APS type 4 is 9:100,000 people. Type I diabetes mellitus was the leading indicator of APS type 4 in 78% subjects and in 9% permitted the diagnosis occurring as second manifestation of the syndrome. Our data, showing that 50% of patients developed APS type 4 within the first ten years, don't suggest any particular follow-up time and, more importantly, don't specify any particular disease. It is important to emphasize that 5% of women developed premature ovarian failure.


Assuntos
Doença Celíaca , Diabetes Mellitus Tipo 1 , Poliendocrinopatias Autoimunes , Insuficiência Ovariana Primária , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Adulto Jovem , Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/epidemiologia , Estudos Retrospectivos , Síndrome
15.
J Clin Invest ; 133(21)2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37909333

RESUMO

Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7-/-) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7-/- mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X-/- mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.


Assuntos
Doenças Autoimunes , Poliendocrinopatias Autoimunes , Adulto , Animais , Pré-Escolar , Humanos , Camundongos , Mutação , Poliendocrinopatias Autoimunes/genética , RNA Mensageiro , Linfócitos T
16.
Genes Cells ; 28(12): 929-941, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37909727

RESUMO

One hallmark of some autoimmune diseases is the variability of symptoms among individuals. Organs affected by the disease differ between patients, posing a challenge in diagnosing the affected organs. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and the development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear. This study aimed to investigate the correlation of TCRα and ß repertoires in blood T cells with the extent of autoimmune signs that varies among individuals. We sequenced TCRα and ß of CD4+ CD44high CD62Llow T cells in the blood and stomachs of mice deficient in autoimmune regulator (Aire) (AIRE KO), a mouse model of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Data analysis revealed that the degree of similarity in TCR sequences between the blood and stomach varied among individual AIRE KO mice and reflected the extent of T cell infiltration in the stomach. We identified a set of TCR sequences whose frequencies in blood might correlate with extent of the stomach manifestations. Our results propose a potential of using TCR repertoires not only for diagnosing disease development but also for diagnosing affected organs in autoimmune diseases.


Assuntos
Doenças Autoimunes , Poliendocrinopatias Autoimunes , Humanos , Camundongos , Animais , Linfócitos T CD4-Positivos , Receptores de Antígenos de Linfócitos T/genética
17.
Artigo em Alemão | MEDLINE | ID: mdl-37956663

RESUMO

The autoimmune polyendocrine syndrome (APS) refers to a combination of autoimmune endocrine disorders. It is rarely described in dogs. The most common combinations are hypoadrenocorticism and hypothyroidism, followed by diabetes mellitus, and less often hypoparathyroidism and orchitis. The diagnosis of the APS is based on the diagnosis of each endocrinopathy, as is the therapy, which involves the substitution of deficient hormones. If a patient was previously stable under treatment and is showing further signs (e.g. polyuria, polydipsia, or weight loss), the development of additional endocrinopathies like hypoadrenocorticism or diabetes mellitus should be considered. The diagnosis of the initially diagnosed endocrinopathy should also be critically questioned. This article summarizes some cases of our own animal hospital and selected cases published in the available literature.


Assuntos
Diabetes Mellitus Tipo 1 , Doenças do Cão , Hipoparatireoidismo , Poliendocrinopatias Autoimunes , Masculino , Cães , Animais , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/veterinária , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/terapia , Poliendocrinopatias Autoimunes/veterinária , Síndrome , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/terapia , Hipoparatireoidismo/veterinária , Doenças do Cão/diagnóstico , Doenças do Cão/terapia
18.
BMC Pediatr ; 23(1): 601, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-38017413

RESUMO

BACKGROUND: Autoimmune enteropathy (AIE) defined by intractable diarrhoea and nonceliac enteropathy with villous atrophy, is a rare digestive disease. Case reports of this disease are sporadic and the clinical characteristics of AIE is seldom discussed. PURPOSE: We evaluate the clinical, laboratory, histopathological features, response to therapy and outcome of AIE in children. METHOD: We conducted a retrospective analysis of five children with AIE in our hospital. A comprehensive search of MEDLINE was performed using PubMed, through keywords of "autoimmune enteropathy, pediatric or children". The clinical manifestations, endoscopic results, pathological results, and medication therapy of these children were collected and the cases were divided into two groups, infants (≤ 1 year old) and children (> 1 year old). RESULTS: Five cases treated in our department: one case took eight years to make the final diagnosis; one case was positive for anti-intestinal epithelial cell (AE) antibody; three cases showed crypt apoptosis in histopathology; and two cases showed celiac-like changes. All cases were responsive to glucocorticoid therapy in the early stage of treatment, while three cases required immunosuppressant maintenance. After reviewing the literature, we performed a statistical analysis of 50 cases with a male-to-female ratio of 31:19. Among them, 35 patients (70%) were within 1 year of age, and their clinical manifestations were mainly watery stool (43 cases, 86%), weight loss (28 cases, 56%), abdominal distension (3 cases, 6%), serum AE or anti-goblet cell (AG) antibody positivity (32 cases, 64%), other immune-related antibodies (21 cases, 42%), gene mutations (9 cases, 18%), and family history (21 cases, 42%). All the children showed different degrees of intestinal villous atrophy. Thirty-seven (74%) of the children were treated early, and their clinical symptoms were relieved. Comparing the cases between different age groups, it was found that the mortality rate of children with onset in infancy was higher (P < 0.05), and there was no difference in other autoimmune diseases, AE antibody positivity rates, and other antibodies between the two groups. In addition to survival rate between different age group (P = 0. 005), there was no difference in sex, autoantibody positivity rate, single gene mutation, or family history between the two groups (P > 0.05) through analysis of mortality and clinical remission cases. CONCLUSION: Endoscopic examination and mucosal pathological examination should be performed to diagnose AIE in children with watery stool and weight loss who fail to be treated with diet therapy. Immunotherapy is the core of medical management of AIE and can improve prognosis. Children with a poor prognosis in infancy should be actively treated to reduce mortality rates associated with AIE.


Assuntos
Enteropatias , Poliendocrinopatias Autoimunes , Lactente , Humanos , Criança , Masculino , Feminino , Estudos Retrospectivos , Poliendocrinopatias Autoimunes/diagnóstico , Enteropatias/diagnóstico , Enteropatias/terapia , Diarreia/etiologia , Atrofia/complicações , Redução de Peso
19.
Nature ; 624(7992): 653-662, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37993717

RESUMO

Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.


Assuntos
Amelogênese Imperfeita , Autoanticorpos , Doença Celíaca , Poliendocrinopatias Autoimunes , Humanos , Amelogênese Imperfeita/complicações , Amelogênese Imperfeita/imunologia , Autoanticorpos/imunologia , Doença Celíaca/complicações , Doença Celíaca/imunologia , Imunoglobulina A/imunologia , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/imunologia , Proteínas/imunologia , Proteínas/metabolismo , Ameloblastos/metabolismo , Esmalte Dentário/imunologia , Esmalte Dentário/metabolismo , Antígenos/imunologia , Antígenos/metabolismo , Intestinos/imunologia , Intestinos/metabolismo
20.
Eur Thyroid J ; 12(6)2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37878416

RESUMO

Purpose: Autoimmune polyendocrine syndrome (APS) is a rare immune-endocrinopathy characterized by the failure of at least two endocrine organs. Clinical characteristics have mainly been described in the Western population. This study comprehensively analyzed the demographic and clinical manifestations of APS II and APS III in Taiwan. Methods: Patients aged ≥20 years with a diagnosis of APS II or APS III in ten hospitals between 2001 and 2021 were enrolled. The clinical and serological characteristics of the patients were retrospectively reviewed. Results: Among the 187 enrolled patients (45 men and 142 women); only seven (3.7%) had APS II, while the others had APS III. Fifty-five patients developed hyperthyroidism and 44 patients developed hypothyroidism. Men were diagnosed with APS at a younger age than women (16.8 vs 27.8 years old, P = 0.007). Most patients were initially diagnosed with type 1 diabetes mellitus. There was a positive correlation between age at diagnosis and the likelihood of developing thyroid dysfunction. For every year older patients were diagnosed with APS III, the risk of developing hyperthyroidism increased by 3.6% (P = 0.002), and the risk of developing hypothyroidism increased by 3.7% (P = 0.035). Positive anti-parietal cell antibodies (APCA) were associated with a higher risk of anemia in patients with APS III (P < 0.001). Conclusion: This study provides the most comprehensive analysis of APS II and APS III in Asia. The percentage of patients with APS II was significantly lower than in the Western population. A second autoimmune endocrinopathy may develop several years after the first one. APCA examination is valuable when evaluating anemia in patients with APS.


Assuntos
Anemia , Hipertireoidismo , Hipotireoidismo , Poliendocrinopatias Autoimunes , Masculino , Humanos , Feminino , Adulto , Poliendocrinopatias Autoimunes/complicações , Taiwan/epidemiologia , Estudos Retrospectivos , Síndrome , Hipertireoidismo/complicações , Hipotireoidismo/complicações , Anemia/complicações
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