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1.
Front Immunol ; 10: 1695, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379878

RESUMO

Graves' disease (GD) involves the presence of agonistic auto-antibodies against the thyrotropin receptor (TSHR), which are responsible for the clinical symptoms. While failure of TSHR tolerance is central to GD pathogenesis, the process leading to this failure remains poorly understood. Two mechanisms intimately linked to tolerance have been proposed to explain the association of SNPs located in TSHR intron 1 to GD: (1) differential alternative splicing in the thyroid; and (2) modulation of expression in the thymus. To elucidate the relative contribution to these two mechanisms to GD pathogenesis, we analyzed the level of full-length and ST4 and ST5 isoform expression in the thyroid (n = 49) and thymus (n = 39) glands, and the influence of intron 1-associated SNPs on such expression. The results show that: (1) the level of flTSHR and ST4 expression in the thymus was unexpectedly high (20% that of the thyroid); (2) while flTSHR is the predominant isoform, the levels are similar to ST4 (ratio flTSHR/ST4 = 1.34 in the thyroid and ratio flTSHR/ST4 in the thymus = 1.93); (3) next-generation sequencing confirmed the effect of the TSHR intron 1 polymorphism on TSHR expression in the thymus with a bias of 1.5 ± 0.2 overexpression of the protective allele in the thymus compared to the thyroid; (4) GD-associated intron 1 SNPs did not influence TSHR alternative splicing of ST4 and ST5 in the thyroid and thymus; and (5) three-color confocal imaging showed that TSHR is associated with both thymocytes, macrophages, and dendritic cells in the thymus. Our findings confirm the effect of intron 1 polymorphisms on thymic TSHR expression and we present evidence against an effect on the relative expression of isoforms. The high level of ST4 expression in the thymus and its distribution within the tissue suggest that this would most likely be the isoform that induces central tolerance to TSHR thus omitting most of the hinge and transmembrane portion. The lack of central tolerance to a large portion of TSHR may explain the relatively high frequency of autoimmunity related to TSHR and its clinical consequence, GD.

2.
J Autoimmun ; 103: 102285, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31182340

RESUMO

Autoimmune thyroid diseases (AITDs), i.e., Graves' disease (GD) and Hashimoto thyroiditis (HT), are the most prevalent organ-specific autoimmune diseases, but their pathogenesis is still incompletely understood. The PD-1/PD-L1 pathway is an important mechanism of peripheral tolerance that has not been investigated in AITDs. Here, we report the analysis of the expression of PD-1, PD-L1 and PD-L2 in PBMCs, infiltrating thyroid lymphocytes (ITLs) and in thyroid follicular cells (TFCs) in GD, HT and multinodular goiter (MNG) patients and healthy controls PBMCs (HC). By combining flow cytometry, tissue immunofluorescence and induction experiments on primary and thyroid cell line cultures, we show that: 1) while PD-1+ T cells are moderately expanded in PBMCs from GD vs HC, approximately half of T cells in the infiltrate are PD-1+ including some PD-1hi; 2) PD-L1, but not PD-L2, is expressed by 81% of GD glands and in 25% of non-autoimmune glands; 3) PD-L1, was expressed by TFCs in areas that also contain abundant PD-1 positive T cells but; 4) co-localization in TFCs indicated only partial overlap between the smaller areas of the PD-L1+ and the larger areas of HLA class II+ expression; 5) IFNγ is capable of inducing PD-L1 in >90% of TFCs in primary cultures and cell lines. Collectively these results indicate that the PD-1/PD-L1 axis is operative in AITD glands and may restrain the autoimmune response. Yet the discrepancy between easy induction in vitro and the limited expression in vivo (compared to HLA) suggests that PD-L1 expression in vivo is partially inhibited in GD and HT glands. In conclusions 1) the PD-1/PD-L1 pathway is activated in AITD glands but probably not to the extent to inhibit disease progression and 2) Thyroid autoimmunity arising after PD-1/PD-L1 blocking therapies in cancer patients may result from interfering PD-1/PD-L1 tolerance mechanism in thyroid with minimal (focal) thyroiditis. Finally acting on the PD-1/PD-L1 pathway could be a new approach to treat AITD and other organ-specific autoimmunity in the future.

3.
Clin Exp Rheumatol ; 37 Suppl 119(4): 41-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30767873

RESUMO

OBJECTIVES: To evaluate the clinical features and survival of patients with positive anti-RNA polymerase III (anti-RNAP III) in a Spanish single centre. METHODS: We analysed 221 patients with SSc according to LeRoy and Medsger criteria. Twenty-six patients with positivity for anti-RNAP III antibodies were compared with 195 negative patients. Epidemiological, clinical, immunological features and survival were analysed. RESULTS: In patients with anti-RNAP III positivity diffuse cutaneous SSc (dcSSc) subset was the most prevalent (20, 76.9% vs. 35, 17.9%, p < 0.001), with shorter diagnosis delay (4.11 ± 7.34 years vs. 6.77 ± 9.22 years, p = 0.005). Patients with anti-RNAP III antibodies had higher frequency of arterial hypertension (13, 50% vs. 55, 28.2%, p = 0.024), scleroderma renal crisis (SRC) (3, 11.5% vs. 3, 1.5%, p = 0.023), arthritis (9, 34.6% vs. 35, 17.9%, p = 0.046), tendon friction rubs (4, 15.4% vs. 1, 0.5%, p = 0.001) and contractures (5, 19.2% vs. 10, 5.1%, p = 0.02). There were no differences found in the presence of cancer or in global survival. In the multivariate survival analysis, severe interstitial lung disease (ILD) (HR: 8.61, 95%CI 3.40 - 21.81), pulmonary arterial hypertension (PAH) (HR: 4.05, 95%CI 1.42 - 11.61) and SRC (HR: 17.27, 95%CI 3.36 - 88.97) were the only factors associated with poor prognosis. CONCLUSIONS: In this cohort anti-RNAP III antibodies are related with dcSSc subset, shorter diagnostic delay and higher prevalence of musculoskeletal involvement, arterial hypertension and SRC. ILD, PAH and SRC were independent prognostic factors.


Assuntos
Autoanticorpos/imunologia , Doenças Pulmonares Intersticiais , RNA Polimerase III/imunologia , Escleroderma Sistêmico , Adulto , Autoanticorpos/sangue , Diagnóstico Tardio , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Espanha
4.
Horm Metab Res ; 50(12): 863-870, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30396220

RESUMO

In the last 3 years, the association of thyrotropin receptor gene (TSHR) variations to Graves' disease (GD) has been confirmed. It is now well established that a 30 Kb region of intron 1 of the TSHR gene is linked to GD predisposition. Elucidating the mechanism(s) by which these polymorphisms confer susceptibility is difficult but would constitute an important advance in endocrine autoimmunity in general. Two hypotheses, both postulating TSHR gene regulatory mechanisms, are discussed. One postulates differential level of expression in the thymus, involving central tolerance. The other postulates a shift in TSHR differential splicing leading to the production of soluble proteins that will have easy access to antigen presenting cells, so it is focused in peripheral tolerance. A combination of the 2 hypothesis is feasible, especially under the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1.


Assuntos
Tolerância Central/imunologia , Estudos de Associação Genética , Doença de Graves/genética , Doença de Graves/imunologia , Receptores da Tireotropina/metabolismo , Autoantígenos/metabolismo , Predisposição Genética para Doença , Humanos , Receptores da Tireotropina/genética
5.
Autoimmun Rev ; 16(5): 461-468, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28285170

RESUMO

OBJECTIVE: Emerging data have shown an increased risk of malignancy among patients diagnosed with systemic sclerosis (SSc) so identification of risk factors linking both disorders might have prognostic implications. The aim of this study was to assess the clinical and treatment-related risk factors for cancer in a single-center cohort of patients with SSc. METHODS: Demographic, clinical, capillaroscopic, immunological and treatment-related data from 432 consecutive SSc patients were retrospectively analyzed. Variables that reached significant association in the univariate analysis were entered into a logistic regression in order to identify independent risk factors for cancer. RESULTS: Malignancy was diagnosed in 53 patients (12.2%). Fifty-eight neoplasms were identified, among which breast (n=15), lung (n=10) and hematologic (n=9) malignancies were the most prevalent. In 19 patients the diagnosis of both scleroderma and tumour was made in <3years apart. Cancer significantly decreased the probability of survival (OR=2.61; 95%CI 1.46-4.69; p=0.001). No association with age, sex, smoking, cutaneous subset or RNA polymerase-III antibodies was found. However, risk of cancer was directly associated with the presence of anti-PM/Scl antibodies (OR=3.90; 95%CI 1.31-11.61; p=0.014), and inversely related to aspirin use (OR=0.33; 95%CI 0.12-0.90; p=0.031), which remained as independent risk factors for cancer on multivariate analysis. CONCLUSIONS: PM/Scl antibodies seem to be associated with a higher risk of cancer in scleroderma. In contrast, the use of aspirin is related to a lower risk of cancer in our series. More studies are needed to ascertain the role of anti PM/Scl antibodies and aspirin in the development of malignancy among patients with SSc.


Assuntos
Neoplasias/etiologia , Escleroderma Sistêmico/complicações , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Estudos Retrospectivos , Fatores de Risco , Escleroderma Sistêmico/patologia
6.
Hum Immunol ; 77(8): 643-651, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27266815

RESUMO

Autoimmune Regulator (AIRE) is a transcriptional regulator that is crucial for establishing central tolerance as illustrated by the Mendelian Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome associated with AIRE-inactivating recessive or dominant mutations. Polymorphisms in AIRE have been proposed to be implicated in genetic susceptibility to non-Mendelian organ specific autoimmune diseases. Because there is evidence that in predisposition to Graves' disease (GD) central tolerance is crucial, we investigated whether AIRE polymorphisms could modulate risk of GD. A case-control association study using 29 variants and conducted in 150 GD patients and 200 controls did not detect any significant association. This result is not exceptional: a systematic review of the literature, including GWAS, on the association of AIRE variants with organ specific autoimmune diseases did not show clear associations; similarly heterozygous recessive mutations are not associated to non-Mendelian autoimmunity. Dominant negative mutations of AIRE are associated to autoimmunity but as mild forms of APECED rather than to non-Mendelian organ specific autoimmunity. The lack of association of common AIRE polymorphisms with polygenic autoimmune diseases is counterintuitive as many other genes less relevant for immunological tolerance have been found to be associated. These findings give rise to the intriguing possibility that evolution has excluded functionally modifying polymorphisms in AIRE.


Assuntos
Doenças Autoimunes/genética , Doença de Graves/genética , Mutação/genética , Polimorfismo Genético , Fatores de Transcrição/genética , Animais , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imunidade/genética , Masculino , Grupos Populacionais
7.
Med. clín (Ed. impr.) ; 145(9): 399-403, nov. 2015. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-142968

RESUMO

Las estatinas son los fármacos más utilizados en la prevención tanto primaria como secundaria de enfermedades cardiovasculares y asociadas a aterosclerosis. Alrededor de 25 millones de personas están en tratamiento con estatinas en el mundo. A pesar de que son bien toleradas por la mayoría de los pacientes y de tener un perfil muy seguro, algunos pacientes presentan alteraciones, especialmente a nivel muscular. Los efectos biológicos asociados a estos fármacos son conocidos como pleiotrópicos; son de tal interés y diversidad que explican, en parte, algunas de las acciones de las estatinas, especialmente en relación con la inflamación y el sistema inmunitario. Algunos pacientes presentan ciertas alteraciones inmunológicas que puede transformarse luego en expresión clínica no deseable. Estudios recientes han mostrado que pueden desencadenar fenómenos autoinmunitarios. Han sido descritas enfermedades en las que actúan como desencadenantes, como la miopatía necrosante inmunomediada, o indirectamente en dermatomiositis o hepatitis autoinmunitaria, entre otras. Es así por lo que dado el elevado número de personas en tratamiento con estatinas, creemos que se trata de un problema clínicamente relevante y, por tanto, merecedor de estudio (AU)


Statins are the most widely used drugs for both primary and secondary prevention of cardiovascular diseases and those associated with atherosclerosis. About 25 million people are on statin therapy in the world. Although they are well tolerated by most patients and have a safety profile, some patients have muscle level alterations. The biological effects associated with these drugs are known as pleiotropic; they are of such interest and diversity that explains, in part, some of the actions of statins, especially in relation to inflammation and the immune system. Some patients have certain immune disorders that can turn into an undesirable clinical expression. Recent studies have shown that they can trigger autoimmune phenomena. Pathologies have been described in which these agents act as triggers such as immune-mediated necrotizing myopathy or indirectly in dermatomyositis or autoimmune hepatitis, among others. Given the high number of people being treated with statins, we believe that this is a clinically relevant problem and therefore worthy of study (AU)


Assuntos
Feminino , Humanos , Masculino , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Autoimunidade , Autoimunidade/imunologia , Hipercolesterolemia/prevenção & controle , Hipercolesterolemia/terapia , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/terapia , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/prevenção & controle , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle
8.
J Immunol ; 194(9): 4199-206, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25801430

RESUMO

Graves' disease (GD) is an autoimmune thyroid disease defined by the production of stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR) (TSAbs) that induce a sustained state of hyperthyroidism in patients. We previously demonstrated that TSHR, the target of this autoimmune response, is also a key susceptibility gene for GD, probably acting through thymic-dependent central tolerance. We also showed that TSHR is, unexpectedly, expressed in thymocytes. In this report, we confirm the expression of TSHR in thymocytes by protein immunoblotting and quantitative PCR, and show that expression is confined to maturing thymocytes. Using functional assays, we show that thymic TSHR is functional and that TSAbs can stimulate thymocytes through this receptor. This new activity of TSAbs on thymocytes may: 1) explain GD-associated thymic enlargement (hyperplasia), and 2) suggest the provocative hypothesis that the continuous stimulation of thymocytes by TSAbs could lead to a vicious cycle of iterative improvement of the affinity and stimulating capability of initially low-affinity antibacterial (e.g., Yersinia) Abs cross-reactive with TSHR, eventually leading to TSAbs. This may help to fill one of the gaps in our present understanding of unusual characteristics of TSAbs.


Assuntos
Autoanticorpos/imunologia , Doença de Graves/imunologia , Ativação Linfocitária/imunologia , Receptores da Tireotropina/imunologia , Timócitos/imunologia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Receptores da Tireotropina/genética , Timócitos/citologia
9.
Med Clin (Barc) ; 145(9): 399-403, 2015 Nov 06.
Artigo em Espanhol | MEDLINE | ID: mdl-25662717

RESUMO

Statins are the most widely used drugs for both primary and secondary prevention of cardiovascular diseases and those associated with atherosclerosis. About 25 million people are on statin therapy in the world. Although they are well tolerated by most patients and have a safety profile, some patients have muscle level alterations. The biological effects associated with these drugs are known as pleiotropic; they are of such interest and diversity that explains, in part, some of the actions of statins, especially in relation to inflammation and the immune system. Some patients have certain immune disorders that can turn into an undesirable clinical expression. Recent studies have shown that they can trigger autoimmune phenomena. Pathologies have been described in which these agents act as triggers such as immune-mediated necrotizing myopathy or indirectly in dermatomyositis or autoimmune hepatitis, among others. Given the high number of people being treated with statins, we believe that this is a clinically relevant problem and therefore worthy of study.


Assuntos
Doenças Autoimunes/induzido quimicamente , Autoimunidade/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hepatite Autoimune/etiologia , Humanos , Doenças Pulmonares Intersticiais/induzido quimicamente , Lúpus Eritematoso Sistêmico/induzido quimicamente , Doenças Musculares/induzido quimicamente , Vasculite Leucocitoclástica Cutânea/induzido quimicamente
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