9 research outputs found
Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene
Self-reactive B repertoire and Auto-immune Polyendocrine Syndrome type 1
La polyendocrinopathie auto-immune de type 1 (PEA1) est liĂ©e aux mutations du gĂšne AIRE. En lâabsence de AIRE se dĂ©veloppe un dĂ©faut de tolĂ©rance immune centrale, Ă lâorigine de pathologies auto-immunes multiples spĂ©cifiques dâorgane. Notre objectif Ă©tait dâĂ©valuer lâeffet dâune altĂ©ration« exemplaire » du rĂ©pertoire T sur les empreintes auto-rĂ©actives humorales. Les donnĂ©es cliniques etimmunologiques ont Ă©tĂ© recueillies chez des patients atteints de PEA1, qui ont bĂ©nĂ©ficiĂ© du sĂ©quençage du gĂšne AIRE. Chez ces patients ont Ă©tĂ© analysĂ©s les profils dâauto-rĂ©activitĂ© sĂ©rique IgGet IgM vis Ă vis des tissus pancrĂ©atique et surrĂ©nalien, en comparaison Ă des patients atteints dâautres endocrinopathies auto-immunes, et Ă des sujets sains. Les bandes antigĂ©niques discriminantes ont Ă©tĂ© sĂ©lectionnĂ©es grĂące Ă un test de Chi-2, et une approche immuno-protĂ©omique a permis leur caractĂ©risation molĂ©culaire. Dix-neuf patients atteints de PEA1 ont pu ĂȘtre Ă©tudiĂ©s. Ils prĂ©sentaient de1 Ă 10 manifestations cliniques liĂ©es Ă la maladie. Quatre mutations du gĂšne AIRE diffĂ©rentes ont Ă©tĂ© identifiĂ©es, et la dĂ©lĂ©tion 13-bp dans lâ exon 8 (c.967-979del13) sâest avĂ©rĂ©e la plus frĂ©quente. LâĂ©tude en immuno-empreinte a permis dâidentifier 6 antigĂšnes prĂ©fĂ©rentiellement reconnus par les patients atteints de PEA1. Leur caractĂ©risation par approche immuno-protĂ©omique a montrĂ© quâil sâagissait Ă lafois dâantigĂšnes tissus-spĂ©cifiques (lipase pancrĂ©atique reconnue Ă la fois par les IgM et les IgG,amylase pancrĂ©atique reconnue par les IgG, Regenerating Protein 1 alpha pancrĂ©atique ciblĂ©e par lesIgM) mais Ă©galement ubiquitaires (pĂ©roxiredoxine-2 reconnue Ă la fois par les IgG et les IgM, HeatShock cognate 71kDa Protein ciblĂ©e par les IgM, aldose rĂ©ductase reconnue par les IgG). Ainsi, une altĂ©ration majeure du rĂ©pertoire T auto-rĂ©actif, telle que celle liĂ©e aux mutations du gĂšne AIRE, affecte de maniĂšre importante les rĂ©ponses humorales auto-rĂ©actives dĂ©pendantes dâ IgG, mais Ă©galement dâIgM. Ces modifications touchent Ă la fois des antigĂšnes tissu-spĂ©cifiques et ubiquitaires, nous faisant Ă©voquer un rĂŽle au moins partiel de AIRE dans des phĂ©nomĂšnes T-indĂ©pendants et /ou des altĂ©rations de lâimmunitĂ© naturelle.Autoimmune polyendocrine syndrome type 1 (APS1) is caused by mutations in the AIRE gene thatinduce central tolerance breakdown which results in tissue-specific autoimmune diseases. Ourobjective was to evaluate the effect of a well-defined T cell repertoire impairment on humoralsystemic self-reactive footprints. Clinical and immunological data were collected, and pathologicalmutations in the AIRE gene were identified by DNA sequencing. Comparative serum self-IgG andself-IgM reactivities, directed towards pancreatic and adrenal protein extracts, of APS1 patients,patients suffering from other autoimmune endocrinopathies and healthy subjects, were tested using Western blotting. Discriminant protein bands were selected using the Chi-square test and molecularcharacterization of these bands was conducted using a proteomic approach. Nineteen patients wereidentified with APS1. Clinical manifestations varied greatly, showing 1 to 10 components. Fourdifferent AIRE gene mutations were identified, and the 13-bp deletion in exon 8 (c.967-979del13) wasthe most prevalent. A singular distortion of seric self-IgG and self-IgM repertoires was noted in APS1patients. IgG and IgM antibodies recognized significantly one tissue-specific (pancreatictriacylglycerol lipase) and one ubiquitous antigens (peroxiredoxin-2). IgM recognized one tissuespecific (Pancreatic regenerating protein 1!) and one ubiquitous antigen (Heat Shock cognate 71kDaProtein). IgG also recognized one tissue-specific (pancreatic amylase) and one ubiquitous antigen(aldose reductase). As expected, a well-defined self-reactive T cell repertoire impairment affected thetissue-specific self-IgG repertoire but also self-IgM repertoire. Our study also reveals discriminant responses against ubiquitous antigens with IgG and IgM antibodies. Some common discriminantantigenic targets were found for IgG and IgM. All these data suggest that T cell-dependent but also T cell-independent mechanisms are involved in APS1. The potent involvement of complementary events related to potent dysfunction in the innate immune response is discussed
Répertoire B auto-réactif T-dépendant et t-indépendant dans la Polyendocrinopathie Auto-immune de type 1
Autoimmune polyendocrine syndrome type 1 (APS1) is caused by mutations in the AIRE gene thatinduce central tolerance breakdown which results in tissue-specific autoimmune diseases. Ourobjective was to evaluate the effect of a well-defined T cell repertoire impairment on humoralsystemic self-reactive footprints. Clinical and immunological data were collected, and pathologicalmutations in the AIRE gene were identified by DNA sequencing. Comparative serum self-IgG andself-IgM reactivities, directed towards pancreatic and adrenal protein extracts, of APS1 patients,patients suffering from other autoimmune endocrinopathies and healthy subjects, were tested using Western blotting. Discriminant protein bands were selected using the Chi-square test and molecularcharacterization of these bands was conducted using a proteomic approach. Nineteen patients wereidentified with APS1. Clinical manifestations varied greatly, showing 1 to 10 components. Fourdifferent AIRE gene mutations were identified, and the 13-bp deletion in exon 8 (c.967-979del13) wasthe most prevalent. A singular distortion of seric self-IgG and self-IgM repertoires was noted in APS1patients. IgG and IgM antibodies recognized significantly one tissue-specific (pancreatictriacylglycerol lipase) and one ubiquitous antigens (peroxiredoxin-2). IgM recognized one tissuespecific (Pancreatic regenerating protein 1!) and one ubiquitous antigen (Heat Shock cognate 71kDaProtein). IgG also recognized one tissue-specific (pancreatic amylase) and one ubiquitous antigen(aldose reductase). As expected, a well-defined self-reactive T cell repertoire impairment affected thetissue-specific self-IgG repertoire but also self-IgM repertoire. Our study also reveals discriminant responses against ubiquitous antigens with IgG and IgM antibodies. Some common discriminantantigenic targets were found for IgG and IgM. All these data suggest that T cell-dependent but also T cell-independent mechanisms are involved in APS1. The potent involvement of complementary events related to potent dysfunction in the innate immune response is discussed.La polyendocrinopathie auto-immune de type 1 (PEA1) est liĂ©e aux mutations du gĂšne AIRE. En lâabsence de AIRE se dĂ©veloppe un dĂ©faut de tolĂ©rance immune centrale, Ă lâorigine de pathologies auto-immunes multiples spĂ©cifiques dâorgane. Notre objectif Ă©tait dâĂ©valuer lâeffet dâune altĂ©ration« exemplaire » du rĂ©pertoire T sur les empreintes auto-rĂ©actives humorales. Les donnĂ©es cliniques etimmunologiques ont Ă©tĂ© recueillies chez des patients atteints de PEA1, qui ont bĂ©nĂ©ficiĂ© du sĂ©quençage du gĂšne AIRE. Chez ces patients ont Ă©tĂ© analysĂ©s les profils dâauto-rĂ©activitĂ© sĂ©rique IgGet IgM vis Ă vis des tissus pancrĂ©atique et surrĂ©nalien, en comparaison Ă des patients atteints dâautres endocrinopathies auto-immunes, et Ă des sujets sains. Les bandes antigĂ©niques discriminantes ont Ă©tĂ© sĂ©lectionnĂ©es grĂące Ă un test de Chi-2, et une approche immuno-protĂ©omique a permis leur caractĂ©risation molĂ©culaire. Dix-neuf patients atteints de PEA1 ont pu ĂȘtre Ă©tudiĂ©s. Ils prĂ©sentaient de1 Ă 10 manifestations cliniques liĂ©es Ă la maladie. Quatre mutations du gĂšne AIRE diffĂ©rentes ont Ă©tĂ© identifiĂ©es, et la dĂ©lĂ©tion 13-bp dans lâ exon 8 (c.967-979del13) sâest avĂ©rĂ©e la plus frĂ©quente. LâĂ©tude en immuno-empreinte a permis dâidentifier 6 antigĂšnes prĂ©fĂ©rentiellement reconnus par les patients atteints de PEA1. Leur caractĂ©risation par approche immuno-protĂ©omique a montrĂ© quâil sâagissait Ă lafois dâantigĂšnes tissus-spĂ©cifiques (lipase pancrĂ©atique reconnue Ă la fois par les IgM et les IgG,amylase pancrĂ©atique reconnue par les IgG, Regenerating Protein 1 alpha pancrĂ©atique ciblĂ©e par lesIgM) mais Ă©galement ubiquitaires (pĂ©roxiredoxine-2 reconnue Ă la fois par les IgG et les IgM, HeatShock cognate 71kDa Protein ciblĂ©e par les IgM, aldose rĂ©ductase reconnue par les IgG). Ainsi, une altĂ©ration majeure du rĂ©pertoire T auto-rĂ©actif, telle que celle liĂ©e aux mutations du gĂšne AIRE, affecte de maniĂšre importante les rĂ©ponses humorales auto-rĂ©actives dĂ©pendantes dâ IgG, mais Ă©galement dâIgM. Ces modifications touchent Ă la fois des antigĂšnes tissu-spĂ©cifiques et ubiquitaires, nous faisant Ă©voquer un rĂŽle au moins partiel de AIRE dans des phĂ©nomĂšnes T-indĂ©pendants et /ou des altĂ©rations de lâimmunitĂ© naturelle
Evaluation clinique, immunologique et génétique du syndrome APECED dans le Nord-Ouest de la France : à propos de 19 observations
LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Etude comparative des Ă©tiologies des hypothyroĂŻdies cliniques et subcliniques
LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1
International audienceAutoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene
Consensus sur l'insuffisance surrénale de la SFE/SFEDP : introduction et guide
International audienceThe French endocrinology society (SFE) and the French pediatric endocrinology society (DFSDP) have drawn up recommendations for the management of primary and secondary adrenal insufficiency in the adult and child, based on an analysis of the literature by 19 experts in 6 work-groups. A diagnosis of adrenal insufficiency should be suspected in the presence of a number of non-specific symptoms except hyperpigmentation which is observed in primary adrenal insufficiency. Diagnosis rely on plasma cortisol and ACTH measurement at 8am and/or the cortisol increase after synacthen administration. When there is a persistant doubt of secondary adrenal insufficiency, insulin hypoglycemia test should be carried out in adults, adolescents and children older than 2 years. For determining the cause of primary adrenal insufficiency, measurement of anti-21-hydroxylase antibodies is the initial testing. An adrenal CT scan should be performed if auto-antibody tests are negative, then assay for very long (Y. Reznik). chain fatty acids is recommended in young males. In children, a genetic anomaly is generally found, most often congenital adrenal hyperplasia. In the case of isolated corticotropin (ACTH) insufficiency, it is recommended to first eliminate corticosteroid-induced adrenal insufficiency, then perform an hypothalamic-pituitary MRI. Acute adrenal insufficiency is a serious condition, a gastrointestinal infection being the most frequently reported initiating factor. After blood sampling for cortisol and ACTH assay, treatment should be commenced by parenteral hydrocortisone hemisuccinate together with the correction of hypoglycemia and hypovolemia. Prevention of acute adrenal crisis requires an education of the patient and/or parent in the case of pediatric patients and the development of educational programs. Treatment of adrenal insufficiency is based on the use of hydrocortisone given at the lowest possible dose, administered several times per day. Mineralocorticoid replacement is often necessary for primary adrenal insufficiency but not for corticotroph deficiency. Androgen replacement by DHEA may be offered in certain conditions. Monitoring is based on the detection of signs of under-and over-dosage and on the diagnosis of associated auto-immune disorders.La SociĂ©tĂ© française d'endocrinologie (SFE) et la SociĂ©tĂ© française d'endocrinologie pĂ©diatrique (SFEDP) ont Ă©laborĂ© des recommandations sur la prise en charge de l'insuffisance surrĂ©nale primaire et secondaire de l'adulte et de l'enfant, Ă partir d'une analyse de la littĂ©rature rĂ©alisĂ©e par 19 experts rĂ©partis en 6 groupes de travail. Le diagnostic d'insuffisance surrĂ©nale doit ĂȘtre Ă©voquĂ© devant l'association de signes cliniques et biologiques non spĂ©-cifiques, en dehors de la mĂ©lanodermie observĂ©e dans l'insuffisance surrĂ©nale primaire. Le diagnostic repose sur les dosages du cortisol et de l'ACTH le matin et/ou le dosage du cortisol aprĂšs stimulation par l'ACTH synthĂ©tique (synacthĂšne). En cas de doute, le test d'hypoglycĂ©mie insulinique est le test de rĂ©fĂ©rence chez l'adulte l'adolescent et l'enfant de plus de 2 ans. La recherche Ă©tiologique est basĂ©e sur le dosage en 1 re intention des anticorps anti 21-hydroxylase. En cas de nĂ©gativitĂ©, un scanner surrĂ©nalien sera rĂ©alisĂ©, puis le dosage des acides gras Ă chaĂźnes longues sera effectuĂ© chez le garçon. Chez l'enfant, une cause gĂ©nĂ©tique sera recherchĂ©e, principalement l'hyperplasie congĂ©nitale des surrĂ©nales. Devant un dĂ©ficit corticotrope, aprĂšs la recherche d'une prise prolongĂ©e de glucocorticoĂŻdes sera effectuĂ©e une imagerie hypothalamo-hypophysaire. L'insuffisance surrĂ©nale aiguĂ« est une complication grave souvent dĂ©clenchĂ©e par une infection gastro-intestinale. Elle nĂ©cessite aprĂšs prĂ©lĂšvement pour dosage du cortisol et ACTH l'administration parentĂ©rale d'hĂ©misuccinate d'hydrocortisone et la correction de l'hypovolĂ©mie et/ou de l'hypoglycĂ©mie. Sa prĂ©vention repose sur l'Ă©ducation thĂ©rapeutique du patient pour laquelle des programmes seront dĂ©veloppĂ©s. Le traitement de l'insuffisance surrĂ©nale s'appuie sur la prise pluriquotidienne d'hydrocortisone Ă la dose la plus faible possible. La substitution minĂ©ralocorticoĂŻde est rĂ©alisĂ©e en cas d'insuffisance surrĂ©nale primaire mais n'est pas nĂ©cessaire en cas d'insuffisance surrĂ©nale secondaire. La substitution androgĂ©nique par la DHEA peut ĂȘtre proposĂ©e dans cer-taines indications prĂ©cises. La monitoring comportera la recherche de signes cliniques et biologiques de sous/surdosage et de maladies auto-immunes associĂ©es
Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study
Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy