A hipogamaglobulinemia é uma alteração da imunidade humoral caracterizada por baixos níveis séricos de anticorpos podendo ter causas primárias e secundárias. Estes pacientes apresentam uma susceptibilidade a infecções bacterianas de repetição ou crônicas, principalmente do trato respiratório. Além disso, há alta prevalência de doenças gastrointestinais infecciosas e inflamatórias, hepatite C, doenças auto-imunes, doenças linfoproliferativas e granulomatosas. Ainda que a doença seja conhecida desde 1954 há poucos trabalhos na literatura sobre manifestações bucais nestes pacientes. Alguns estudos sugerem uma maior prevalência de lesões liquenóides, doença periodontal, candidíase pseudomembranosa, úlcera aftosa recorrente e hipoplasia de esmalte. Desta forma, o objetivo deste trabalho foi avaliar a prevalência das manifestações e alterações bucais, e caracterizar a saúde bucal de pacientes com hipogamaglobulinemias e correlacioná-las com o estado imunológico do paciente, comparativamente a um grupo de pacientes saudáveis. Para tanto avaliamos 100 pacientes com hipogamaglobulinemias atendidos no Ambulatório de Imunologia e Alergia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e 93 pacientes normorreativos da Clínica Odontológica da Faculdade de Odontologia da Universidade de São Paulo, sendo realizado exame clínico bucal, anamnese e compilação de exames laboratoriais recentes. Do total de pacientes com hipogamaglobulinemias, 59 pacientes apresentaram alguma alteração bucal, sendo as mais frequentes lesões de cárie (21), hipoplasia de esmalte (21), gengivite (18), periodontite (8), boca seca (6), língua geográfica (5) e úlcera aftosa recorrente (2). Vinte e sete pacientes apresentaram queixas de úlcera aftosa recorrente com frequência. Dos 93 pacientes do grupo controle, 84 (90,3%) apresentaram alguma alteração bucal, sendo as mais frequentes lesões de cárie (66), gengivite (31), periodontite (44) e candidíase (3). Dezoito pacientes apresentaram queixas de úlcera aftosa recorrente com freqüência. Concluímos que os pacientes com hipogamaglobulinemias, apesar de apresentarem diminuição das imunoglobulinas do sangue, e alguns pacientes apresentarem uma diminuição de células da imunidade celular, não se encontrou relação positiva entre a incidência de cárie e IgA, doença periodontal e IgA e doença periodontal e CD4. / The hypogammaglobulinemia is an alteration in humoral immunity characterized by low levels of antibodies may have primary and secondary causes. These patients have a susceptibility to recurrent bacterial infections or chronic diseases, mainly respiratory tract. Moreover, there is a high prevalence of infectious and inflammatory gastrointestinal diseases, hepatitis C, autoimmune diseases, lymphoproliferative diseases and granulomatous disease. Although the disease is known since 1954 there are few available studies on oral manifestations in these patients. Some studies suggest a higher prevalence of lichenoid lesions, periodontal disease, pseudomembranous candidiasis, recurrent aphthous ulcer and enamel hypoplasia. Thus, the objective was to assess the prevalence of manifestations diseases and to characterize the oral health of patients with hypogammaglobulinemia and correlate with the immune status, compared with healthy patients. For that evaluated 100 patients with hypogammaglobulinemia in the Outpatient Immunology and Allergy Hospital of the Faculty of Medicine, University of São Paulo and 93 healthy patients of School of Dentistry, University of São Paulo, and was conducted oral clinical examination, medical history and compilation of recent laboratory tests. Of all patients with hypogammaglobulinemia, 59 patients showed abnormalities of the mouth, with 21 patients exhibited caries, 21 enamel hypoplasia, 18 gingivitis, 8 periodontitis, 6 dry mouth, 5 geographic tongue and 2 recurrent aphthous ulcer. Twenty-seven patients complained of frequent recurrent aphthous ulcer. Of the 93 control group patients, 84 (90.3%) showed abnormalities, being the most frequent caries (66), gingivitis (31), periodontitis (44) and candidiasis (3). Eighteen patients complained of recurrent aphthous ulcers frequently. We conclude that patients with hypogammaglobulinemia, despite showing decreased blood immunoglobulins, and some patients had a decrease of cells in cellular immunity, we did not find a positive relationship between the incidence of caries and IgA, IgA and periodontal disease and periodontal disease and CD4.

A hipogamaglobulinemia é uma alteração da imunidade humoral caracterizada por baixos níveis séricos de anticorpos podendo ter causas primárias e secundárias. Estes pacientes apresentam uma susceptibilidade a infecções bacterianas de repetição ou crônicas, principalmente do trato respiratório. Além disso, há alta prevalência de doenças gastrointestinais infecciosas e inflamatórias, hepatite C, doenças auto-imunes, doenças linfoproliferativas e granulomatosas. Ainda que a doença seja conhecida desde 1954 há poucos trabalhos na literatura sobre manifestações bucais nestes pacientes. Alguns estudos sugerem uma maior prevalência de lesões liquenóides, doença periodontal, candidíase pseudomembranosa, úlcera aftosa recorrente e hipoplasia de esmalte. Desta forma, o objetivo deste trabalho foi avaliar a prevalência das manifestações e alterações bucais, e caracterizar a saúde bucal de pacientes com hipogamaglobulinemias e correlacioná-las com o estado imunológico do paciente, comparativamente a um grupo de pacientes saudáveis. Para tanto avaliamos 100 pacientes com hipogamaglobulinemias atendidos no Ambulatório de Imunologia e Alergia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e 93 pacientes normorreativos da Clínica Odontológica da Faculdade de Odontologia da Universidade de São Paulo, sendo realizado exame clínico bucal, anamnese e compilação de exames laboratoriais recentes. Do total de pacientes com hipogamaglobulinemias, 59 pacientes apresentaram alguma alteração bucal, sendo as mais frequentes lesões de cárie (21), hipoplasia de esmalte (21), gengivite (18), periodontite (8), boca seca (6), língua geográfica (5) e úlcera aftosa recorrente (2). Vinte e sete pacientes apresentaram queixas de úlcera aftosa recorrente com frequência. Dos 93 pacientes do grupo controle, 84 (90,3%) apresentaram alguma alteração bucal, sendo as mais frequentes lesões de cárie (66), gengivite (31), periodontite (44) e candidíase (3). Dezoito pacientes apresentaram queixas de úlcera aftosa recorrente com freqüência. Concluímos que os pacientes com hipogamaglobulinemias, apesar de apresentarem diminuição das imunoglobulinas do sangue, e alguns pacientes apresentarem uma diminuição de células da imunidade celular, não se encontrou relação positiva entre a incidência de cárie e IgA, doença periodontal e IgA e doença periodontal e CD4. / The hypogammaglobulinemia is an alteration in humoral immunity characterized by low levels of antibodies may have primary and secondary causes. These patients have a susceptibility to recurrent bacterial infections or chronic diseases, mainly respiratory tract. Moreover, there is a high prevalence of infectious and inflammatory gastrointestinal diseases, hepatitis C, autoimmune diseases, lymphoproliferative diseases and granulomatous disease. Although the disease is known since 1954 there are few available studies on oral manifestations in these patients. Some studies suggest a higher prevalence of lichenoid lesions, periodontal disease, pseudomembranous candidiasis, recurrent aphthous ulcer and enamel hypoplasia. Thus, the objective was to assess the prevalence of manifestations diseases and to characterize the oral health of patients with hypogammaglobulinemia and correlate with the immune status, compared with healthy patients. For that evaluated 100 patients with hypogammaglobulinemia in the Outpatient Immunology and Allergy Hospital of the Faculty of Medicine, University of São Paulo and 93 healthy patients of School of Dentistry, University of São Paulo, and was conducted oral clinical examination, medical history and compilation of recent laboratory tests. Of all patients with hypogammaglobulinemia, 59 patients showed abnormalities of the mouth, with 21 patients exhibited caries, 21 enamel hypoplasia, 18 gingivitis, 8 periodontitis, 6 dry mouth, 5 geographic tongue and 2 recurrent aphthous ulcer. Twenty-seven patients complained of frequent recurrent aphthous ulcer. Of the 93 control group patients, 84 (90.3%) showed abnormalities, being the most frequent caries (66), gingivitis (31), periodontitis (44) and candidiasis (3). Eighteen patients complained of recurrent aphthous ulcers frequently. We conclude that patients with hypogammaglobulinemia, despite showing decreased blood immunoglobulins, and some patients had a decrease of cells in cellular immunity, we did not find a positive relationship between the incidence of caries and IgA, IgA and periodontal disease and periodontal disease and CD4.

Justification de l’étude. Les déficits immunitaires primitifs (DIP) sont caractérisés par une grande hétérogénéité clinique, biologique, génétique et thérapeutique. Très peu de connaissances sont disponibles quant au devenir à long terme des patients en termes d’état de santé et de qualité de vie. Objectif : L'objectif principal de l’étude est de mettre en place un dispositif capable d’étudier les déterminants du devenir à long terme d’une cohorte de patients présentant un diagnostic de DIP diagnostiqué au cours de leur enfance. Résultats. Au 1er juin 2016, 1014 patients ont été inclus dans la cohorte sur les 1800 interrogés. La cohorte adulte montre que l’état de santé est marqué par la prévalence très élevée d’évènements de santé sévère ou très sévères (touchant 87% des adultes), avec un taux de cancer de 7.6%. Comparé aux normes françaises, tous les domaines de qualité de vie sont significativement altérés. Seuls les patients greffés présentent une qualité de vie meilleure par rapport aux patients non greffés. Nous montrons que la QoL est inversement proportionnelle à la survenue de complications sévères. L’étude pédiatrique fait le même constat, démontrant que c’est très tôt pendant l’enfance que surviennent les complications sévères dont l’impact sur leur qualité de vie est majeur. Conclusion : les patients atteints de DIP présentent un état de santé marqué par une fréquence très élevée d’évènements de santé de haut grade, et ceci très précocement dans l’enfance. La lourdeur de leur état de santé est le déterminant principal de la mauvaise qualité de vie des patients, justifiant d’une prise en charge spécialisée et multidisciplinaires dès le diagnostic posé. / Importance: Most children with primary immunodeficiencies (PID) now reach adulthood. Assessment of their long-term health status represents a major challenge. We aimed to gain insight into how PID affects patient health status and quality of life (QoL). Design: The French Reference Center for PIDs (CEREDIH) initiated a prospective multicenter cohort which enrolled participants who met all inclusion criteria: (1) patient with PID included in the CEREDIH registry, (2) clinical diagnosis before 18 years, (3) alive and living in France. Among 1810 patients eligible for inclusion (on 1/17/2016), 1047 were children, and 763 were adults. A severity score was assigned to each health condition: grade 1 (mild) to grade 4 (life-threatening/disabling). We report the health status of children by focusing on two endpoints: grade 4 conditions and grade 3 or 4 conditions. Results: In the adult study, only 12% of adults with PID had never experienced severe or life-threatening conditions, and 7.6% of patients had been diagnosed with cancer. Furthermore, adults reported significantly lower scores for all domains of QoL, and QoL was strongly associated with poor health conditions. In the pediatric study, the response rate was 62.5%. Of the 656 children participants, 83% experienced at least one grade 3 or 4 condition. Children with PID scored significantly lower for most QoL domains. QoL was strongly associated with heavy burden of health conditions. Conclusions: Taken together, these studies demonstrate that the deleterious health effects bore by patients with PID become heavy since childhood, emphasizing the need to establish multidisciplinary healthcare teams, from childhood.

Orientador: Antonio Condino Neto / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-04T01:07:19Z (GMT). No. of bitstreams: 1 AgudeloFlorez_PiedadMatilde_D.pdf: 7673448 bytes, checksum: 14c8d7fc8437933b652076b21b9f6ff6 (MD5) Previous issue date: 2004 / Resumo: Doença Granulomatosa. Crônica (DOC) é uma imunodeficiência caracterizada por infecções recorrentes graves. Os defeitos moleculares que lavam a DGC são geralmente devidos a mau funcionamento, ausência o baixa expressão de um dos componentes do sistema NADPH oxidase. Este trabalho analisou o uso de RT-PCR para a triagem de defeitos moleculares responsáveis por DGC ligada ao X em 8 pacientes. RNA total foi preparado de linfócitos B transformados com vírus de Epstein-Barr e transcrição reversa com hexâmeros randomicos. O cDNA resultante foi amplificado por PCR com oligonucleotídeos específicos para 3 regiões exônicas abrangendo toda a extensão do gene. Com esta estratégia foi possível a detecção da expressão defeituosa de gp91-phox em 7 pacientes. Concluímos que a análise por meio de RT-PCR, um método alternativo menos complexo, rápido e econômico foi apropriado para detecção inicial de defeitos moleculares em 7 de 8 pacientes com DOC ligada ao X. Posteriormente investigamos em detalhe os defeitos genetico-moleculares de 7 crianças não relacionadas com DGC ligada ao X. Todos os pacientes foram procedentes do Chile e Brasil. Encontramos uma inserção c.1267_1268insA no paciente JY no exon 10 levando a uma mutação tipo "&ameshill:". Esta mutação é um novo registro na literatura. Detectamos duas substituições "nonsense", uma no paciente PT, c.95 G>A no exon 2 que leva a um códon de parada W28X e outra no paciente MF, c.229 C>T no exon 3 que leva a um códon de parada R73X. Em 4 casos, nos pacientes IC, Vin, RS, GO, diferentes erros de "splicing" foram encontrados. Dois pacientes apresentaram uma subtitução c.264 G> A ao final do exon 3. Os dois restantes apresentaram uma subtitução c.1326 + 1 G>A no intron 10 e outra subtitução c.1164 - 2 A>O no intron 9. Esta última mutação também é um novo registro na lit_ratura. As mutações identificadas na proteína gp91-phox confirmam um alto grau de heterogeneidade molecular como é relatado em outros grupos étnicos e a importância de investigar os defeitos moleculares em diferentes populações. Contrastando com esta heterogeneidade, a DGC associada com defeitos na proteína p47-phox, apresentam pouca variabilidade. Neste estudo, os pacientes analisados, dois irmãos, mostram uma deleção homozigota OT (L}.GT) no começo do exon 2. L Também é analisado o caso de um paciente com infecções recorrentes que inicaJmente recebeu o diagnóstico de deficiência de G6PD. Estudos moleculares mostraram que a deficiência de G6PD foi devida a uma mutação 202 G_A, variante Afi:icana. . O paciente também mostrou uma reduzida atividade da explosão respiratória como observado em DGC ligada ao X. A análise do gDNA mostrou uma subtitução 264 G_A na região do splicing do exon 3 da proteína gp91-phox. A seqüência do cDNA detectou uma deleção do exon 3, levando a uma mutante inestável ou não funcional da proteina gp91-phox e resultando no fenótipo de DGC ligada ao X. Propomos que ftente a um paciente com deficiência de G6PD com episódios de infecções graves considerem a possibilidade de um defeito na atividade fagocítica e uma eventual associação com DGC / Abstract: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency characterized by ear1y onset recurrent severe infections. The molecular defects causing CGD are generally due to the absence, low expression or malfunctioning of one of the NADPH oxidase components. This work analyzed the potential use of reverse transcription (RT)PCR for screening molecular defects responsible for X-linked CGD in 8 Brazilian patients. Total RNA was prepared from EBV-transformed B-lymphocytes and reverse transcribed using random hexamers. The resultant cDNA was PCR-amplified by specific and overlapping pairs of primers regarding 3 exonic regions of gp91-phox gene. This strategy made possible the detection of defective gp91-phox expression in 7 patients. We conclude that RT -PCR analysis, a less complex, more economic and faster alternative method, was appropriate for screening molecular defects in 7 out 8 X-linked CGD patients. We further investigated the molecular genetic defects in 7 unrelated patients with X-linked CGD, from Chile and Brazil. We found an insertion c.1267_1268insA in exon 10 leading to a frameshift mutation. This mutation is a novel reporto we detected two single base-pair substitutions that lead to nonsense mutations. The first was a c.95 G>A substitution in the exon 2 which predicts a stop codon W28X and the second was a c.229 C> T substitution in the exon 3 which predicts a stop codon R73X. We also identified different splice site mutations in 4 cases. Two patients presented a c.264 G> A substitution at the end of exon 3. The remaining two patients presented either a c.1326 + 1 G>A substitution in intron 10 or a c.1164 - 2 A>G substitution in intron 9. This Iast mutation is also novel. The gp91-phox mutations identified in these patients show a high degree of molecular heterogeneity as reported in other ethnic groups and the importance to investigate molecular genetic defects in diferent populations. Contrasting with the heterogeneity of mutations observed in X-linked CGD, the disease associated with defect in p47-phox shows less variability. In this report, the patients with CGD, two sib1ings, show a homozygotous dinucleotide GT deletion (.6.GT) at the beginning of exon 2. We also reported a child with recurrent infections who initially received the diagnosis of G6PD deficiency. Molecular studies showed that the G6PD deficiency was due a 202 G-+A mutation, the A- variant common in African ethnic groups. The proband also exln'bited severely impaired respiratory burst activity, as observed in X-linked CGD. Sequence analysis of genomic DNA showed a 264 G-+A substitution at the 3' splice junction of gp91-phox exon 3. The cDNA sequence showed a deletion of gp91-phox exon 3, giving rise to an unstable or nonfunctional mutant gp91-phox and to the phenotype of Xlinked CGD. We propose that clinicians in face of a patient with G6PD deficiency under a severe infection episode consider the possibility of temporary or permanent impairment of the phagocytes microbicidal activity, and the eventual association of G6PD deficiencyand chronic granulomatous disease / Doutorado / Saude da Criança e do Adolescente / Doutor em Saude da Criança e do Adolescente

As imunodeficiências primárias são um grupo heterogêneo de doenças hereditárias do sistema. Aqui nós descrevemos 4 famílias (2 Turcas e 2 Brasileiras), que apresentaram infecções recorrentes desde os primeiros dias de vida. Após uma análise clínica bem detalhada, combinamos as técnicas de sequenciamento de alta geração para identificar novos defeitos genéticos que levam ao fenótipo de IDP. Finalizamos com a identificação e caracterização de três IDP, sendo que duas inéditas. A primeira identificada (P1) foi causada por uma mutação bialélica no sítio de splice do gene PRKCD (c.1352+1G>A). A segunda (P2 e P3) foi causada por uma mutação bialélica no gene que codifica NIK (c. C1694G; p. Pro565Arg). A terceira (P4) foi causada uma mutação no gene IL7Rα (c.G353A). Finalizamos a análise da P5, mas nenhum dos genes candidatos foi confirmado. A análise genética e a identificação do defeito genético, permite que nossos pacientes possam ter uma melhor sobrevida, podendo realizar um tratamento correto e permite o aconselhamento genético na família. / Primary immunodeficiencies are a heterogeneous group of inherited diseases of the immune system. Here we describe 5 patients from 4 families (2 Turks and 2 Brazilian), all patients had recurrent infections since the firsts days of life. After a very detailed clinical analysis, we applied the Next Generation Sequencing to identify new genes that could be lead to PID phenotype. We finished with the identification and characterization of 3 PID, where 2 of them was new. The first identified (P1) was a biallelic mutation in the splice site of the gene PRKCD (c.1352 + 1G>A). The second (P2 and P3) was a biallelic mutation in the gene encoding NIK (MAP3K14; c.C1694G;. p.Pro565Arg). The third (P4) has a mutation in the gene IL7Rα (c.G353A). We finished the analysis of P5, but no candidate gene was confirmed to be the defect cause. Genetic analysis and identification of the genetic defect allows our patients may have a better survival and can perform a proper treatment and genetic counseling allows the family.

As imunodeficiências primárias são um grupo heterogêneo de doenças hereditárias do sistema. Aqui nós descrevemos 4 famílias (2 Turcas e 2 Brasileiras), que apresentaram infecções recorrentes desde os primeiros dias de vida. Após uma análise clínica bem detalhada, combinamos as técnicas de sequenciamento de alta geração para identificar novos defeitos genéticos que levam ao fenótipo de IDP. Finalizamos com a identificação e caracterização de três IDP, sendo que duas inéditas. A primeira identificada (P1) foi causada por uma mutação bialélica no sítio de splice do gene PRKCD (c.1352+1G>A). A segunda (P2 e P3) foi causada por uma mutação bialélica no gene que codifica NIK (c. C1694G; p. Pro565Arg). A terceira (P4) foi causada uma mutação no gene IL7Rα (c.G353A). Finalizamos a análise da P5, mas nenhum dos genes candidatos foi confirmado. A análise genética e a identificação do defeito genético, permite que nossos pacientes possam ter uma melhor sobrevida, podendo realizar um tratamento correto e permite o aconselhamento genético na família. / Primary immunodeficiencies are a heterogeneous group of inherited diseases of the immune system. Here we describe 5 patients from 4 families (2 Turks and 2 Brazilian), all patients had recurrent infections since the firsts days of life. After a very detailed clinical analysis, we applied the Next Generation Sequencing to identify new genes that could be lead to PID phenotype. We finished with the identification and characterization of 3 PID, where 2 of them was new. The first identified (P1) was a biallelic mutation in the splice site of the gene PRKCD (c.1352 + 1G>A). The second (P2 and P3) was a biallelic mutation in the gene encoding NIK (MAP3K14; c.C1694G;. p.Pro565Arg). The third (P4) has a mutation in the gene IL7Rα (c.G353A). We finished the analysis of P5, but no candidate gene was confirmed to be the defect cause. Genetic analysis and identification of the genetic defect allows our patients may have a better survival and can perform a proper treatment and genetic counseling allows the family.

Mon projet de thèse a consisté en l’identification et la caractérisation moléculaire et immunologique de patients présentant une susceptibilité accrue aux infections fongiques par Candida sp. dans le syndrome Mendélien de candidose cutanéo-muqueuse chronique (CCMC).La CCMC est caractérisée par des infections persistantes ou récurrentes de la peau, des ongles et des muqueuses par les champignons Candida, principalement C. albicans. Elle est fréquemment associée à d’autres infections opportunistes dans certaines immunodéficiences primaires ou acquises, ou bien elle peut être associée à un tableau auto-immun. La CCMC peut finalement être isolée (CCMCi) sans autre tableau clinique sévère: la plupart des cas rapportés sont sporadiques, mais il existe également des cas familiaux avec une hérédité mendélienne autosomique principalement dominante (AD) ou plus rarement récessive (AR).Basés sur les données de la littérature, qui démontrent un rôle majeur de l’immunité dépendante des IL-17s dans la résistance aux infections mucocutanées vis-à-vis de C. albicans et nos résultats récents, qui démontrent un défaut de cette immunité dans certaines immunodéficiences primaires associées à une CCMC [les syndromes AD-HIES et AR APS-1, ainsi que chez les patients déficients en CARD9, nous avons émis l’hypothèse que parmi les patients atteints de CCMCi, certains pourraient présenter un défaut génétique affectant spécifiquement l’immunité IL-17-dépendante. Au début de ma thèse, j’ai participé à l’identification des deux premières étiologies génétiques de la CCMCi : le défaut autosomique récessif (AR) complet en IL-17RA et autosomique dominant (AD) en IL-17F. Plus récemment, j’ai identifié la troisième et la plus fréquente étiologie génétique de la CCMC par l’identification de mutations gain de fonction dans le gène STAT1 suite à une approche explorant l’ensemble du génome (séquençage de l’ensemble des exons). Ces mutations engendrent une « hyper-réponse » aux interférons de type I et II et à l’IL-27 qui inhibent la différentiation des lymphocytes T sécréteurs d’IL-17, impliqués dans l’immunité mucocutanée vis-à-vis de C. albicans chez l’homme.En conclusion, nous avons identifié, en 2011, des trois premières étiologies génétiques de la CCMCi, avec les défauts AR en IL-17RA, AD en IL-17F et des mutations gain-de-fonction de STAT1, toutes associées à un défaut de l’immunité dépendante de l’IL-17. Des mutations gain-de-fonction de STAT1 représentent à ce jour la cause génétique la plus fréquente de la CCMCi avec au total 94 patients rapportés dans la littérature depuis 2011. Nous avons ainsi démontré que la CCMCi est une immunodéficience primaire, associée à un défaut de l’immunité réalisée par les IL-17s. Ces travaux ont des implications majeures dans le domaine immunologique avec la description et la caractérisation des mécanismes biologiques impliqués dans l’immunité protectrice spécifique de C. albicans et une meilleure compréhension des mécanismes physiopathologiques associés à une susceptibilité accrue aux infections fongiques, dans des conditions naturelles d’infection ; et dans le domaine médical, avec la possibilité de diagnostics moléculaires, un conseil génétique en cas de diagnostic positif, une meilleure prise en charge des patients. / My project consists in the molecular and immunological identification and characterization of patients with increased susceptibility to fungal infections with Candida sp. suffering from the Mendelian syndrome of chronic mucocutaneous candidiasis (CMC).CMC is characterized by persistent or recurrent infections of the skin, nails and mucosae by Candida fungi, especially C. albicans. CMC is frequently associated with other opportunistic infections in some acquired or primary immunodeficiencies, or can be associated with autoimmune disorders. Finally, CMC may be present as an isolated form (chronic mucocutaneous candidiasis disease or CMCD) without any other severe infectious or autoimmune clinical manifestation: most reported cases are sporadic, but there are also familial cases with autosomal dominant (AD) or recessive (AR) Mendelian inheritance.Based the literature, which demonstrated a major role of IL-17 cytokines in mucocutaneous immunity with C. albicans, and our recent results, which show an impairment of IL-17 immunity in some primary immunodeficiencies associated with CMC (AD-HIES syndrome, AR APS-1, and CARD9-deficient patients), we hypothesized that among CMCD patients, some might have a genetic defect affecting specifically the IL-17-dependent immunity.At the beginning of my PhD, I participated in the identification of the first two genetic etiologies of CMCD: complete AR IL-17RA and partial AD IL-17F deficiencies. More recently, I identified the third and most common genetic etiology of CMCD by identifying gain of function mutations in the STAT1 gene following an approach exploring the whole genome (sequencing of all exons). These mutations are responsible for a "hyper-response" to type I and II interferons and IL-27, which inhibit the differentiation of IL-17-producing T cells. Impaired IL-17 immunity results in reduced mucocutaneous defenses against C. albicans in humans. In conclusion, we have identified in 2011, the first three genetic etiologies of CMCD with AR IL-17RA and AD IL-17F deficiencies and gain-of-function STAT1 mutations, all associated with an impaired IL-17-dependent immunity. Gain-of-function STAT1 mutations represent the most frequent genetic cause of CMCD with a total of 94 patients reported in the literature since 2011. We have shown that CMCD is a primary immunodeficiency associated with inborn errors of IL-17 immunity. This work has important implications in the field of immunology with the description and characterization of the biological mechanisms involved in protective immunity specific to C. albicans and a better understanding of the pathophysiological mechanisms associated with increased susceptibility to fungal infections in natural conditions of infection, and in the medical field, with the possibility of molecular diagnostics, genetic counseling for a positive diagnosis, and a better follow-up of the patients.