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Pas de résumé / Chronic mucocutaneous candidiasis (CMC) is seen in human patients with a variety of conditions and refers to recurrent or persistent infection of the skin, nails and/or mucosae by commensal Candida species. Its pathogenesis had long remained elusive, until human genetic studies of rare patients with inherited forms of idiopathic CMC (whether isolated or syndromic), incriminated impaired interleukin (IL)-17A/F immunity. The first genetic etiologies of idiopathic isolated CMC, autosomal dominant (AD) IL-17F and autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiencies, were reported in 2011 in a multiplex and in a sporadic case, respectively. Using Whole Exome Sequencing (WES), we identified 26 novel patients bearing 15 different homozygous mutations in the IL17RA gene. The mutations identified are either nonsense; missense; frameshift deletions; frameshift insertions; or non-coding essential splice site mutations. Interestingly, 2 alleles encode for surface expressed receptors, whereas all the other tested alleles are not detected at the surface of the patient’s cells (fibroblasts or leucocytes). IL-17RA deficiency is a fully penetrant AR disease, with early onset symptoms, usually within the first year of life. CMC is always present. In addition, 17 patients present with staphylococcal skin infections, and some patients with pyogenic infections of the respiratory tract, including pneumonia. Interestingly, tuberculosis occurred in two unrelated BCG-vaccinated patients. The response to IL-17A and IL-17F homo- and heterodimers is abrogated in fibroblasts, as well as the response to IL-17E/IL-25 in T cells. Human IL-17RA is thus essential for mucocutaneous immunity against Candida and Staphylococcus, but otherwise largely redundant. AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both. In a separate project, I investigated a female child patient born to consanguineous parents who suffered from CMC, recurrent viral infections, disseminated BCG disease and biliary cryptosporidiosis, suggestive of combined immunodeficiency, and who is homozygous for a mutation in REL, encoding the NF-kB protein c-REL. Sanger sequencing confirmed that the patient is homozygous and that both parents are heterozygous for the mutation, consistent with an AR inheritance. The candidate mutation is a nucleotide substitution localized in an acceptor splice site; is not reported in available public databases; and is predicted to be damaging in silico. The mutation disrupts mRNA splicing and is loss-of expression. The patient shows normal counts of lymphoid subsets, with the exception of diminished frequencies of memory CD4+ T, Th2, Th1*, and memory B cells. The patient’s T cells fail to proliferate in response to recall antigens. Naïve CD4+ T cells produce little IL-2 and respond poorly to polyclonal stimulation, a phenotype reverted by exogenous IL-2. Memory CD4+ T cells also produce little amounts of IL-2, and strongly diminished amounts of key effector cytokines (IFN-γ, IL-4, IL-17A and IL-21). The patient exhibited with no detectable specific antibody response following vaccination. Survival and therefore proliferation of naïve B cells are compromised leading to poor generation of plasma cell, and immunoglobulins secretion. The patient shows normal counts of myeloid cells, and frequencies of dendritic cell subsets. IL-12 production is abolished in whole blood in response to BCG+IFN-γ and B-EBV cells in response to mitogens. Although further investigation is needed to fully characterize the patient’s phenotype, these results strongly suggest that the patient suffers from AR complete c-REL deficiency.

Submitted by Luis Guilherme Macena (guilhermelg2004@gmail.com) on 2013-04-08T13:34:24Z No. of bitstreams: 1 Ana Luiza Machado Pinto_Dissertação.pdf: 11575246 bytes, checksum: b2a8644ada3f970b5e35478d390a6c3b (MD5) / Made available in DSpace on 2013-04-08T13:34:24Z (GMT). No. of bitstreams: 1 Ana Luiza Machado Pinto_Dissertação.pdf: 11575246 bytes, checksum: b2a8644ada3f970b5e35478d390a6c3b (MD5) Previous issue date: 2011 / Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil / Os fagócitos são elementos fundamentais na resposta imunológica a diversos patógenos. Nas imunodeficiências primárias, defeitos quantitativos ou qualitativos do desenvolvimento do sistema imune, que afetam esta classe de células são responsáveis por um aumento do número de infecções graves ainda na primeira infância, que pode acometer, entre outros sítios, a cavidade oral destes pacientes. Apesar da grande importância clínica, pela gravidade das manifestações e pela cronicidade da doença, as imunodeficiências primárias apresentam dificuldades importantes para o não-especialista, pela sua relativa raridade na população, pela grande heterogeneidade de mecanismos patogênicos, e pela diversidade de apresentações clínicas. Assim, a freqüência e a natureza das manifestações na cavidade oral dependem da natureza do defeito na imunidade, podendo variar consideravelmente de uma doença a outra. No entanto, um estudo detalhado da literatura científica sobre manifestações orais nas diferentes categorias de imunodeficiência primária. Neste trabalho, procuramos suprir parcialmente esta lacuna, fazendo uma revisão sistemática dos relatos de casos das imunodeficiências de células fagocitárias, e estabelecendo a freqüência das manifestações orais e dentárias descrita para esta classe de doenças, com o intuito de aprimorar o olhar do odontólogo na abordagem destes pacientes. Resultados: A presente revisão sistemática do nosso estudo permitiu a avaliação de 1721 pacientes e entre estes pacientes, 653 pacientes (37,9%) apresentaram relato de alguma manifestação oral e/ou dentária na descrição clínica do caso. A doença periodontal foi a manifestação oral mais freqüente (54,5%), seguida da perda precoce de dentes decíduos, encontrada em 142 pacientes (21,7%) e da gengivite, encontrada em 72 pacientes (11,0%), além da presença de aftas (8,1%) e a candidíase oral (7,5%). / Phagocytic cells are essential elements in the host reponse to a wide variety of pathogens. In Primary Immune Deficiency (PID) diseases, quantitative or qualitative defects in the development of the immune system, affecting phagocytes, account for an increase in the number of severe infections in infancy and childhood, which may involve, among other sites, the oral cavity. Despite their great clinical relevance, in view of the diverse manifestations and chronicity of the disease, PID present important practical difficulties for the nonspecialist practicioner, due to their relative scarcity in the general population, great heterogeneity in pathogenetic mechanisms, and diversity of presentation. Therefore, the frequency and nature of oral manifestations depend on the nature of the defect in immunity, varying considerably among specific PID. To our knowledge, there is no systematic study of the existing scientific literature with respect to oral manifestations in different subtypes of PID. In this study, we attempted to fill this gap, by carrying out a systematic review of case reports of PID affecting phagocytes, and establishing the frequency of the different oral and dental manifestations in this group of PID, with the goal of providing dental health professionals with more accurate information concerning these patients. Results: Case reports describing 1721 patients enabled us to detect reports of oral or dental manifestations in the clinical description of 653 pacients (37,9%). Periodontal disease was the most frequent oral manifestation (54,5%), followed by the early loss of decidual teeth, which was found in 142 pacients (21,7%) and gingivitis, found in 72 pacients (11,0%). Ulcerations (8,1%) and oral candidiasis (7,5%) were also reported. This analysis also provided evidence that recent advances in biomedical research, with an increasing focus on molecular analyses, significantly influenced the content of case reports, which are nowadays more often focused on the identification of mutated genes, rather than on the detailed description of clinical findings. As a result, online and computer-assisted information retrieval strategies do not necessarily recover the same references, when articles are searched on the basis of clinical descriptions, or on the basis of well-characterized molecular defects.

L’association entre déficits immunitaires primitifs (DIPs) et manifestations auto-immunes peut sembler paradoxale lorsque l’on aborde les DIPs comme des défauts d’immunité opposés à l’autoimmunité vue comme excès d’immunité adaptative à l’encontre du soi. Néanmoins, loin de se résumer à un simple défaut d’une ou plusieurs composantes du système immunitaire qui prédispose aux infections par divers agents pathogènes, les DIPs sont fréquemment associés à une autoimmunité; parfois révélatrice. Ainsi, les données épidémiologiques issues de registres ou de larges séries de patients atteints de DIPs s’accordent sur une prévalence globale de 25 à 30% de complications auto-immunes (au premier rang desquelles figurent les cytopénies auto-immunes). Différentes hypothèses sont avancées pour rendre compte de l’auto-immunité dans les DIPs. On peut citer : 1°) une perturbation profonde de l’homéostasie lymphocytaire, en particulier dans les déficits immunitaires combinés sévères (CID) avec lymphopénies T et B ; 2°) des défauts intrinsèques des lymphocytes B permettant une rupture de tolérance précoce des LB auto réactifs ; 3°) un comportement aberrant des LT (défaut de maturation, excès d’activation) ; 4°) une absence de lymphocytes T ou de B régulateurs ; 5°) une production inappropriée de certaines cytokines proinflammatoires comme dans les interféronopathies. Ces hypothèses concernent surtout les DIPs pédiatriques sévères. Mon travail de thèse explore la rupture de tolérance immunitaire adaptative au cours des DIPs de l’adulte par différentes approches. Nous nous sommes en particulier attachés au plus fréquent, le DICV (Déficit Immunitaire Commun Variable), déficit immunitaire humoral pas toujours bien défini sur le plan génétique et physiopathologique qui constitue un défi thérapeutique lorsqu’il est compliqué d’une auto-immunité nécessitant un traitement immunosuppresseur. / The association between primary immune deficiency (PID) and autoimmunity may seem paradoxical when PID is considered only as an immune response defect against pathogens and autoimmunity only as an excess of immunity. Nevertheless, far from being simple immune defects increasing the risk of infections, DIPs are frequently associated with autoimmunity. Even more, autoimmunes manifestations can sometimes reveal a PID. Thus, epidemiological data from registers or large series of patients with PIDs agree on an overall prevalence of 25 to 30% of autoimmune complications (with auto-immune cytopenias as first causes). Several hypotheses have been proposed with different underlying mechanisms to explain the tolerance breakdown in PIDs. We can cite : 1°) a severe disturbance of lymphocyte homeostasis, for example in severe combined immunodeficiencies ; 2°) an impaired B-cell developpement with earlystage defects of tolerance ; 3°) a dysregulation of T cells (developpement or activation impairments) ; 4°) a dysfunction of T-reg (or B-reg) ; 5°) an excess of production of proinflammatory cytokines. These hypotheses are especially true for early-onset PIDs (in infancy). In this work (PhD), we explore the mechanisms of tolerance breakdown involved in adults PIDs. We use several approaches to describe the pathways leading to autoimmunity, focusing on the most common PID in adult : CVID (common variable immunodeficiency). This syndrome is not well defined on the genetic and physiopathological level. It is still a therapeutic challenge when complicated by autoimmunity (requiring immunosuppressive therapy).