RESUMO
Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
Assuntos
Proteínas de Ligação a DNA/deficiência , Mutação em Linhagem Germinativa , Mutação com Perda de Função , Transtornos Linfoproliferativos/genética , Proteínas Proto-Oncogênicas/deficiência , Imunodeficiência Combinada Severa/genética , Aloenxertos , Apoptose , Subpopulações de Linfócitos B/patologia , Técnicas de Reprogramação Celular , Códon sem Sentido , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Dioxigenases , Evolução Fatal , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Recém-Nascido , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Masculino , Mutação de Sentido Incorreto , Neoplasias Primárias Múltiplas/genética , Linhagem , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Imunodeficiência Combinada Severa/patologia , Subpopulações de Linfócitos T/patologia , Sequenciamento do ExomaRESUMO
OBJECTIVE: The objective of this study was to map evidence of the association of ABO blood groups with allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and asthma. DESIGN: A scoping review. DATA SOURCES: PubMed, Scopus, Direct Open Access Journal, Medline, Cumulative Index to Nursing and Allied Health Literature, ScienceDirect and SpringerLink were searched from October 2017 until May 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We selected all types of studies including case-control studies, prospective or retrospective cohort studies, cross-sectional studies and experimental studies, and we included reviews such as literature reviews, systematic reviews with or without meta-analysis and scoping reviews that were published in English and associated the ABO blood group with the three allergic diseases (asthma, AR and AD) in humans of all age groups. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened the titles and abstracts and assessed the full-text articles of the abstracts that met the eligibility requirements. Data from the included studies were extracted, evaluated and reported in the form of narrative synthesis. RESULTS: Of the 10 246 retrieved titles, only 14 articles were selected for a scoping review based on the eligibility criteria. The majority of the studies demonstrated a significant association between ABO blood groups and allergic diseases. We found that blood group O is prominent in patients with AR and asthma, while a non-O blood group is common in patients with AD. CONCLUSION: This scoping review serves as preliminary evidence for the association of ABO blood groups with allergic diseases. Further studies need to be conducted so that the relationship between ABO blood groups and allergic diseases can be fully established. This could be helpful for clinicians and health professionals in consulting and managing patients who suffer from allergic diseases in the future.