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Nat Commun ; 10(1): 4364, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554793


Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/ß-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.

J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643


BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

Science ; 349(6246): 436-40, 2015 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-26206937


Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)-immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.

Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doenças Autoimunes/tratamento farmacológico , Antígeno CTLA-4/deficiência , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunoconjugados/uso terapêutico , Abatacepte , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Doenças Autoimunes/metabolismo , Antígeno CTLA-4/genética , Criança , Cloroquina/farmacologia , Imunodeficiência de Variável Comum/metabolismo , Endossomos/metabolismo , Feminino , Fatores de Transcrição Forkhead/análise , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/metabolismo , Ativação Linfocitária , Lisossomos/metabolismo , Masculino , Proteólise , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Adulto Jovem
J Allergy Clin Immunol ; 133(6): 1667-75, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24797421


BACKGROUND: Autosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking. OBJECTIVE: We investigated whether reversions contributed to the variable disease expression. METHODS: Patients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets. RESULTS: We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation. CONCLUSIONS: In patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time.

Fatores de Troca do Nucleotídeo Guanina/genética , Síndromes de Imunodeficiência/genética , Mutação , Fenótipo , Adolescente , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Reparo do DNA , Genótipo , Mutação em Linhagem Germinativa , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/mortalidade , Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
Pediatr Blood Cancer ; 51(5): 706-9, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18615703


Immunodeficient patients are at an increased risk of developing Epstein-Barr virus (EBV) associated lymphomas. We report a patient with X-linked severe combined immunodeficiency (X-SCID), who presented with an EBV-negative, B-cell non-Hodgkin lymphoma. The tumor did not resolve with chemotherapy or rituximab, but only after recovery of functional donor T-cells cell following hematopoietic stem cell transplantation (HSCT). This case illustrates that the cancer predilection associated with immunodeficient hosts may not be a specific immune defect in the recognition of viral specific antigens, and it could be a defect in immune surveillance necessary for elimination of cells with abnormalities in proliferation, function and/or apoptosis.

Herpesvirus Humano 4/imunologia , Vigilância Imunológica , Linfoma de Células B/etiologia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/imunologia , Antineoplásicos/uso terapêutico , Transplante de Medula Óssea , Humanos , Lactente , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Masculino