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1.
Nat Immunol ; 18(7): 813-823, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530713

RESUMO

The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.


Assuntos
Doenças Autoimunes/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Síndromes de Imunodeficiência/genética , Corticosteroides/uso terapêutico , Adulto , Doenças Autoimunes/complicações , Colite/complicações , Colite/genética , Colite/patologia , Feminino , Febre/complicações , Febre/tratamento farmacológico , Febre/genética , Haploinsuficiência , Heterozigoto , Humanos , Síndromes de Imunodeficiência/complicações , Linfopenia/complicações , Linfopenia/genética , Masculino , Pessoa de Meia-Idade , Mutação , Pancitopenia/complicações , Pancitopenia/tratamento farmacológico , Pancitopenia/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Recidiva , Infecções Respiratórias/complicações , Infecções Respiratórias/diagnóstico por imagem , Infecções Respiratórias/genética , Esplenomegalia/complicações , Esplenomegalia/genética , Síndrome , Tomografia Computadorizada por Raios X , Adulto Jovem
2.
J Clin Immunol ; 44(1): 30, 2023 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-38133879

RESUMO

Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.


Assuntos
Receptor gp130 de Citocina , Interleucina-11 , Síndrome de Job , Humanos , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Interleucina-11/metabolismo , Interleucina-6/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT3/metabolismo
3.
Blood ; 128(26): 3020-3021, 2016 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-28034865
4.
Drug Des Devel Ther ; 16: 2901-2917, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36068788

RESUMO

Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation. Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 µg/kg and AZD4604 at 30 µg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]). Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model. Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.


Assuntos
Asma , Inibidores de Janus Quinases , Animais , Asma/metabolismo , Citocinas/metabolismo , Humanos , Janus Quinase 1/metabolismo , Inibidores de Janus Quinases/farmacologia , Pulmão/metabolismo , Ovalbumina , Ratos , Transdução de Sinais
5.
Artigo em Inglês | MEDLINE | ID: mdl-31501268

RESUMO

The lipid and protein phosphatase and tensin homolog (PTEN) controls the differentiation and activation of multiple immune cells. PTEN acts downstream from T- and B-cell receptors, costimulatory molecules, cytokine receptors, integrins, and also growth factor receptors. Loss of PTEN activity in human and mice is associated with cellular and humoral immune dysfunction, lymphoid hyperplasia, and autoimmunity. Although most patients with PTEN hamartoma tumor syndrome (PHTS) have no immunological symptoms, a subclinical immune dysfunction is present in many, and clinical immunodeficiency in few. Comparison of the immune phenotype caused by PTEN haploinsufficiency in PHTS, phosphoinositide 3-kinase (PI3K) gain-of-function in activated PI3K syndrome, and mice with conditional biallelic Pten deletion suggests a threshold model in which coordinated activity of several phosphatases control the PI3K signaling in a cell-type-specific manner. Emerging evidence highlights the role of PTEN in polygenic autoimmune disorders, infection, and the immunological response to cancer. Targeting the PI3K axis is an emerging therapeutic avenue.


Assuntos
Imunidade Adaptativa/genética , Síndrome do Hamartoma Múltiplo/imunologia , Imunidade Inata/genética , PTEN Fosfo-Hidrolase/genética , Animais , Síndrome do Hamartoma Múltiplo/genética , Humanos , Camundongos , PTEN Fosfo-Hidrolase/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/imunologia
6.
Br J Haematol ; 132(3): 255-67, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16409290

RESUMO

Chemokines are a family of over 40 small (8 kDa) related proteins with the function of moving cells along a chemotactic gradient, either to organise cells within an organ or to facilitate the movement of leucocytes around the body. Mouse models have implicated the importance of the chemokine CXCL12 in haematopoiesis and this has lead to the use of the inhibitor AMD3100 for autologous transplantation. This review will briefly discuss the biology of chemokines and their role in haematopoiesis and haematological malignancy together with the possible benefits and hazards of therapeutic modification of the chemokine system.


Assuntos
Quimiocinas/fisiologia , Hematopoese/fisiologia , Leucemia/fisiopatologia , Linfoma/fisiopatologia , Medula Óssea/fisiologia , Adesão Celular/fisiologia , Quimiocina CXCL12 , Quimiocinas/metabolismo , Quimiocinas CXC/metabolismo , Quimiotaxia/fisiologia , Matriz Extracelular/fisiologia , Fatores de Crescimento de Células Hematopoéticas/fisiologia , Humanos , Modelos Biológicos , Receptores de Quimiocinas/metabolismo
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