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1.
Nat Commun ; 13(1): 931, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177641

RESUMO

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1+/- mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac functions. Moreover, we discovered that the FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/- mice by promoting autophagosome-lysosome fusion. Hence, these findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Mitofagia/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/patologia , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/patologia , Córtex Cerebral/citologia , Córtex Cerebral/patologia , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/imunologia , Modelos Animais de Doenças , Feminino , Haploinsuficiência/imunologia , Células HeLa , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/imunologia , Deficiência Intelectual/patologia , Isotretinoína/farmacologia , Isotretinoína/uso terapêutico , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Lisossomos/patologia , Camundongos , Camundongos Transgênicos , Mitofagia/efeitos dos fármacos , Mitofagia/imunologia , Neurônios , Proteínas Nucleares/metabolismo , Cultura Primária de Células
2.
Clin Exp Allergy ; 51(7): 892-901, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33987892

RESUMO

BACKGROUND: Several childhood asthma risk loci that relate to immune function have been identified by genome-wide association studies (GWAS), but the underlying mechanisms remain unknown. OBJECTIVE: Here, we examined whether perturbed innate immune responses mediate the association between known genetic risk variants and development of childhood asthma. METHODS: Peripheral blood mononuclear cells from 336 six-month-old infants from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000 ) cohort were stimulated in vitro with six different innate ligands (LPS, CpG, poly(I:C), R848, HDMAPP and aluminium hydroxide together with low levels of LPS) followed by quantification of 18 released cytokines and chemokines 40 h after the stimulations. The innate immune response profiles were decomposed by principal component (PC) analysis, and PC1-5 were used in mediation analyses of the effect of 25 known genetic risk variants on childhood asthma until age 7. RESULTS: The effects of two variants from the 17q21 locus (rs7216389, rs2305480) on asthma and exacerbation risk were significantly mediated by immune parameters induced in response to ligands mimicking intracellular colonization; bacterial DNA (CpG) and double-stranded viral RNA (poly(I:C)). The Th17 and innate lymphoid cell type 3-amplifying cytokine IL-23 was the most prominent cytokine involved. CONCLUSION: The 17q21 effect on childhood asthma and exacerbations was partly mediated by deregulation of IL-23 in response to intracellular microbial ligands, which may suggest ineffective clearance of intracellular pathogens in the lungs.


Assuntos
Asma/imunologia , Cromossomos Humanos Par 17/imunologia , Imunidade Inata/imunologia , Interleucina-23/imunologia , Células Th17/imunologia , Asma/genética , Cromossomos Humanos Par 17/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imunidade Inata/genética , Lactente , Masculino , Polimorfismo de Nucleotídeo Único
4.
Proc Natl Acad Sci U S A ; 116(19): 9543-9551, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30988175

RESUMO

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.


Assuntos
Antígeno de Maturação de Linfócitos B , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Mieloma Múltiplo , Proteínas de Neoplasias , Receptores de Antígenos Quiméricos , Adolescente , Adulto , Idoso , Autoenxertos , Antígeno de Maturação de Linfócitos B/análise , Antígeno de Maturação de Linfócitos B/genética , Antígeno de Maturação de Linfócitos B/imunologia , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia
5.
Curr Hematol Malig Rep ; 13(2): 69-77, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29480432

RESUMO

PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) has multiple current frontline therapy options, including chemoimmunotherapy (CIT) and most recently, ibrutinib. Here, we review the most recent updates in the frontline treatment of CLL, including updates in CIT, updates in targeted therapies, and ongoing clinical trials. RECENT FINDINGS: Ibrutinib was FDA-approved for the upfront treatment of CLL in 2016 after being studied in older patients and those with 17p deletions or TP53 mutations. The introduction of ibrutinib has dramatically changed the treatment paradigm of CLL. Recent updates in CIT include that immunoglobulin heavy chain variable (IGHV) gene mutation status is strongly predictive of response to CIT. Regarding targeted therapy, next-generation BTK and PI3K inhibitors are currently being studied in the upfront treatment of CLL, which may have less toxicity than their first-generation counterparts. Other novel targeted therapies are being studied in the frontline setting, most notably venetoclax including in combinations, with hopes to achieve chemotherapy-free, time-limited treatment options. Multiple key ongoing phase 3 clinical trials will be answering these important clinical questions.


Assuntos
Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Piperidinas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
6.
Adv Immunol ; 135: 1-52, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28826527

RESUMO

Chromosome 17q21 contains a cluster of genes including ORMDL3 and GSDMB, which have been highly linked to asthma in genome-wide association studies. ORMDL3 is localized to the endoplasmic reticulum and regulates downstream pathways including sphingolipids, metalloproteases, remodeling genes, and chemokines. ORMDL3 inhibits serine palmitoyl-CoA transferase, the rate-limiting enzyme for sphingolipid biosynthesis. In addition, ORMDL3 activates the ATF6α branch of the unfolded protein response which regulates SERCA2b and IL-6, pathways of potential importance to asthma. The SNP-linking chromosome 17q21 to asthma is associated with increased ORMDL3 and GSDMB expression. Mice expressing either increased levels of human ORMDL3, or human GSDMB, have an asthma phenotype characterized by increased airway responsiveness and increased airway remodeling (increased smooth muscle and fibrosis) in the absence of airway inflammation. GSDMB regulates expression of 5-LO and TGF-ß1 which are known pathways involved in the pathogenesis of asthma. GSDMB is one of four members of the GSDM family (GSDMA, GSDMB, GSDMC, and GSDMD). GSDMD (located on chromosome 8q24 and not linked to asthma) has emerged as a key mediator of pyroptosis. GSDMD is a key component of the NLPR3 inflammasome and is required for its activation. GSDMD undergoes proteolytic cleavage by caspase-1 to release its N-terminal fragment, which in turn mediates pyroptosis and IL-1ß secretion. Chromosome 17q21 has not only been linked to asthma but also to type 1 diabetes, inflammatory bowel disease, and primary biliary cirrhosis suggesting that future insights into the biology of genes located in this region will increase our understanding of these diseases.


Assuntos
Asma/imunologia , Diabetes Mellitus Tipo 1/imunologia , Doenças Inflamatórias Intestinais/imunologia , Cirrose Hepática Biliar/imunologia , Proteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Animais , Asma/genética , Asma/patologia , Quimiocinas/genética , Quimiocinas/imunologia , Cromossomos Humanos Par 17/química , Cromossomos Humanos Par 17/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Regulação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/patologia , Proteínas de Membrana/genética , Camundongos , Família Multigênica , Proteínas de Neoplasias/genética , Polimorfismo Genético , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Transdução de Sinais , Esfingolipídeos/imunologia , Esfingolipídeos/metabolismo
7.
Hematology Am Soc Hematol Educ Program ; 2016(1): 137-145, 2016 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-27913472

RESUMO

The advent of novel small-molecule inhibitors has transformed the treatment approaches for patients with chronic lymphocytic leukemia (CLL). These therapies are becoming increasingly used in patients with relapsed disease, patients with 17p deletion, and, as of recently, also in the frontline setting for previously untreated patients with CLL. Moreover, many of these are oral therapies that are significantly less myelosuppressive than chemoimmunotherapy. However, these agents have their own set of unique toxicities with which providers must gain familiarity. There is also ongoing development of second-generation agents which have the promise of less toxicity than the US Food and Drug Administration (FDA)-approved compounds. In addition, immunotherapy and the role of the microenvironment are becoming increasingly important and have therapeutic implications in the treatment of patients with CLL. Ultimately, investigators need to evaluate how to position these and other new exciting therapies and decide on the ultimate role for chemoimmunotherapy in modern times.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Síndrome de Smith-Magenis/terapia , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/imunologia , Aprovação de Drogas , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/imunologia , Microambiente Tumoral/imunologia , Estados Unidos , United States Food and Drug Administration
8.
PLoS One ; 11(11): e0166414, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27835674

RESUMO

Single nucleotide polymorphisms (SNPs) located in the chromosome region 17q12-q21 are risk factors for asthma. Particularly, there are cis-regulatory haplotypes within this region that regulate differentially the expression levels of ORMDL3, GSDMB and ZPBP2 genes. Remarkably, ORMDL3 has been shown to modulate lymphocyte activation parameters in a heterologous expression system. In this context, it has been shown that Th2 and Th17 cytokine production is affected by SNPs in this region. Therefore, we aim to assess the impact of hereditary components within region 17q12-q21 on the activation profile of human T lymphocytes, focusing on the haplotype formed by allelic variants of SNPs rs7216389 and rs12936231. We measured calcium influx and activation markers, as well as the proliferation rate upon T cell activation. Haplotype-dependent differences in mRNA expression levels of IL-2 and INF-γ were observed at early times after activation. In addition, the allelic variants of these SNPs impacted on the extent of calcium influx in resting lymphocytes and altered proliferation rates in a dose dependent manner. As a result, the asthma risk haplotype carriers showed a lower threshold of saturation during activation. Finally, we confirmed differences in activation marker expression by flow cytometry using phytohemagglutinin, a strong polyclonal stimulus. Altogether, our data suggest that the genetic component of pro-inflammatory pathologies present in this chromosome region could be explained by different T lymphocyte activation dynamics depending on individual allelic heredity.


Assuntos
Asma/genética , Cromossomos Humanos Par 17/química , Proteínas do Ovo/imunologia , Ativação Linfocitária/efeitos dos fármacos , Proteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Fito-Hemaglutininas/farmacologia , Alelos , Asma/imunologia , Asma/patologia , Cálcio/imunologia , Cálcio/metabolismo , Proliferação de Células/efeitos dos fármacos , Cromossomos Humanos Par 17/imunologia , Proteínas do Ovo/genética , Expressão Gênica , Predisposição Genética para Doença , Haplótipos , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Pulmão/imunologia , Pulmão/patologia , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Risco , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/patologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/patologia
9.
J Immunol ; 196(6): 2627-36, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26851217

RESUMO

NK cells play a crucial role in innate immunity due to their direct cytotoxicity toward tumors, virally infected cells, and stressed cells, and they also contribute to the orchestration of the adaptive response by their ability to produce immunoregulatory cytokines. In secondary lymphoid organs, NK cells compose the third most abundant lymphocyte subset after T cells and B cells. In this study, we perform an unbiased linkage analysis to determine the genetic loci that may limit the size of the NK cell compartment. Specifically, we exploit differences in NK cell proportion and absolute number between the C57BL/6 and the NOD mice. In addition to the previously identified linkage to chromosome 8, we find that a locus on chromosome 17, which encompasses the MHC locus, impacts NK cell number. Moreover, we identify a locus on mouse chromosome 9 that is strongly linked to the proportion and absolute number of NK cells. Using NOD congenic mice, we validate that both the MHC and the chromosome 9 loci influence the proportion and absolute number of NK cells. We have thus identified additional loci specifically linked to the proportion of NK cells and present some of the potential candidate genes comprised within these loci.


Assuntos
Imunidade Adaptativa/genética , Cromossomos Humanos Par 17/imunologia , Cromossomos Humanos Par 8/imunologia , Cromossomos Humanos Par 9/imunologia , Células Matadoras Naturais/imunologia , Animais , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 9/genética , Citometria de Fluxo , Ligação Genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL/genética , Camundongos Endogâmicos C57BL/imunologia , Camundongos Endogâmicos NOD/genética , Camundongos Endogâmicos NOD/imunologia , Camundongos Transgênicos
10.
FASEB J ; 29(8): 3446-57, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25917331

RESUMO

Multiple sclerosis (MS) is a debilitating autoimmune neuroinflammatory disease influenced by genetics and the environment. MS incidence in female subjects has approximately tripled in the last century, suggesting a sex-specific environmental influence. Recent animal and human studies have implicated dietary sodium as a risk factor in MS, whereby high sodium augmented the generation of T helper (Th) 17 cells and exacerbated experimental autoimmune encephalomyelitis (EAE), the principal model of MS. However, whether dietary sodium interacts with sex or genetics remains unknown. Here, we show that high dietary sodium exacerbates EAE in a strain- and sex-specific fashion. In C57BL6/J mice, exposure to a high-salt diet exacerbated disease in both sexes, while in SJL/JCrHsd mice, it did so only in females. In further support of a genetic component, we found that sodium failed to modify EAE course in C57BL6/J mice carrying a 129/Sv-derived interval on chromosome 17. Furthermore, we found that the high-sodium diet did not augment Th17 or Th1 responses, but it did result in increased blood-brain barrier permeability and brain pathology. Our results demonstrate that the effects of dietary sodium on autoimmune neuroinflammation are sex specific, genetically controlled, and CNS mediated.


Assuntos
Encefalomielite Autoimune Experimental/etiologia , Sódio na Dieta/efeitos adversos , Animais , Barreira Hematoencefálica/metabolismo , Cromossomos Humanos Par 17/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/etiologia , Esclerose Múltipla/imunologia , Fatores de Risco , Caracteres Sexuais , Sódio na Dieta/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
11.
Lancet Respir Med ; 2(8): 621-30, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24835835

RESUMO

BACKGROUND: The relationship between early-life antibiotic use and the development of wheeze and asthma has been reported in several studies but might arise as a consequence of bias rather than causal relationship. We investigated the association between antibiotic prescription and subsequent development of atopy, wheeze, and asthma exacerbations, and the relation of early life antibiotic prescription with anti-infective immunity and genetic variants on asthma susceptibility locus 17q21. METHODS: Children in a population-based birth cohort were followed from birth to age 11 years. Information on antibiotic prescription, wheeze, and asthma exacerbations was extracted from medical records, and the effect of antibiotic prescription assessed with longitudinal analyses. We assessed immune responses of peripheral blood mononuclear cells, taken at age 11 years, to viruses (rhinovirus and respiratory syncytial virus; RSV) and bacteria (Haemophilus influenzae and Streptococcus pneumoniae) in children who either received at least one or no antibiotic prescriptions in infancy. Finally, we assessed the association of 17q21 polymorphisms with antibiotic prescription. FINDINGS: Of 984 families who gave consent, we extracted data for 916 children. We noted significantly higher risk of physician-confirmed wheezing after antibiotic prescription (hazard ratio [HR] 1·71, 95% CI 1·32-2·23; p<0·0001) and severe wheeze or asthma exacerbation after antibiotic prescription (HR 2·26, 95% CI 1·03-4·94; p=0·041). In children who wheezed, the hazards of exacerbations (2·09, 1·51-2·90; p<0·0001) and admissions to hospital (2·64, 1·49-4·70; p=0·0009) were significantly increased in the 2 years after the first antibiotic prescription. Children who received antibiotics in infancy had significantly lower induction of cytokines, which are important in host defence against virus infections to both RSV and rhinovirus; there were no differences in antibacterial responses. Variants in 17q21 were associated with an increased risk of early life antibiotic prescription. INTERPRETATION: The association between antibiotics and asthma might arise through a complex confounding by indication. Hidden factors that may increase the likelihood of both early life antibiotic prescription and later asthma are an increased susceptibility to viral infections consequent upon impaired antiviral immunity and genetic variants on 17q21. FUNDING: Moulton Charitable Foundation and Medical Research Council.


Assuntos
Antibacterianos/efeitos adversos , Asma/etiologia , Cromossomos Humanos Par 17 , Leucócitos Mononucleares/imunologia , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Sons Respiratórios/etiologia , Fatores Etários , Células Cultivadas , Criança , Pré-Escolar , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/imunologia , Progressão da Doença , Prescrições de Medicamentos/estatística & dados numéricos , Proteínas do Ovo/genética , Seguimentos , Genótipo , Haemophilus influenzae/imunologia , Humanos , Lactente , Recém-Nascido , Leucócitos Mononucleares/efeitos dos fármacos , Proteínas de Membrana/genética , Estudos Prospectivos , Rhinovirus/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Testes Cutâneos , Streptococcus pneumoniae/imunologia , Inquéritos e Questionários
12.
Ann Allergy Asthma Immunol ; 108(6): 402-411.e9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22626592

RESUMO

BACKGROUND: Although an association between 17q12-21 and asthma has been replicated across different populations, some inconsistencies have been found between different studies. OBJECTIVE: We investigated the association between genetic variation in this region with asthma, lung function, airway inflammation, hyperresponsiveness (AHR), and atopy in a case-control study of United Kingdom adults. The interaction between genotype and smoking was also evaluated. METHODS: Study subjects (n = 983) were carefully phenotyped using questionnaires, measurement of lung function, AHR (methacholine challenge), exhaled nitric oxide (eNO), and assessment of atopic status. Blood/saliva/buccal swabs were collected, and 47 single nucleotide polymorphisms (SNPs) in 17q12-21 were genotyped using MALDI-TOF (Matrix-assisted LASER desorption/ionisation-time of flight) mass spectrometry. We conducted a comprehensive investigation of 28 common SNPs within 6 genes of interest (IKZF3, ZPBP2, ORMDL3, GSDMA, GSDMB, TOP2A). RESULTS: Sixteen SNPs were significantly associated with asthma after multiple testing correction (P ≤ .01), of which 5 (rs2290400, rs8079416, rs3894194, rs7212938, and rs3859192) were strongly associated (FDR P ≤ .0002), and one was novel (IKZF3-rs1453559). For 3 of these SNPs, we found significant interaction with smoking and asthma (rs12936231, rs2290400, and rs8079416). Smoking modified the associations between 8 SNPs and lung function (rs9911688, rs9900538, rs1054609, rs8076131, rs3902025, rs3859192, rs11540720, and rs11650680). We observed significant interaction between 5 SNPs and smoking on AHR, and 3 interacted with smoking in relation to asthma with AHR (rs4795404, rs4795408, rs3859192). CONCLUSION: We found 1 novel association and replicated several previously reported associations between 17q12-21 polymorphisms and asthma. We demonstrated significant interactions between active smoking and polymorphisms in 17q12-21 with asthma, lung function, and AHR in adults. Our data confirm that 17q12-21 is an important asthma susceptibility locus.


Assuntos
Asma/genética , Cromossomos Humanos Par 17/genética , Loci Gênicos/imunologia , Pulmão/efeitos dos fármacos , Fumar/efeitos adversos , Adulto , Idoso , Asma/imunologia , Asma/fisiopatologia , Estudos de Casos e Controles , Cromossomos Humanos Par 17/imunologia , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Desequilíbrio de Ligação , Pulmão/imunologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória , Fumar/imunologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Inquéritos e Questionários , Reino Unido
13.
Hematology ; 10(2): 135-9, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16019459

RESUMO

T-cell receptor Vss gene repertoire and clonality have been studied in patients with leukemia and solid tumors, by assaying the CDR3 size of TCR genes, using RT-PCR and genescan analysis. Few studies have studied leukemia-associated oligoclonal expanded T-cells in leukemia, therefore, the aim of this study was to investigate the distribution and clonal expansion of T-cell receptor, Vss subfamily T-cells in patients with acute promyelocytic leukemia (APL) with t(15;17). The CDR3 of TCR Vbeta24 subfamily genes were analyzed in peripheral blood mononuclear cells from 17 cases with PML-RARalpha+ APL using RT-PCR and genescan technique. Ten normal individuals served as controls. The results showed that the number of expressed Vss subfamilies (from 2 to 21 subfamilies) varied in different patients with APL. The most frequently expressed Vss subfamilies were Vbeta2 (64.7%), Vbeta15 (58.8%), Vbeta3 and Vbeta5 (47.1%), with a lower expression rate found in Vbeta11 and Vbeta20 (11.7%). Clonally expanded T-cells in the Vss subfamilies could be identified in patients with APL in all but two of the cases studied, predominantly in Vbeta10, Vbeta23, Vbeta3 and Vbeta21. In conclusion, skewed distribution and clonal expansion of TCR Vss subfamily T-cells could be found in patients with APL. The clonal expansion of T-cells were considered to be a specific anti-leukemic immune response by host T-cells activated by the leukemia-associated-antigen.


Assuntos
Regulação Leucêmica da Expressão Gênica/genética , Rearranjo Gênico do Linfócito T/genética , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Leucemia Promielocítica Aguda/genética , Adolescente , Adulto , Criança , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/imunologia , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/imunologia , Feminino , Regulação Leucêmica da Expressão Gênica/imunologia , Rearranjo Gênico do Linfócito T/imunologia , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/imunologia , Humanos , Leucemia Promielocítica Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Translocação Genética/genética , Translocação Genética/imunologia
14.
J Immunol ; 159(3): 1140-9, 1997 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-9233607

RESUMO

By searching the expressed sequence tag (EST) database, we identified partial cDNA sequences encoding a polypeptide with significant sequence identity to the human CC chemokine macrophage-inflammatory protein-1 alpha (MIP-1 alpha)/LD78 alpha. We determined the complete cDNA sequence that contained a reading frame of 89 amino acids with 61% identity to human MIP-1 alpha/LD78 alpha. The mRNA was expressed constitutively at high levels in human lung and at low levels in some lymphoid tissues. Furthermore, the mRNA was strongly induced in several human cell lines, including monocytic U937 cells, by PMA. From these results, we designated this novel CC chemokine as PARC from pulmonary and activation-regulated chemokine. In situ hybridization analyses showed that alveolar macrophages, follicular dendritic cells in the germinal centers of regional lymph nodes, and peripheral blood monocytes stimulated with LPS express PARC mRNA. Using the human CC chemokine yeast artificial chromosome contig that we constructed recently, we mapped the PARC gene (SCYA18) within one of the two subregions of the CC chemokine gene cluster at chromosome 17q11.2. To investigate its biologic activity, the PARC protein was expressed in insect cells. PARC was chemotactic for both activated (CD3+) T cells and nonactivated (CD14-) lymphocytes, but not for monocytes or granulocytes. Binding analysis using PARC fused with alkaline phosphatase-(His)6 showed the presence of a single class of receptors for PARC on lymphocytes with a Kd of 1.9 nM and 590 sites/cell. Thus, PARC is a novel CC chemokine with a close phylogenic relationship with MIP-1 alpha/LD78 alpha, but with a highly selective activity on lymphocytes.


Assuntos
Quimiocinas CC , Quimiocinas/isolamento & purificação , Quimiotaxia de Leucócito/imunologia , Proteínas Inflamatórias de Macrófagos/química , Monócitos/fisiologia , Linfócitos T/fisiologia , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Quimiocina CCL4 , Quimiocinas/química , Quimiocinas/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 17/imunologia , Clonagem Molecular , DNA Complementar/isolamento & purificação , Humanos , Hibridização In Situ , Melanoma , Dados de Sequência Molecular , Família Multigênica/imunologia , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , RNA Mensageiro/biossíntese , Receptores de Citocinas/química , Linfócitos T/metabolismo , Células Tumorais Cultivadas
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