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1.
Immunity ; 36(5): 769-81, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22608497

RESUMO

The coordination of nutrient and energy availability with cell growth and division is essential for proper immune cell development and function. By using a chemical mutagenesis strategy in mice, we identified a pedigree that has a complete block in B cell development at the pre-B cell stage resulting from a deletion in the Fnip1 gene. Enforced expression of an immunoglobulin transgene failed to rescue B cell development. Whereas essential pre-B cell signaling molecules were activated normally in Fnip1-null pre-B cells, the metabolic regulators AMPK and mTOR were dysregulated, resulting in excessive cell growth and enhanced sensitivity to apoptosis in response to metabolic stress (pre-B cell receptor crosslinking, oncogene activation). These results indicate that Folliculin-interacting protein 1 (Fnip1) is vital for B cell development and metabolic homeostasis and reveal a metabolic checkpoint that may ensure that pre-B cells have sufficient metabolic capacity to support division, while limiting lymphomagenesis caused by deregulated growth.


Assuntos
Linfócitos B/citologia , Linfócitos B/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Diferenciação Celular/genética , Estrona/genética , Estrona/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Animais , Apoptose/genética , Divisão Celular/genética , Hematopoese/genética , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/metabolismo , Camundongos , Camundongos Transgênicos , Células Precursoras de Linfócitos B/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
2.
J Proteome Res ; 19(1): 346-359, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31618575

RESUMO

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that (1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or (2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2, and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin, or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.


Assuntos
Proteínas de Fase Aguda/análise , Doença de Lyme/sangue , Adulto , Idoso , Biomarcadores/sangue , Western Blotting , Estudos de Casos e Controles , Eritema Migrans Crônico/sangue , Eritema Migrans Crônico/etiologia , Feminino , Humanos , Imunidade Inata , Doença de Lyme/tratamento farmacológico , Doença de Lyme/etiologia , Doença de Lyme/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Especificidade de Órgãos
3.
PLoS Genet ; 13(4): e1006675, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28448578

RESUMO

The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.


Assuntos
Adaptação Fisiológica/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Genoma Humano , Seleção Genética/genética , Altitude , Sistema Enzimático do Citocromo P-450/genética , Feminino , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Masculino , Anotação de Sequência Molecular , Proteínas/genética , Receptores de Calcitriol/genética , Tibet
4.
Proc Natl Acad Sci U S A ; 112(11): 3576-81, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25730879

RESUMO

We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Predisposição Genética para Doença , Variação Genética , Neurônios/fisiologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Transdução de Sinais/genética , População Branca/genética
5.
Alzheimers Dement ; 10(5 Suppl): S277-S283.e10, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24239249

RESUMO

BACKGROUND: A mutation in presenilin 1 (E280A) causes early-onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics. METHODS: We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity-by-descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation. RESULTS: All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2-12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11-25) generations ago. We infer a western European geographic origin of the shared haplotype. CONCLUSIONS: The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Mutação , Presenilina-1/genética , Idade de Início , Colômbia , Efeito Fundador , Haplótipos , Humanos , Padrões de Herança , População Branca/genética
6.
Hum Genome Var ; 3: 15060, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27081563

RESUMO

Currently, the best clinical predictor for inflammatory bowel disease (IBD) is family history. Over 163 sequence variants have been associated with IBD in genome-wide association studies, but they have weak effects and explain only a fraction of the observed heritability. It is expected that additional variants contribute to the genomic architecture of IBD, possibly including rare variants with effect sizes larger than the identified common variants. Here we applied a family study design and sequenced 38 individuals from five families, under the hypothesis that families with multiple IBD-affected individuals harbor one or more risk variants that (i) are shared among affected family members, (ii) are rare and (iii) have substantial effect on disease development. Our analysis revealed not only novel candidate risk variants but also high polygenic risk scores for common known risk variants in four out of the five families. Functional analysis of our top novel variant in the remaining family, a rare missense mutation in the ubiquitin ligase TRIM11, suggests that it leads to increased nuclear factor of kappa light chain enhancer in B-cells (NF-κB) signaling. We conclude that an accumulation of common weak-effect variants accounts for the high incidence of IBD in most, but not all families we analyzed and that a family study design can identify novel rare variants conferring risk for IBD with potentially large effect size, such as the TRIM11 p.H414Y mutation.

7.
Front Genet ; 6: 45, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25741365

RESUMO

The identification of DNA copy numbers from short-read sequencing data remains a challenge for both technical and algorithmic reasons. The raw data for these analyses are measured in tens to hundreds of gigabytes per genome; transmitting, storing, and analyzing such large files is cumbersome, particularly for methods that analyze several samples simultaneously. We developed a very efficient representation of depth of coverage (150-1000× compression) that enables such analyses. Current methods for analyzing variants in whole-genome sequencing (WGS) data frequently miss copy number variants (CNVs), particularly hemizygous deletions in the 1-100 kb range. To fill this gap, we developed a method to identify CNVs in individual genomes, based on comparison to joint profiles pre-computed from a large set of genomes. We analyzed depth of coverage in over 6000 high quality (>40×) genomes. The depth of coverage has strong sequence-specific fluctuations only partially explained by global parameters like %GC. To account for these fluctuations, we constructed multi-genome profiles representing the observed or inferred diploid depth of coverage at each position along the genome. These Reference Coverage Profiles (RCPs) take into account the diverse technologies and pipeline versions used. Normalization of the scaled coverage to the RCP followed by hidden Markov model (HMM) segmentation enables efficient detection of CNVs and large deletions in individual genomes. Use of pre-computed multi-genome coverage profiles improves our ability to analyze each individual genome. We make available RCPs and tools for performing these analyses on personal genomes. We expect the increased sensitivity and specificity for individual genome analysis to be critical for achieving clinical-grade genome interpretation.

8.
PLoS One ; 10(5): e0127045, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25996915

RESUMO

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.


Assuntos
Hemiplegia/genética , ATPase Trocadora de Sódio-Potássio/genética , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Hemiplegia/fisiopatologia , Humanos , Lactente , Masculino , Sistema de Registros
9.
Am J Med Genet ; 110(2): 144-52, 2002 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12116252

RESUMO

Van Buchem disease is an autosomal recessive sclerosing bone dysplasia characterized by skeletal hyperostosis, overgrowth of the mandible, and a liability to entrapment of the seventh and eighth cranial nerves. The genetic determinant maps to chromosome 17q12-q21. We refined the critical interval to the < 1-Mb region between D17S2250 and D17S2253 in 15 affected individuals, all of whom shared a common disease haplotype. Furthermore, we report here the identification of a 52-kb deletion located within the interval and encompassing D17S1789 that is 100% concordant with the disorder. Although the deletion itself does not appear to disrupt the coding region of any known or novel gene(s), the closest flanking genes are MEOX1 on the proximal side, and SOST on the distal side of the deletion. MEOX1 is known to be important for the development of the axial skeleton, whereas the SOST gene is the determinant of sclerosteosis, a disorder that shares many features with van Buchem disease, thus raising the possibility that van Buchem disease results from dysregulation of the expression of one or both of these genes.


Assuntos
Proteínas Morfogenéticas Ósseas , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Marcadores Genéticos , Osteocondrodisplasias/genética , Proteínas Adaptadoras de Transdução de Sinal , África , Sequência de Bases , DNA Intergênico/genética , Feminino , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Países Baixos , Osteocondrodisplasias/patologia , Osteosclerose/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética
10.
Drug Discov Today ; 18(13-14): 637-43, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23579167

RESUMO

In the 1990s there was a tremendous mood of optimism among pharmaceutical scientists that identification of disease-associated variations in the human genome would result in a surge of new drug targets (the 'gene-to-drug' mantra). To date the expected deluge of new drugs has not arrived. However, a small number of drugs arising directly from the study of rare human disorders showing Mendelian inheritance are now entering late stage clinical trials. Here we describe the advantages of this approach and discuss the background and early clinical trial findings with antibodies directed at a target identified in this way.


Assuntos
Anticorpos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Proteínas Morfogenéticas Ósseas/genética , Descoberta de Drogas , Marcadores Genéticos/genética , Hiperostose/tratamento farmacológico , Terapia de Alvo Molecular , Mutação , Osteoporose/tratamento farmacológico , Sindactilia/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal , Animais , Anticorpos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/imunologia , Marcadores Genéticos/imunologia , Predisposição Genética para Doença , Humanos , Hiperostose/genética , Hiperostose/metabolismo , Osteoporose/genética , Osteoporose/metabolismo , Fenótipo , Sindactilia/genética , Sindactilia/metabolismo , Resultado do Tratamento
12.
J Exp Med ; 205(12): 2899-913, 2008 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-19015308

RESUMO

Hem1 (Hematopoietic protein 1) is a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins. Orthologues of Hem1 in Dictyostelium discoideum, Drosophila melanogaster, and Caenorhabditis elegans are essential for cytoskeletal reorganization, embryonic cell migration, and morphogenesis. However, the in vivo functions of mammalian Hem1 are not known. Using a chemical mutagenesis strategy in mice to identify novel genes involved in immune cell functions, we positionally cloned a nonsense mutation in the Hem1 gene. Hem1 deficiency results in defective F-actin polymerization and actin capping in lymphocytes and neutrophils caused by loss of the Rac-controlled actin-regulatory WAVE protein complex. T cell development is disrupted in Hem1-deficient mice at the CD4(-)CD8(-) (double negative) to CD4(+)CD8(+) (double positive) cell stages, whereas T cell activation and adhesion are impaired. Hem1-deficient neutrophils fail to migrate in response to chemotactic agents and are deficient in their ability to phagocytose bacteria. Remarkably, some Rac-dependent functions, such as Th1 differentiation and nuclear factor kappaB (NF-kappaB)-dependent transcription of proinflammatory cytokines proceed normally in Hem1-deficient mice, whereas the production of Th17 cells are enhanced. These results demonstrate that Hem1 is essential for hematopoietic cell development, function, and homeostasis by controlling a distinct pathway leading to cytoskeletal reorganization, whereas NF-kappaB-dependent transcription proceeds independently of Hem1 and F-actin polymerization.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Imunidade Inata/fisiologia , Linfopoese/fisiologia , Proteínas de Membrana , Mutação Puntual , Actinas/metabolismo , Anemia/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/fisiologia , Movimento Celular/fisiologia , Análise Mutacional de DNA , Células-Tronco Hematopoéticas/fisiologia , Sistema Hematopoético/citologia , Sistema Hematopoético/fisiologia , Interferon gama/imunologia , Interleucina-17/metabolismo , Interleucina-2/imunologia , Ativação Linfocitária , Linfopenia/imunologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/fisiologia , Fagocitose/fisiologia , Linfócitos T/citologia , Linfócitos T/fisiologia , Quimeras de Transplante
13.
EMBO J ; 22(23): 6267-76, 2003 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-14633986

RESUMO

There is an unmet medical need for anabolic treatments to restore lost bone. Human genetic bone disorders provide insight into bone regulatory processes. Sclerosteosis is a disease typified by high bone mass due to the loss of SOST expression. Sclerostin, the SOST gene protein product, competed with the type I and type II bone morphogenetic protein (BMP) receptors for binding to BMPs, decreased BMP signaling and suppressed mineralization of osteoblastic cells. SOST expression was detected in cultured osteoblasts and in mineralizing areas of the skeleton, but not in osteoclasts. Strong expression in osteocytes suggested that sclerostin expressed by these central regulatory cells mediates bone homeostasis. Transgenic mice overexpressing SOST exhibited low bone mass and decreased bone strength as the result of a significant reduction in osteoblast activity and subsequently, bone formation. Modulation of this osteocyte-derived negative signal is therapeutically relevant for disorders associated with bone loss.


Assuntos
Desenvolvimento Ósseo/fisiologia , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/fisiologia , Marcadores Genéticos/fisiologia , Osteócitos/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Fosfatase Alcalina/metabolismo , Animais , Sequência de Bases , Densidade Óssea , Doenças Ósseas Metabólicas/genética , Proteína Morfogenética Óssea 6 , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/farmacologia , Linhagem Celular , Clonagem Molecular , Primers do DNA , Marcadores Genéticos/genética , Glicoproteínas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Cinética , Mesoderma/efeitos dos fármacos , Mesoderma/fisiologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Am J Hum Genet ; 75(6): 1032-45, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15514891

RESUMO

Osteoporosis has a strong genetic component, but the genes involved are poorly defined. We studied whether the sclerosteosis/van Buchem disease gene (SOST) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD). Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease. We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and women from a large population-based prospective-cohort study of Dutch whites. A 3-bp insertion (f=0.38) in the presumed SOST promoter region (SRP3) was associated with decreased BMD in women at the femoral neck (FN) (P=.05) and lumbar spine (LS) (P=.01), with evidence of an allele-dose effect in the oldest age group (P=.006). Similarly, a G variant (f=0.40) in the van Buchem deletion region (SRP9) was associated with increased BMD in men at the FN (P=.007) and LS (P=.02). In both cases, differences between extreme genotypes reached 0.2 SD. We observed no genotype effects on fracture risk, for the 234 osteoporotic fractures validated during 8.2 years of follow-up and for the 146 vertebral prevalent fractures analyzed. We did not find association between any of several frequent haplotypes across the SOST gene region and BMD. We did find evidence of additive effects of SRP3 with the COLIA1 Sp1 polymorphism but not with haplotypes of 3' polymorphisms in the vitamin-D receptor gene. The SOST-COLIA1 additive effect increased with age and reached 0.5 SD difference in BMD at LS in the oldest age group (P=.02). The molecular mechanism whereby these moderate SOST genotype effects are mediated remains to be elucidated, but it is likely to involve differences in regulation of SOST gene expression.


Assuntos
Densidade Óssea/genética , Proteínas Morfogenéticas Ósseas/genética , Marcadores Genéticos/genética , Osteoporose/genética , Polimorfismo Genético , Proteínas Adaptadoras de Transdução de Sinal , Idoso , Análise de Variância , Proteínas Morfogenéticas Ósseas/metabolismo , Estudos de Coortes , Primers do DNA , Feminino , Frequência do Gene , Genótipo , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Países Baixos , Razão de Chances , Regiões Promotoras Genéticas/genética , Análise de Regressão , Análise de Sequência de DNA , Traumatismos da Coluna Vertebral/genética , Traumatismos da Coluna Vertebral/patologia , População Branca
15.
J Immunol ; 173(5): 2995-3001, 2004 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15322158

RESUMO

Using a mouse mutagenesis screen, we have identified CD83 as being critical for the development of CD4(+) T cells and for their function postactivation. CD11c(+) dendritic cells develop and function normally in mice with a mutated CD83 gene but CD4(+) T cell development is substantially reduced. Additionally, we now show that those CD4(+) cells that develop in a CD83 mutant animal fail to respond normally following allogeneic stimulation. This is at least in part due to an altered cytokine expression pattern characterized by an increased production of IL-4 and IL-10 and diminished IL-2 production. Thus, in addition to its role in selection of CD4(+) T cells, absence of CD83 results in the generation of cells with an altered activation and cytokine profile.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunoglobulinas/genética , Glicoproteínas de Membrana/genética , Sequência de Aminoácidos , Animais , Antígenos CD , Sequência de Bases , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Células Dendríticas/imunologia , Feminino , Imunoglobulinas/imunologia , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos , Dados de Sequência Molecular , Mutação , Linhagem , Antígeno CD83
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