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1.
J Clin Immunol ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388879

RESUMO

While widespread genome sequencing ushers in a new era of preventive medicine, the tools for predictive genomics are still lacking. Time and resource limitations mean that human diseases remain uncharacterized because of an inability to predict clinically relevant genetic variants. A strategy of targeting highly conserved protein regions is used commonly in functional studies. However, this benefit is lost for rare diseases where the attributable genes are mostly conserved. An immunological disorder exemplifying this challenge occurs through damaging mutations in RAG1 and RAG2 which presents at an early age with a distinct phenotype of life-threatening immunodeficiency or autoimmunity. Many tools exist for variant pathogenicity prediction, but these cannot account for the probability of variant occurrence. Here, we present a method that predicts the likelihood of mutation for every amino acid residue in the RAG1 and RAG2 proteins. Population genetics data from approximately 146,000 individuals was used for rare variant analysis. Forty-four known pathogenic variants reported in patients and recombination activity measurements from 110 RAG1/2 mutants were used to validate calculated scores. Probabilities were compared with 98 currently known human cases of disease. A genome sequence dataset of 558 patients who have primary immunodeficiency but that are negative for RAG deficiency were also used as validation controls. We compared the difference between mutation likelihood and pathogenicity prediction. Our method builds a map of most probable mutations allowing pre-emptive functional analysis. This method may be applied to other diseases with hopes of improving preparedness for clinical diagnosis.

2.
J Exp Med ; 216(9): 1986-1998, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31235509

RESUMO

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.

3.
J Exp Med ; 216(6): 1311-1327, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31040185

RESUMO

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) ß chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rß and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rß expression and function. IL-2Rß loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rß also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

4.
Clin Immunol ; 203: 23-27, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953794

RESUMO

Genetic studies are identifying an increasing number of monogenic causes of Common Variable Immunodeficiency (CVID). Pathogenic variants in the C-terminus of NFKB2 have been identified in the subset of CVID patients whose immunodeficiency is associated with ectodermal dysplasia and central adrenal insufficiency. We describe 2 unrelated CVID pedigrees with 4 cases of pathogenic stop gain variants (c.1903C > T) in the ankyrin repeat domain (ARD) of NF-κB2, leading to a premature truncation of the protein at p.Arg635Term (R635X). By immunophenotyping and functional ex vivo B- and T-cell experiments we characterized the variant by reduced class-switched memory B-cell counts and immature plasmablasts, unable to produce IgG and IgA. Features of a poor proliferative T-cell response and reduced expansion of CD4+CXCR5+ T cells was only observed in the two clinically affected index cases without any clear clinical correlate. In conclusion, pathogenic stop variants in the ARD of NFKB2 can cause 'infection-only' CVID with an abnormal B-cell phenotype and a variable clinical penetrance.

7.
J Allergy Clin Immunol ; 142(4): 1285-1296, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29477724

RESUMO

BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

9.
Blood ; 123(6): 863-74, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24345756

RESUMO

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.


Assuntos
Linfócitos B/patologia , Células Dendríticas/patologia , Fator de Transcrição GATA2/genética , Células Matadoras Naturais/patologia , Monócitos/patologia , Mutação/genética , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Evolução Clonal , Estudos Transversais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Linhagem , Prognóstico , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/metabolismo
10.
Curr Opin Immunol ; 25(3): 321-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23747000

RESUMO

Immunity to intracellular pathogens and cancer relies on the generation of robust CD8(+) T cell effector responses as well as the establishment of immunological memory. During a primary immune response CD8(+) T cells experience diverse extracellular environmental cues and cell-cell interactions that trigger downstream transcriptional programs ultimately guiding a CD8(+) T cell to undertake either an effector or a memory cell fate. Here, we discuss our current understanding of the signaling pathways and transcriptional networks that regulate effector and memory commitment in CD8(+) T lymphocytes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula , Regulação da Expressão Gênica , Memória Imunológica/imunologia , Transcrição Genética , Animais , Linfócitos T CD8-Positivos/citologia , Humanos , Transdução de Sinais
11.
Drugs Aging ; 30(7): 503-12, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23605785

RESUMO

Primary immunodeficiency disease (PID) has traditionally been viewed as a group of illnesses seen in the paediatric age group. New advances in diagnosis and treatment have led to an increase in the number of elderly PID patients. However, there is lack of research evidence on which to base clinical management in this group of patients. Management decisions often have to be based therefore on extrapolations from other patient cohorts or from younger patients. Data from the European Society for Immunodeficiencies demonstrates that the vast majority of elderly patients suffer from predominantly antibody deficiency syndromes. We review the management of PID disease in the elderly, with a focus on antibody deficiency disease.


Assuntos
Agamaglobulinemia/tratamento farmacológico , Imunodeficiência de Variável Comum/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Etários , Idoso , Antibacterianos/uso terapêutico , Transplante de Medula Óssea , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/terapia , Terapia Genética , Humanos
12.
Eur J Immunol ; 43(2): 323-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23408319

RESUMO

Prior murine studies have demonstrated the pivotal role that Blimp-1 has in the exhausted phenotype of T lymphocytes in chronic viral infection. In this issue of the European Journal of Immunology, Seddiki et al. [Eur. J. Immunol. 2013. 43: 510-520] demonstrate the applicability of this research to HIV infection. The authors do so by demonstrating differences in Blimp-1 expression between T lymphocytes isolated from patients with chronic active HIV versus those from long-term nonprogressors and showing that this is matched by differences in the cells' capacity to produce IL-2 and the level of expression of the inhibitory receptor PD-1. The data presented here suggest that this may relate to differential regulation of Blimp-1 by the micro RNA, mIR-9. These findings complement current murine work and fit squarely within the research priorities, as outlined by the International AIDS Society, for determining a cure for AIDS.


Assuntos
Infecções por HIV/imunologia , HIV/imunologia , Proteínas Repressoras/imunologia , Animais , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Repressoras/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia
13.
Proc Natl Acad Sci U S A ; 109(33): E2223-9, 2012 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-22745171

RESUMO

During the primary response, the commitment of the CD8(+) T cell to Blimp-1 expression and the terminal differentiation that Blimp-1 induces must be timed so as not to impair the process of clonal expansion. We determined whether the Hippo pathway, which links cell-cell contact to differentiation in other cell lineages, controls Blimp-1 expression. Activating the CD8(+) T cell with antigen and IL-2 causes expression of the core Hippo pathway components, including the pivotal transcriptional cofactor Yap. Contact between activated CD8(+) T cells induces Hippo pathway-mediated Yap degradation and Blimp-1 expression; a Hippo-resistant, stable form of Yap suppresses Blimp-1 expression. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and CD80 comprise the receptor-ligand pair that mediates contact-dependent Hippo pathway activation. In vivo, CD8(+) T cells expressing Hippo resistant-Yap or lacking CTLA-4 have diminished expression of the senescence marker, KLRG1, during a viral infection. The CTLA-4/Hippo pathway/Blimp-1 system may couple terminal differentiation of CD8(+) T cell with the magnitude of clonal expansion.


Assuntos
Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/metabolismo , Ativação Linfocitária/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/imunologia , Fatores de Transcrição/metabolismo , Animais , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Membrana Celular/metabolismo , Ativação Enzimática , Ligantes , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo
14.
Adv Immunol ; 111: 47-107, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21970952

RESUMO

Common variable immune deficiency (CVID) is the commonest symptomatic primary immunodeficiency and represents a heterogenous collection of disorders resulting mostly in antibody deficiency and recurrent infections. However, autoimmunity, granulomatous inflammation and malignancy frequently occur as part of the syndrome. The etiology of the condition has been poorly understood although in recent years, significant progress has been made in elucidating genetic mechanisms that can result in a CVID phenotype. In parallel to this, advances in treatment of the condition have also resulted in improved survival and quality of life for patients. There still remains significant work to be done in improving our understanding of the disease. In addition, recognition of the condition remains poor with significant diagnostic delays and avoidable morbidity. In this article, we review CVID with a particular focus on the areas of improving diagnosis and classification, recent developments in understanding the underlying etiology and genetics; and current treatment and monitoring recommendations for patients.


Assuntos
Imunodeficiência de Variável Comum , Imunoglobulinas/deficiência , Antígenos CD19/genética , Antígenos CD20/genética , Receptor do Fator Ativador de Células B/genética , Linfócitos B/classificação , Proteínas de Ciclo Celular/genética , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/epidemiologia , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/fisiopatologia , Estudo de Associação Genômica Ampla , Humanos , Imunoglobulinas/administração & dosagem , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Receptores de Complemento 3d/genética , Linfócitos T/classificação , Tetraspanina 28/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética
16.
Proc Natl Acad Sci U S A ; 103(51): 19454-9, 2006 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-17159138

RESUMO

The clonal expansion of antigen-specific CD8+ T cells in response to microbial infections is essential for adaptive immunity. Although IL-2 has been considered to be primarily responsible for this process, quantitatively normal expansion occurs in the absence of IL-2 receptor signaling. Here, we show that ligating CD27 on CD8+ T cells that have been stimulated through the T cell receptor causes their expansion in the absence of IL-2 by mediating two distinct cellular processes: enhancing cell cycling and promoting cell survival by maintaining the expression of IL-7 receptor alpha. This pathway for clonal expansion of the CD8+ T cell is not associated with the development of a capacity either for production of IFN-gamma or for cytotoxic T lymphocyte function and, therefore, is uncoupled from differentiation. Furthermore, ligating CD27 increases the threshold concentration at which IL-2 induces IFN-gamma-producing capability by the CD8+ T cell, suggesting that CD27 signaling may suppress effector differentiation. Finally, CD8+ T cells that have been stimulated by the TCR/CD27 pathway maintain their capacity for subsequent expansion and effector differentiation in response to a viral challenge in vivo. Thus, the TCR/CD27 pathway enables the CD8+ T cell to replicate by a process of self-renewal, which may contribute to the continuous generation of new effector CD8+ T cells in persistent viral infections.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/fisiologia , Proliferação de Células , Transdução de Sinais/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Camundongos , Receptores de Interleucina-7/metabolismo
17.
Immunol Rev ; 211: 104-18, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16824121

RESUMO

Clones of CD8+ T cells that have been selected in the primary response must have a mechanism by which they can continuously or intermittently generate new effector cells. Several years ago, this mechanism was proposed to involve a self-renewing, stem cell-like subset that could avoid the differentiating effects of interleukin-2 (IL-2). The model considered the stem cell subset to be contained within the central memory population of CD8+ T cells (T(CM)). This proposal was inconsistent with subsequent findings suggesting that all antigen-activated CD8+ T cells differentiated to effector cells (T(EFF)) during the primary response and that T(CM) developed during the memory phase by de-differentiating from effector memory cells (T(EM)). However, findings have since been reported that support the stem cell model. First, studies indicate that T(EM) do not serve as the precursors of T(CM). Second, transcriptional repressors of IL-2 signaling do enhance the memory response. Third, memory cells lacking effector functions and with a capacity to replicate in a secondary response develop in the absence of signaling through the IL-2/IL-15 receptor. Taken together, these findings suggest that antigen-activated CD8+ T cells with a stem cell-like capability for maintaining proliferative potential develop by an unknown IL-2-independent process. The challenge is now to identify this unknown pathway of clonal expansion.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Interleucina-2/imunologia , Animais , Humanos , Interleucina-15/imunologia , Selectina L/imunologia , Camundongos , Receptores CCR7 , Receptores de Quimiocinas/imunologia
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