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1.
Nat Immunol ; 15(8): 727-37, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24952505

RESUMO

Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adaptor ASC and the assembly of ASC specks. ASC specks recruit and activate caspase-1, which induces maturation of the cytokine interleukin 1ß (IL-1ß) and pyroptotic cell death. Here we found that after pyroptosis, ASC specks accumulated in the extracellular space, where they promoted further maturation of IL-1ß. In addition, phagocytosis of ASC specks by macrophages induced lysosomal damage and nucleation of soluble ASC, as well as activation of IL-1ß in recipient cells. ASC specks appeared in bodily fluids from inflamed tissues, and autoantibodies to ASC specks developed in patients and mice with autoimmune pathologies. Together these findings reveal extracellular functions of ASC specks and a previously unknown form of cell-to-cell communication.


Assuntos
Apoptose/imunologia , Caspase 1/imunologia , Proteínas do Citoesqueleto/imunologia , Inflamação/imunologia , Interleucina-1beta/imunologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Anticorpos/imunologia , Proteínas Reguladoras de Apoptose , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Transporte/genética , Caspase 1/genética , Inibidores de Caspase/farmacologia , Comunicação Celular/imunologia , Proteínas do Citoesqueleto/genética , Humanos , Inflamassomos/imunologia , Lisossomos/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fagocitose/imunologia , Príons/química , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Transdução de Sinais/imunologia
2.
Ann Rheum Dis ; 83(2): 184-193, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-37890976

RESUMO

OBJECTIVES: Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primary care physicians, specialists and patients in Germany. METHODS: This prospective non-randomised multicentre study involved 2340 primary care physicians, 72 rheumatologists, 4 university hospitals and 4 rheumatology centres in 4 German Federal States. The two coprimary endpoints (time to diagnosis and screening performance of primary care physicians) were evaluated for early versus late implementation phase. Additionally, time to diagnosis and secondary endpoints (decrease of disease activity, increase in quality of life and overall well-being, improvement of fatigue, depression, functional ability, and work ability, reduction in drug and medical costs and hospitalisation) were compared with a reference cohort of the German Rheumatism Research Centre (DRFZ) reflecting standard care. RESULTS: A total of 7049 patients were enrolled in the coordination centres and 1537 patients were diagnosed with a rheumatic disease and consented to further participation. A follow-up consultation after 1 year was realised in 592 patients. The time to diagnosis endpoint and the secondary endpoints were met. In addition, the calculation of cost-effectiveness shows that Rheuma-VOR has a dominant cost-benefit ratio compared with standard care. DISCUSSION: Rheuma-VOR has shown an improvement in rheumatological care, patient-reported outcome parameters and cost savings by coordinating the cooperation of primary care physicians, rheumatologists and patients, in a nationwide approach.


Assuntos
Artrite Reumatoide , Doenças Reumáticas , Humanos , Artrite Reumatoide/diagnóstico , Qualidade de Vida , Estudos Prospectivos , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/terapia , Atenção à Saúde
3.
Int Arch Allergy Immunol ; 183(3): 337-349, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34619682

RESUMO

INTRODUCTION: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders characterized by increased susceptibility to infections, immune dysregulation, and/or malignancy. Genetic studies, especially during the last decade, led to a better understanding of the pathogenesis of primary immunodeficiencies and contributed to their classification into distinct monogenic disorders falling under one of the >430 currently known inborn errors of immunity (IEI). The growing availability of molecular genetic testing resulted in the increasing identification of patients with IEI. Here, we evaluated the diagnostic yield and the clinical consequences of targeted next-generation sequencing (tNGS) in a cohort of 294 primary immunodeficiency patients, primarily consisting of cases with sporadic primary antibody deficiency. METHOD: We have custom designed a tNGS panel to sequence a cohort of PID patients. Agilent's HaloPlex Target Enrichment System for Illumina was used for DNA target enrichment. RESULTS: tNGS identified a definite or predicted pathogenic variant in 15.3% of patients. The highest diagnostic rate was observed among patients with combined immunodeficiency or immune dysregulation, for whom genetic diagnosis may affect therapeutic decision-making. CONCLUSION: Next-generation sequencing has changed diagnostic assignment and paved the way for targeted therapeutic intervention with agents directed at reverting the disease-causing molecular abnormality or its pathophysiological consequences. Therefore, such targeted therapies and identifying the genetic basis of PID can be essential for patients with manifested immune dysregulation as conventional immunomodulatory regimens may exert an immunosuppressive effect, aggravating their immunodeficiency or may only inadequately control autoimmune or lymphoproliferative manifestations.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Estudos de Coortes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/terapia
4.
Ann Rheum Dis ; 80(3): 392-399, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33046446

RESUMO

OBJECTIVES: Treatment of rheumatic diseases requires immunomodulatory agents which can compromise antibody production. However, even in case of agents directly targeting B cells, a minority of patients develop hypogammaglobulinaemia, suggesting a genetic predisposition, which has not been investigated so far. The phenotypic overlap between primary immunodeficiency disorders (PIDs) and rheumatic diseases suggests a shared genetic basis, especially in case of patients with rheumatic diseases with hypogammaglobulinaemia. METHODS: 1008 patients with rheumatic diseases visiting the outpatient clinics of the Hannover University Hospital were screened for hypogammaglobulinaemia. Those with persistent hypogammaglobulinaemia and an equal number of patients without it underwent targeted next-generation sequencing, searching for variations in genes linked with hypogammaglobulinaemia in the context of PIDs. RESULTS: We identified 33 predicted pathogenic variants in 30/64 (46.9%) patients with persistent secondary hypogammaglobulinaemia. All 33 variants were monoallelic and 10 of them in 10/64 (15.6%) patients were found in genes associated with autosomal dominant PIDs. 2/64 (3.1%) patients harboured variants which were previously reported to cause PIDs. In the group without hypogammaglobulinaemia we identified seven monoallelic variants in 7/64 (10.9%), including a variant in a gene associated with an autosomal dominant PID. CONCLUSIONS: Approximately half of patients with persistent secondary hypogammaglobulinaemia harboured at least a variant in a PID gene. Despite the fact that previous immunomodulatory treatment is an exclusion criterion in the diagnosis of PIDs, we identified genetic variants that can account for PID in patients with clear rheumatic phenotypes who developed hypogammaglobulinaemia after the introduction of immunomodulatory treatment. Our data suggest the common genetic causes of primary and secondary hypogammaglobulinaemia.


Assuntos
Agamaglobulinemia , Doenças Reumáticas , Agamaglobulinemia/genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Doenças Reumáticas/genética
5.
Ann Rheum Dis ; 80(12): 1537-1544, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34226189

RESUMO

OBJECTIVES: The monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses. METHODS: CD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens. RESULTS: Rituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I. CONCLUSIONS: Depending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunogenicidade da Vacina/imunologia , Vacinas contra Influenza/imunologia , Interferon Tipo I/imunologia , Rituximab/efeitos adversos , Animais , Estudos de Casos e Controles , Citocinas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Camundongos , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/imunologia , Vacínia/imunologia , Vaccinia virus/imunologia
6.
J Immunol ; 203(4): 795-800, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31292215

RESUMO

Protein arginine deiminase (PAD) enzymes catalyze the conversion of protein-bound arginine into citrulline, an irreversible posttranslational modification with loss of a positive charge that can influence protein-protein interactions and protein structure. Protein arginine deiminase activity depends on high intracellular calcium concentrations occurring in dying cells. In this study, we demonstrate that protein citrullination is common during pyroptotic cell death in macrophages and that inhibition of PAD enzyme activity by Cl-amidine, a pan-PAD inhibitor, blocks NLRP3 inflammasome assembly and proinflammatory IL-1ß release in macrophages. Genetic deficiency of either PAD2 or PAD4 alone in murine macrophages does not impair IL-1ß release; however, pharmacological inhibition or small interfering RNA knockdown of PAD2 within PAD4-/- macrophages does. Our results suggest that PAD2 and 4 activity in macrophages is required for optimal inflammasome assembly and IL-1ß release, a finding of importance for autoimmune diseases and inflammation.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Desiminases de Arginina em Proteínas/metabolismo , Animais , Citrulinação/fisiologia , Humanos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/fisiologia
7.
J Allergy Clin Immunol ; 146(4): 901-911, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32278790

RESUMO

BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Mutação , Subunidade p50 de NF-kappa B/genética , Fenótipo , Adulto , Idoso , Autoimunidade/genética , Variação Biológica da População , Biomarcadores , Gerenciamento Clínico , Feminino , Imunofluorescência , Estudos de Associação Genética/métodos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Tomografia Computadorizada por Raios X
8.
Clin Immunol ; 210: 108269, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683054

RESUMO

Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.


Assuntos
Mutação com Ganho de Função/genética , Síndromes de Imunodeficiência/diagnóstico , Leucócitos Mononucleares/imunologia , Meningites Bacterianas/diagnóstico , Inibidor de NF-kappaB alfa/genética , Neisseria meningitidis/fisiologia , Papillomaviridae/fisiologia , Infecções por Pseudomonas/diagnóstico , Pseudomonas aeruginosa/fisiologia , Viroses/imunologia , Adulto , Artrite Juvenil , Azitromicina/uso terapêutico , Bronquiectasia , Proliferação de Células , Células Cultivadas , Criança , Displasia Ectodérmica , Gentamicinas/uso terapêutico , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Meningites Bacterianas/tratamento farmacológico , Linhagem , Infecções por Pseudomonas/tratamento farmacológico , Viroses/diagnóstico , Verrugas , Adulto Jovem
9.
Eur J Immunol ; 48(4): 696-704, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29277896

RESUMO

IgG Fc receptors (FcγRs) and the C5a anaphylatoxin receptor (C5aR) were identified as key regulators of type II autoimmune injury in mice. However, and with respect to C5aR, the relative importance of C5a for IgG autoantibody-induced cellular destruction remained unclear. Using an experimental model of autoimmune hemolytic anemia (AIHA), we here report marked differences in the development of AIHA between mice lacking C5aR and C5-deficient (Hc0 ) strain, indicating a limited role of C5 in this type of C5aR-regulated disease. Ex-vivo-analyses of liver homogenates from anemic Hc0 mice demonstrate C5a-independent C5aR activation, upregulation of FcγR expression and amplification of erythrophagocytosis by macrophages. As assessed by pharmacological inhibition studies, targeting of C5aR, but not of C5, is effective in treating experimental AIHA. Collectively, these results define a previously unrecognized disease mechanism of C5aR activation in AIHA that does not necessarily involve C5 and C5a.


Assuntos
Anemia Hemolítica Autoimune/imunologia , Autoimunidade/imunologia , Complemento C5a/deficiência , Células de Kupffer/imunologia , Receptor da Anafilatoxina C5a/metabolismo , Receptores de IgG/imunologia , Animais , Eritrócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/imunologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/genética , Receptores de IgG/biossíntese
10.
Clin Immunol ; 179: 1-7, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28216420

RESUMO

Here we describe novel mutations in recombination activation gene 1 (RAG1) in a compound heterozygous male patient with combined T and B cell immunodeficiency (CID). Clinical manifestations besides antibody deficiency included airway infections, granulomatosis and autoimmune features. He died at the age of 37 due to PML caused by JC virus infection. By targeted next-generation sequencing we detected post mortem in this patient three mutations in RAG1. One allele harbored two novel mutations (c.1123C>G, p.H375D and c.1430delC, p.F478Sfs*14), namely a missense variant and a frameshift deletion, of which the latter leads to a truncated RAG1 protein. The other allele revealed a previously described missense mutation (c.1420C>T, p.R474C, rs199474678). Functional analysis of the p.R474C variant in an in vitro V(D)J recombination assay exhibited reduced recombination activity compared to a wild-type control. Our findings suggest that mutations in RAG1, specifically the p.R474C variant, can be associated with relatively mild clinical symptoms or delayed occurrence of T cell and B cell deficiencies but may predispose to PML.


Assuntos
Proteínas de Homeodomínio/genética , Síndromes de Imunodeficiência/genética , Leucoencefalopatia Multifocal Progressiva/genética , Adulto , Linfócitos B/imunologia , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Proliferação de Células , Humanos , Imunoglobulinas/sangue , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/diagnóstico por imagem , Síndromes de Imunodeficiência/imunologia , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/imunologia , Contagem de Linfócitos , Imageamento por Ressonância Magnética , Masculino , Mutação , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Recombinação V(D)J
11.
Cytokine ; 96: 71-74, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28324805

RESUMO

We used whole exome sequencing to determine the genetic background of CVID in two non-consanguineous German families. We identified IFNK (interferon-kappa) as the only candidate gene that harbored truncating mutations in affected members from both families. One family segregated c.30_31insTGTT, a known frameshift variant, while the other family segregated the novel IFNK mutation p.K199X that creates a premature stop codon. We sequenced the whole coding region of IFNK in a further series of 167 CVID patients and 192 healthy controls. Frameshift mutation c.30_31insTGTT was identified in 12 cases and 17 controls (OR 0.79, 95% CI 0.33-1.81, p=0.79), whereas the p.K199X mutation remained restricted to the original family. No additional truncating variants were found. We conclude that, given their frequent occurrence in non-diseased family members and controls, it is unlikely that truncating variants in IFNK constitute a major factor in the development of CVID.


Assuntos
Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Mutação da Fase de Leitura , Interferon Tipo I/genética , Adulto , Idoso , Imunodeficiência de Variável Comum/congênito , Feminino , Genoma Humano , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNA , Sequenciamento do Exoma
13.
Eur J Immunol ; 45(7): 2143-53, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25912155

RESUMO

Stromal interaction molecule 1 (STIM1)-dependent store operated calcium-entry (SOCE) through Orai1-mediated calcium (Ca(2+) ) influx is considered a major pathway of Ca(2+) signaling, serving T-cell, mast cell, and platelet responses. Here, we show that Orai1 is critical for neutrophil function. Orai1-deficient neutrophils present defects in fMLP and complement C5a-induced Ca(2+) influx and migration, although they respond normally to another chemoattractant, CXCL2. Up until now, no specific contribution of Orai1 independent from STIM1 or SOCE has been recognized in immune cells. Here, we observe that Orai1-deficient neutrophils exhibit normal STIM1-dependent SOCE and STIM1-deficient neutrophils respond to fMLP and C5a efficiently. Despite substantial cytokine production, Orai1(-/-) chimeric mice show impaired neutrophil recruitment in LPS-induced peritonitis. Moreover, Orai1 deficiency results in profoundly defective C5a-triggered neutrophil lung recruitment in hypersensitivity pneumonitis. Comparative evaluation of inflammation in Stim1(-/-) chimeras reveals a distinct pathogenic contribution of STIM1, including its involvement in IgG-induced C5a production. Our data establish Orai1 as key signal mediator of C5aR activation, contributing to inflammation by a STIM1-independent pathway of Ca(2+) -influx in neutrophils.


Assuntos
Canais de Cálcio/imunologia , Complemento C5a/imunologia , Inflamação/imunologia , Infiltração de Neutrófilos/imunologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína ORAI1 , Receptor da Anafilatoxina C5a/imunologia
14.
Int Arch Allergy Immunol ; 171(2): 136-140, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27902982

RESUMO

AIM OF STUDY: We used a triplex real-time polymerase chain reaction (PCR) to classify our common variable immunodeficiency (CVID) patients into distinct groups according to the amount of their T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs). MATERIALS AND METHODS: TREC and KREC analysis was performed using a multiplex real-time PCR assay. The T- and B-lymphocyte subsets were measured by flow cytometry. RESULTS: The copy number of TRECs and KRECs was significantly reduced in CVID patients compared to healthy controls. The TREC copy number was inversely correlated with age in both healthy subjects and patients; however, the KREC copy number was inversely correlated with age only in CVID patients. Moreover, no association was seen between TREC/KREC copy number and clinical manifestations such as bronchiectasis, splenomegaly, granulomata, autoimmune cytopenias, organ-specific autoimmunity, enteropathy and lymphoid hyperplasia. CONCLUSION: TREC and KREC quantification might be a useful tool to differentiate between CVID and combined immunodeficiency, but considering the results of this study a classification of CVID patients in certain groups is hardly possible.


Assuntos
Imunodeficiência de Variável Comum/genética , Reação em Cadeia da Polimerase Multiplex , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/genética , Recombinação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Imunodeficiência de Variável Comum/imunologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Virol J ; 13: 67, 2016 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-27091211

RESUMO

BACKGROUND: HIV-HCV co-infection is associated with accelerated progression to hepatic fibrosis, cirrhosis and hepatocellular carcinoma than HCV mono-infection. The contribution of innate immunity during HIV-HCV co-infection has been a relatively under-investigated area. Natural killer (NK) cells are pivotal sentinels of innate immunity against viruses and tumour cells. In this study we evaluated the effect of HIV-HCV co-infection on peripheral blood NK cell subsets with emphasis on the phenotype of CD56(bright) NK cells. METHODS: Sixty patients were included in the study; HIV mono-infected (n = 12), HCV mono-infected (n = 15), HCV-HIV co-infected (n = 21) and healthy controls (n = 16). PBMCs were isolated and immunophenotyping of NK cells was performed by flowcytometry. RESULTS: We observed an expansion of CD56(bright) NK cell subset in HIV-HCV co-infection as compared to healthy controls and HIV mono-infected group. All the infected groups had an upregulated expression of the activating receptor NKG2D on CD56(bright) NK cells in comparison to healthy controls while not differing amongst themselves. The expression of NKp46 in HIV-HCV co-infected group was significantly upregulated as compared to both HIV as well as HCV mono-infections while NKp30 expression in the HIV-HCV co-infected group significantly differed as compared to HIV mono-infection. The CD56(bright) NK cell subset was activated in HIV-HCV co-infection as assessed by the expression of CD69 as compared to healthy controls but was significantly downregulated in comparison to HIV mono-infection. CD95 expression on CD56(bright) NK cells followed the same pattern where there was an increased expression of CD95 in HIV mono-infection and HIV-HCV co-infection as compared to healthy controls. In contrast to CD69 expression, CD95 expression in HCV mono-infection was decreased when compared to HIV mono-infection and HIV-HCV co-infection. Finally, expression of CXCR3 on CD56(bright) NK cells was increased in HIV-HCV co-infection in comparison to HIV mono-infection while remaining similar to HCV mono-infection. CONCLUSION: Thus, HIV-HCV co-infection is able to modulate the phenotype of CD56(bright) NK cell subset in a unique way such that NKp46 and CXCR3 expressions are distinct for co-infection while both mono-infections have an additive effect on CD56(bright), CD69 with CD95 expressions. HCV mono-infection has a dominant effect on NKp30 expression while NKG2D and CD127 expressions remained same in all the groups.


Assuntos
Antígenos CD/análise , Coinfecção/patologia , Infecções por HIV/complicações , Infecções por HIV/patologia , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Células Matadoras Naturais/imunologia , Adulto , Idoso , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Receptor 1 Desencadeador da Citotoxicidade Natural/análise , Fenótipo , Receptores CXCR3/análise
16.
Cell Mol Life Sci ; 72(16): 3037-49, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25939268

RESUMO

Natural killer (NK) cells are innate immune effectors that provide first line of defence against viruses. Human NK cells are heterogeneous in nature, and their functions rely on a dynamic balance between germ-line-encoded activating and inhibitory receptors. HIV-1 infection results in altered NK cell receptor repertoire and impaired effector functions including the ability to lyse virus-infected cells and secretion of antiviral cytokine IFN-γ. Over the last decade, additional NK cell subset-specific molecules have been identified, leading to emergence of a more complex cellular diversity than previously thought. Herein, we discuss NK cell subset redistribution, altered receptor repertoire and influence of interaction of polymorphic leucocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIR) on HIV-1 disease progression.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , HIV-1 , Imunidade Inata/imunologia , Células Matadoras Naturais/citologia , Receptores KIR/imunologia , Receptores Desencadeadores da Citotoxicidade Natural/imunologia , Antígenos HLA/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Lectinas Tipo C/metabolismo , Receptores KIR/metabolismo
17.
Nat Genet ; 39(9): 1065-7, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17660818

RESUMO

TREX1 acts in concert with the SET complex in granzyme A-mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3' UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 x 10(-7)). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.


Assuntos
Exodesoxirribonucleases/genética , Lúpus Eritematoso Cutâneo/genética , Mutação , Fosfoproteínas/genética , Regiões 3' não Traduzidas/genética , Endossomos/metabolismo , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Mutação da Fase de Leitura , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Lúpus Eritematoso Cutâneo/enzimologia , Mutação de Sentido Incorreto , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
18.
Artigo em Alemão | MEDLINE | ID: mdl-27090247

RESUMO

BACKGROUND: Currently only vague estimates exist for the seroprevalence and vaccination status for viral hepatitis B (HBV) in refugees arriving in Germany during the current refugee crisis. OBJECTIVES: To assess the prevalence of hepatitis B in refugees arriving in northern Germany in 2015. METHODS: In a cross-sectional study in 793 patients from all age groups tests for serological markers of hepatitis B virus infection (HBsAg, anti-HBc) and liver enzymes (ALT, AST, bilirubin, γGT, alkaline phosphatase) were performed in August 2015 at six reception centers in northern Germany. In 258 patients anti-HBs antibodies were assessed additionally. RESULTS: Of the tested refugees, 76.7 % were male, the median age was 28.8 ± 11.4 years, and 7.8 % were children under the age of 18. The overall prevalence of HBsAg and total anti-HBc was 2.3 % and 14.0 % respectively (2.5 % and 14.5 % in men; 1.2 % and 13.5 % in women). Prevalence was highest in 35 to 49-year-old patients for HBsAg (3.1 %) and for refugees over 50 years for anti-HBc (38 %). No immunity to Hepatitis B was found in 62 %, 18.6 % had been vaccinated against Hepatitis B, while 50 % of children aged up to 15 years (n = 12) had been vaccinated. Positive predictive values of elevated AST and ALT for detection of HBsAg was 0 and 0.016, respectively. Only two patients with a positive HBsAg had elevated transaminases. CONCLUSIONS: This study showed a high prevalence of HBsAg in a German refugee sample in comparison to the general German population. Liver enzymes are not an appropriate tool for screening for hepatitis B virus infection.


Assuntos
Hepatite B/diagnóstico , Hepatite B/epidemiologia , Refugiados/estatística & dados numéricos , Transaminases/sangue , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Pré-Escolar , Ensaios Enzimáticos Clínicos/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Hepatite B/prevenção & controle , Vacinas contra Hepatite B/uso terapêutico , Humanos , Lactente , Recém-Nascido , Testes de Função Hepática/métodos , Testes de Função Hepática/estatística & dados numéricos , Masculino , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , Distribuição por Sexo , Adulto Jovem
20.
Eur J Immunol ; 44(12): 3717-28, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25229755

RESUMO

Human blood NK cells exert strong cytotoxicity against transformed cells and produce different cytokines and chemokines with an important role in modulating immune responses. However, the nature of NK-cell function depends on NK-cell interaction with other immune cells. One type of immune cells that communicate with NK cells are 6-sulfo LacNAc DCs (slanDCs), which comprise a major subpopulation of proinflammatory human blood DCs. In this study, we investigated the molecular mechanisms by which slanDCs interact with NK cells. Our in vitro studies demonstrate that LPS-stimulated slanDCs enhance activation and function of NK cells essentially via membrane-bound TNF-α (mTNF-α). LPS stimulation upregulates expression of mTNF-α in slanDCs, and surface TNF receptor 2 (TNFR2) is upregulated on NK cells after coincubation with slanDCs. IL-12 secreted by slanDCs increases surface expression of TNFR2 in NK cells. TNFR2 signaling in NK cells leads to activation of NF-kB, a transcription factor for cytokines such as GM-CSF. GM-CSF provided by NK cells is responsible for enhancing IL-12 secretion in slanDCs. In conclusion, TNFR2 and IL-12 signaling, which support one another, enables slanDCs to enhance NK-cell function through mTNF-α, thereby regulating immune responses.


Assuntos
Membrana Celular/imunologia , Células Dendríticas/imunologia , Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/imunologia , Amino Açúcares/imunologia , Células Dendríticas/citologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Células Matadoras Naturais/citologia , Lipopolissacarídeos/farmacologia , Masculino , NF-kappa B/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
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