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Transplante de Células-Tronco Hematopoéticas , Escleroderma Sistêmico , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Escleroderma Sistêmico/terapia , Feminino , Transplante Autólogo , Herpes Zoster , Pessoa de Meia-Idade , Vacinação/efeitos adversos , Masculino , Vacina BNT162RESUMO
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.
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Artrite Reumatoide , Doenças Reumáticas , Humanos , Artrite Reumatoide/diagnóstico , Qualidade de Vida , Estudos Prospectivos , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/terapia , Atenção à SaúdeRESUMO
Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.
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Artrite Psoriásica/genética , Predisposição Genética para Doença , Peroxidase/genética , Psoríase/genética , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/epidemiologia , Testes Genéticos , Alemanha/epidemiologia , Humanos , Polimorfismo de Nucleotídeo Único , Psoríase/diagnóstico , Psoríase/epidemiologia , Índice de Gravidade de DoençaRESUMO
PURPOSE: Previous published data showed an impact of single-nucleotide polymorphisms in the VEGF A and VEGFR2 genes on the survival of patients with various malignancies, among others diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: We investigated the role of four VEGF-A and two VEGFR-2 gene polymorphisms on the outcome of 273 patients with diffuse large B-cell lymphoma who were treated with R-CHOP within a prospective, randomized trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). The genomic DNA samples were analyzed using commercial DNA Probes (Applied Biosystems, USA) to detect single-nucleotide polymorphisms in the VEGF A rs699947, rs1570360, rs2010963, rs3025039 and rs1870377, and rs2305948 in the VEGFR2 receptor. Hundred healthy blood donors served as a control. RESULTS: There was no difference between the SNP allele frequencies in lymphoma patients compared to the control group for all investigated SNPs. None of the investigated SNPs was significantly associated with EFS or OS. After adjusting for the International Prognostic Index risk factors in a multivariate analysis, these results could be confirmed. CONCLUSION: Single-nucleotide polymorphisms of the VEGF and VEGFR2 were not associated with a worse outcome in Caucasian patients with DLBCL.
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Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Polimorfismo Genético , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , População Branca/genética , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Feminino , Frequência do Gene , Genótipo , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prednisona , Prognóstico , Rituximab , Resultado do Tratamento , VincristinaRESUMO
Priapism as a sign of a severe hematological disease is a rare event, which has to be considered as both a urological and a hematological emergency that requires immediate treatment. This article describes a clinical case of priapism as the first clinical manifestation of a hitherto undiagnosed chronic myeloid leukemia (CML) and discusses the results of a literature review on this topic.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Priapismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Priapismo/diagnóstico , Priapismo/etiologiaRESUMO
Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
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Inflamação/genética , Interleucinas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Adulto , Animais , Citocinas/genética , Armadilhas Extracelulares/genética , Feminino , Humanos , Inflamação/patologia , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Camundongos , Mutação/genética , Neutrófilos/metabolismo , Psoríase/patologia , Doenças Raras/enzimologia , Doenças Raras/genética , Doenças Raras/patologia , Pele/enzimologia , Pele/patologia , Dermatopatias/patologiaRESUMO
BACKGROUND: Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) present two diseases of a dermatologic and rheumatologic spectrum that are variable in manifestation und therapeutic response. Genetic risk factors have long been assumed in both diseases, but no single reliable factor has been identified yet. Therefore, we aimed to clinically characterize a patient group with syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) (n = 47) and chronic recurrent multifocal osteomyelitis (CRMO)/ chronic non-bacterial osteomyelitis (CNO) (n = 9) and analyze a CRMO candidate gene. METHODS: Clinical data of all patients were collected and assessed for different combinations of clinical symptoms. SAPHO patients were grouped into categories according to the acronym; disease-contribution by pathogens was evaluated. We sequenced coding exons of FBLIM1. RESULTS: Palmoplantar pustular psoriasis (PPP) was the most common skin manifestation in CRMO/CNO and SAPHO patients; most SAPHO patients had sterno-costo-clavicular hyperostosis. The most common clinical category of the acronym was S_PHO (n = 26). Lack of pathogen detection from bone biopsies was more common than microbial isolation. We did not identify autosomal-recessive FBLIM1 variants. CONCLUSIONS: S_PHO is the most common combination of symptoms of its acronym. Genetic analyses of FBLIM1 did not provide evidence that this gene is relevant in our patient group. Our study indicates the need to elucidate SAPHO's and CRMO/CNO's pathogenesis.
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Síndrome de Hiperostose Adquirida/genética , Moléculas de Adesão Celular/genética , Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Osteomielite/genética , Síndrome de Hiperostose Adquirida/fisiopatologia , Adolescente , Adulto , Criança , Feminino , Humanos , Hiperostose/genética , Hiperostose/fisiopatologia , Masculino , Osteomielite/fisiopatologia , Psoríase/genética , Psoríase/fisiopatologia , Fatores de RiscoRESUMO
NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.
Assuntos
Injúria Renal Aguda/imunologia , Apolipoproteína C-III/imunologia , Caspase 8/metabolismo , Nefropatias/imunologia , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Injúria Renal Aguda/patologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apolipoproteína C-III/genética , Linhagem Celular , Modelos Animais de Doenças , Células HEK293 , Humanos , Inflamassomos/imunologia , Inflamação/genética , Inflamação/imunologia , Nefropatias/patologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
OBJECTIVES: Previously we discovered antibodies against progranulin (PGRN-abs) in a protein array-based screening of sera from various rheumatic diseases. Here we conducted a study to evaluate the prevalence of PGRN-abs in seropositive and seronegative rheumatoid arthritis (RA). METHODS: PGRN-abs were determined in the sera from 257 RA patients being seropositive for RF-IgM and/or ACPA-IgG and from 224 seronegative RA patients who were prospectively included in this study (total RA cohort n=481). All serum samples from the included participants were tested for RF-IgM as well as for ACPA-IgG, and PGRN-abs were determined using a previously described ELISA. Statistics was performed using the χ2 test for evaluating differences in clinical data; to evaluate independent statistical effects on the frequency of PGRN-abs status a logistic regression model with Wald-test was performed. RESULTS: PGRN-abs were detected in 25.3% from seropositive RA and in 21.0% from RF- and ACPA-negative RA resulting in a prevalence of 23.7% for both cohorts together. Comparing mean DAS28 values in the PGRN-abs positive cohort with the PGRN-abs negative cohort, the DAS28 value was significantly higher in PGRN-abs positive RA patients (3.81 vs. 3.50, p=0.038). A trend for higher frequencies of PGRN-abs in sera of RA patients with unfavourable characteristics such as erosive disease or requiring TNFi medication was observed. CONCLUSIONS: These data suggest that the determination of PGRN-abs in seronegative RA patients may reduce their seronegative status. Further studies are required to evaluate PGRN-abs as a potential diagnostic marker in RA.
Assuntos
Artrite Reumatoide/sangue , Autoanticorpos/sangue , Progranulinas/imunologia , Anticorpos Antiproteína Citrulinada , Artrite Reumatoide/diagnóstico , Humanos , Peptídeos Cíclicos , Fator ReumatoideRESUMO
OBJECTIVE: The present study aimed to investigate progranulin autoantibodies in systemic sclerosis and autoimmune connective tissue disorders. Progranulin is a physiologic tumor necrosis factor (TNF) antagonist. Progranulin antibodies decrease progranulin levels. METHODS: Serum samples of 123 patients with systemic sclerosis and various autoimmune connective tissue disorders (Sjoegren's syndrome [SjS], mixed connective tissue disorder, polymyositis [PM] and dermatomyositis [DM], antiphospholipid syndrome [APLS], and undifferentiated connective tissue disease [UCTD]) were tested for progranulin antibodies using enzyme-linked immunosorbent assay. RESULTS: Progranulin antibodies were found in 34 of 123 (27.6%) patients at least once during their disease. In detail, 2 of 8 (25%) patients with limited cutaneous systemic sclerosis, 10 of 31 (32.3%) patients with diffuse cutaneous systemic sclerosis, 9 of 22 (40.9%) patients with SjS, 1 of 3 (33.33%) patients with mixed connective tissue disease, 4 of 33 (12.1%) patients with DM or PM, 6 of 15 (40%) patients with APLS, and 2 of 11 (18.2%) patients with UCTD were positive for progranulin antibodies during the course of disease. CONCLUSIONS: Progranulin antibodies are frequently present in patients with systemic sclerosis and other autoimmune connective tissue disorders. Despite the lack of specificity for a given autoimmune disease, progranulin antibodies might not only indicate a potential subtype but also play a pathogenic role in patients with autoimmune connective disorders. Given the important role of TNF-α in inflammatory processes in autoimmune connective tissue disorders, progranulin antibodies might support the proinflammatory environment by neutralizing the TNF blocker progranulin.
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Autoanticorpos , Doenças Autoimunes , Progranulinas , Escleroderma Sistêmico , Idoso , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Progranulinas/sangue , Progranulinas/imunologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologiaAssuntos
Rearranjo Gênico , Linfoma Plasmablástico , Proteínas Proto-Oncogênicas c-myc , Idoso , Humanos , Masculino , Linfoma Plasmablástico/genética , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Remissão EspontâneaRESUMO
BACKGROUND: Varicella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed VZV-specific T cells in patients with rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA), and we assessed how their levels and functionality were impacted by disease-modifying antirheumatic drugs (DMARDs). A polyclonal stimulation was carried out to analyze effects on general effector T cells. METHODS: CD4 T cells in 98 blood samples of patients with RA (n = 78) or SpA (n = 20) were quantified by flow cytometry after stimulation with VZV antigen and the polyclonal stimulus Staphylococcus aureus enterotoxin B (SEB), and they were characterized for expression of cytokines (interferon-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-2) and markers for activation (CD69), differentiation (CD127), or functional anergy programmed death 1 molecule [PD-1], cytotoxic T-lymphocyte antigen 4 [CTLA-4]. Results of patients with RA were stratified into subgroups receiving different antirheumatic drugs and compared with samples of 39 healthy control subjects. Moreover, direct effects of biological DMARDs on cytokine expression and proliferation of specific T cells were analyzed in vitro. RESULTS: Unlike patients with SpA, patients with RA showed significantly lower percentages of VZV-specific CD4 T cells (median 0.03%, IQR 0.05%) than control subjects (median 0.09%, IQR 0.16%; p < 0.001). Likewise, SEB-reactive CD4 T-cell levels were lower in patients (median 2.35%, IQR 2.85%) than in control subjects (median 3.96%, IQR 4.38%; p < 0.05); however, expression of cytokines and cell surface markers of VZV-specific T cells did not differ in patients and control subjects, whereas SEB-reactive effector T cells of patients showed signs of functional impairment. Among antirheumatic drugs, biological DMARDs had the most pronounced impact on cellular immunity. Specifically, VZV-specific CD4 T-cell levels were significantly reduced in patients receiving TNF-α antagonists or IL-6 receptor-blocking therapy (p < 0.05 and p < 0.01, respectively), whereas SEB-reactive T-cell levels were reduced in patients receiving B-cell-depleting or IL-6 receptor-blocking drugs (both p < 0.05). CONCLUSIONS: Despite absence of clinical symptoms, patients with RA showed signs of impaired cellular immunity that affected both VZV-specific and general effector T cells. Strongest effects on cellular immunity were observed in patients treated with biological DMARDs. These findings may contribute to the increased susceptibility of patients with RA to VZV reactivation.
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Antirreumáticos/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Herpesvirus Humano 3/metabolismo , Doenças Reumáticas/sangue , Doenças Reumáticas/tratamento farmacológico , Adulto , Idoso , Antirreumáticos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Estudos de Coortes , Feminino , Herpesvirus Humano 3/efeitos dos fármacos , Herpesvirus Humano 3/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Reumáticas/imunologiaRESUMO
OBJECTIVES: Autoantibodies may play a role in the pathogenesis of primary vasculitides (PVs) like giant cell arteritis (GCA). We recently identified 3 cytoskeletal proteins (lamin C [laC], nuclear autoantigen of 14kD [NA14] and cytokeratin 15 [CK15]) as autoantigens in GCA and postulated a frequent autoantibody response against these antigens in PVs. METHODS: To test this hypothesis we studied a cohort of patients with PVs (n=61) and healthy individuals (n=27) for the presence of these autoantibodies using a recombinant cDNA expression library. To define their specifity for PV, we also examined patients with other autoimmune diseases such as rheumatoid arthritis (RA) and connective tissue diseases (CTD). RESULTS: We found no statistically significant differences in autoantibody responses between patients with PV and healthy controls, although there was a trend for an association between PVs and the occurrence of antibodies against laC and CK15. However, in patients with RA (n=33) or Sjögren's syndrome (SS, n=11) with vasculitides we observed more frequently autoantibodies against NA14, laC and CK15 compared to healthy controls. In patients with systemic lupus erythematosus (SLE, n=23) autoantibodies against laC were more frequent. The presence of autoantibodies in RA, SS and SLE was associated with systemic secondary vasculitis (SSV). In RA, laC- and NA14-seropositive patients were in a more advanced disease stage than seronegative patients with more frequent extraarticular manifestations (p=0.004). In SLE laC-autoantibody-positive patients had a higher SLE activity index (p<0.001). CONCLUSIONS: Serum autoantibodies against laC and NA14 are frequent in patients with RA and CTD and are associated with extensive disease and SSV. The potential pathogenic and prognostic role of these antibodies should be further investigated.
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Autoanticorpos/sangue , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Queratina-15/imunologia , Lamina Tipo A/imunologia , Proteínas Nucleares/imunologia , Vasculite/imunologia , Adulto , Idoso , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Recently we identified in a wide spectrum of autoimmune diseases frequently occurring proinflammatory autoantibodies directed against progranulin, a direct inhibitor of TNFR1 & 2 and of DR3. In the present study we investigated the mechanisms for the breakdown of self-tolerance against progranulin. Isoelectric focusing identified a second, differentially electrically charged progranulin isoform exclusively present in progranulin-antibody-positive patients. Alkaline phosphatase treatment revealed this additional progranulin isoform to be hyperphosphorylated. Subsequently Ser81, which is located within the epitope region of progranulin-antibodies, was identified as hyperphosphorylated serine residue by site directed mutagenesis of candidate phosphorylation sites. Hyperphosphorylated progranulin was detected exclusively in progranulin-antibody-positive patients during the courses of their diseases. The occurrence of hyperphosphorylated progranulin preceded seroconversions of progranulin-antibodies, indicating adaptive immune response. Utilizing panels of kinase and phosphatase inhibitors, PKCß1 was identified as the relevant kinase and PP1 as the relevant phosphatase for phosphorylation and dephosphorylation of Ser81. In contrast to normal progranulin, hyperphosphorylated progranulin interacted exclusively with inactivated (pThr320) PP1, suggesting inactivated PP1 to cause the detectable occurrence of phosphorylated Ser81 PGRN. Investigation of possible functional alterations of PGRN due to Ser81 phosphorylation revealed, that hyperphosphorylation prevents the interaction and thus direct inhibition of TNFR1, TNFR2 and DR3, representing an additional direct proinflammatory effect. Finally phosphorylation of Ser81 PGRN alters the conversion pattern of PGRN. In conclusion, inactivated PP1 induces hyperphosphorylation of progranulin in a wide spectrum of autoimmune diseases. This hyperphosphorylation prevents direct inhibition of TNFR1, TNFR2 and DR3 by PGRN, alters the conversion of PGRN, and is strongly associated with the occurrence of neutralizing, proinflammatory PGRN-antibodies, indicating immunogenicity of this alternative secondary modification.
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Autoanticorpos/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Precursores de Proteínas/imunologia , Serina/imunologia , Animais , Autoanticorpos/genética , Autoanticorpos/metabolismo , Sítios de Ligação/genética , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Citometria de Fluxo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mutagênese Sítio-Dirigida , Fosforilação , Progranulinas , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Proteína Quinase C beta/genética , Proteína Quinase C beta/imunologia , Proteína Quinase C beta/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Serina/genética , Serina/metabolismoRESUMO
BACKGROUND: Varicella zoster virus (VZV) establishes lifelong persistence and may reactivate in individuals with impaired immune function. To investigate immunologic correlates of protection and VZV reactivation, we characterized specific immunity in 207 nonsymptomatic immunocompetent and 132 immunocompromised individuals in comparison with patients with acute herpes zoster. METHODS: VZV-specific CD4 T cells were quantified flow cytometrically after stimulation and characterized for expression of interferon-γ, interleukin 2, and tumor necrosis factor α and surface markers for differentiation (CD127) and anergy (cytotoxic T lymphocyte antigen 4 [CTLA-4] and programmed death [PD]-1). Immunoglobulin G and A levels were quantified using an enzyme-linked immunosorbent assay. RESULTS: In healthy individuals, VZV-specific antibody and T-cell levels were age dependent, with the highest median VZV-specific CD4 T-cell frequencies of 0.108% (interquartile range, 0.121%) during adolescence. VZV-specific T-cell profiles were multifunctional with predominant expression of all 3 cytokines, CD127 positivity, and low expression of CTLA-4 and PD-1. Nonsymptomatic immunocompromised patients had similar VZV-specific immunologic properties except for lower T-cell frequencies (P<.001) and restricted cytokine expression. In contrast, significantly elevated antibody- and VZV-specific CD4 T-cell levels were found in patients with zoster. Their specific T cells showed a shift in cytokine expression toward interferon γ single positivity, an increase in CTLA-4 and PD-1, and a decrease in CD127 expression (all P<.001). This phenotype normalized after resolution of symptoms. CONCLUSIONS: VZV-specific CD4-T cells in patients with zoster bear typical features of anergy. This phenotype is reversible and may serve as adjunct tool for monitoring VZV reactivations in high-risk patients.
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Herpes Zoster/epidemiologia , Herpes Zoster/imunologia , Herpesvirus Humano 3/imunologia , Imunidade Celular/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Células Cultivadas , Criança , Pré-Escolar , Citocinas/análise , Citocinas/imunologia , Feminino , Herpes Zoster/virologia , Humanos , Hospedeiro Imunocomprometido/imunologia , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Linfócitos T/imunologia , Adulto JovemRESUMO
BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) belongs to the systemic ANCA-associated vasculitides which may develop life-threatening major organ involvement, such as eosinophilic pulmonary infiltration, neuropathy, acute nephritis, myocarditis, and gastrointestinal (GI) tract involvement. Here, two cases of EGPA are presented developing perforation of the bowel at primary diagnosis after 7 respectively 10 days of initiation of high-dose glucocorticosteroides (GC) therapy. FINDINGS: Two male patients, aged 32 (case 1) and 36 years (case 2), were admitted to the hospital with the symptoms of dyspnea, fatigue, fever, and chest pain. The patients completed the previously published revised international Chapel Hill nomenclature of EGPA. The two patients (case 1 and 2) developed acute abdominal pain after 7 (case 1) and ten days (case 2) on GC treatment. Computed tomography followed by surgery detected acute perforation of the small intestine (middle part of jejunum, case 1) and colon transversum (case 2). The resected specimens disclosed bowel perforation with severe transmural inflammation, edema, hemorrhage and vasculitis typically of EGPA. On the first post-operative day, therapy with cyclophosphamide (according to the Austin protocol) with a dosage of 750 mg/qm every 3 weeks (for 8 cycles) was initiated with good response within three months of treatment. CONCLUSION: The course of disease of the two presented EGPA patients suggest that very early initiation of intensified immunosuppressive treatment, preferentially with cyclophophomide or B cell depletion strategies, needs to be considered to avoid life-threatening complications of GI involvement.