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BACKGROUND: Assessment of T-cell receptor excision circles (TRECs) in dried blood spots of newborns allows the detection of severe combined immunodeficiency (SCID) (T cells <300/µL at birth) with a presumed sensitivity of 100%. TREC screening also identifies patients with selected combined immunodeficiency (CID) (T cells >300/µL, yet <1500/µL at birth). Nevertheless, relevant CIDs that would benefit from early recognition and curative treatment pass undetected. OBJECTIVE: We hypothesized that TREC screening at birth cannot identify CIDs that develop with age. METHODS: We analyzed the number of TRECs in dried blood spots in archived Guthrie cards of 22 children who had been born in the Berlin-Brandenburg area between January 2006 and November 2018 and who had undergone hematopoietic stem-cell transplantation (HSCT) for inborn errors of immunity. RESULTS: All patients with SCID would have been identified by TREC screening, but only 4 of 6 with CID. One of these patients had immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 (ICF2). Two of 3 patients with ICF whom we have been following up at our institution had TREC numbers above the cutoff value suggestive of SCID at birth. Yet all patients with ICF had a severe clinical course that would have justified earlier HSCT. CONCLUSIONS: In ICF, naïve T cells may be present at birth, yet they decline with age. Therefore, TREC screening cannot identify these patients. Early recognition is nevertheless crucial, as patients with ICF benefit from HSCT early in life.
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Receptores de Antígenos de Linfócitos T , Imunodeficiência Combinada Severa , Criança , Humanos , Recém-Nascido , Receptores de Antígenos de Linfócitos T/genética , Triagem Neonatal , Linfócitos T , Imunodeficiência Combinada Severa/diagnóstico , SíndromeRESUMO
Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.
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Antígenos HLA-DR , Traumatismos da Medula Espinal , Humanos , Estudos de Coortes , Estudos Prospectivos , Traumatismos da Medula Espinal/complicações , Síndrome , MonócitosRESUMO
Background: Non-pharmaceutical interventions (NPI) during the COVID-19 pandemic aimed at prevention of SARS-CoV-2 transmission also influenced transmission of viruses other than SARS-CoV-2. The aim of this study was to describe and compare the burden of common viral respiratory and gastrointestinal infections in children admitted to Berlin University Children's Hospital (BCH) before and during the COVID-19 pandemic at different levels of public NPI measures. Methods: In this retrospective study, we analyzed the frequency of detection of common human respiratory and gastrointestinal viruses from January 2016 through January 2022 in all patients admitted to BCH. We compared virus detection before and during the COVID-19 pandemic at different levels of public NPI measures. Results: The frequency of detection of seasonal enveloped and non-enveloped viruses [Boca-, Corona-, Influenza-, Metapneumo-, Parainfluenza-, Rota-, and Respiratory Syncytial Viruses (RSV)] was diminished during the COVID-19 pandemic, whereas detection rates of non-seasonal viruses (Rhino-/Entero-, and Adenoviruses) were stable during the pandemic. After withdrawal of major NPI measures, we observed an out of season surge of the detection rates of Boca-, Corona-, Parainfluenzaviruses, and RSV. In contrast, no increased detection frequency was observed for Influenza-, Metapneumo-, and Rotaviruses as of January 2022. Conclusion: Corona-, Boca-, Parainfluenzaviruses, and RSV returned as frequently detected pathogens after withdrawal of major NPI measures. The out of season rise might be attributed to an "immune-debt" due to missing contact to viral antigens resulting in waning of population immunity during the COVID-19 pandemic.
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Most of the few patients with homozygous CD70 deficiency described to date suffered from EBV-related malignancies in early childhood. We present a woman with CD70 deficiency diagnosed in adulthood. She presented in childhood with recurrent airway infections due to encapsulated bacteria, herpes zoster and a fulminant EBV infection followed by chronic EBV infection with mild lymphoproliferation and severe gingivitis/periodontal disease with high EBV viral load in saliva and gingival plaques as an adult. Up to the age of 24 years she developed no malignancy despite constant EBV viremia since primary EBV infection 15 years previously. Immunologic evaluation in childhood showed hypogammaglobulinemia with impaired polysaccharide responsiveness. She has been stable on immunoglobulin substitution with no further severe viral infections and no bacterial airway infections in adulthood. Targeted panel sequencing at the age of 20 years revealed a homozygous CD70 missense mutation (ENST00000245903.3:c.2T>C). CD70 deficiency was confirmed by absent CD70 expression of B cells and activated T cell blasts. The patient finished high school, persues an academic career and has rarely sick days at college. The clinical course of our patient may help to counsel parents of CD70-deficient patients with regard to prognosis and therapeutic options including haematopoetic stem cell transplantation.
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Ligante CD27/deficiência , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/etiologia , Gengivite/etiologia , Herpesvirus Humano 4/fisiologia , Infecções do Sistema Genital/etiologia , Adolescente , Adulto , Biomarcadores , Criança , Infecções por Vírus Epstein-Barr/diagnóstico , Feminino , Predisposição Genética para Doença , Gengivite/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linhagem , Radiografia , Recidiva , Reinfecção , Infecções do Sistema Genital/diagnóstico , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto JovemRESUMO
Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. Disease severity depends on genotype and gene dose with most serious clinical courses observed in patients with M694V homozygosity. Neutrophils are thought to play an important role in the initiation and perpetuation of inflammatory processes in FMF, but little is known about the specific characteristics of these cells in FMF patients. To further characterize neutrophilic inflammatory responses in FMF and to delineate gene-dose effects on a cellular level, we analyzed cytokine production and activation levels of isolated neutrophils derived from patients and subjects with distinct MEFV genotypes, as well as healthy and disease controls. Serum levels of interleukin-18 (IL-18) (median 11,485 pg/ml), S100A12 (median 9,726 ng/ml), and caspase-1 (median 394 pg/ml) were significantly increased in patients with homozygous M694V mutations. Spontaneous release of S100A12, caspase-1, proteinase 3, and myeloperoxidase (MPO) was restricted to ex vivo cultured neutrophils derived from patients with two pathogenic MEFV mutations. IL-18 secretion was highest in patients with two mutations but also increased in neutrophils from healthy heterozygous MEFV mutation carriers, exhibiting an ex vivo gene-dose effect, which was formerly described by us in patients' serum. CD62L (l-selectin) was spontaneously shed from the surface of ex vivo cultured neutrophils [median of geometric mean fluorescence intensity (gMFI) after 5 h: 28.8% of the initial level]. While neutrophils derived from healthy heterozygous mutation carriers again showed a gene-dose effect (median gMFI: 67.1%), healthy and disease controls had significant lower shedding rates (median gMFI: 83.6 and 82.9%, respectively). Co-culture with colchicine and/or stimulation with adenosine triphosphate (ATP) and lipopolysaccharide (LPS) led to a significant increase in receptor shedding. Neutrophils were not prevented from spontaneous shedding by blocking IL-1 or the NLRP3 inflammasome. In summary, the data demonstrate that ex vivo cultured neutrophils derived from FMF patients display a unique phenotype with spontaneous release of high amounts of IL-18, S100A12, MPO, caspase-1, and proteinase 3 and spontaneous activation as demonstrated by the loss of CD62L. Neutrophilic activation seems to be independent from IL-1 activation and displays a gene-dose effect that may be responsible for genotype-dependent phenotypes.
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Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Mutação com Ganho de Função , Dosagem de Genes , Ativação de Neutrófilo , Neutrófilos/imunologia , Pirina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Caspase 1/sangue , Células Cultivadas , Criança , Estudos de Coortes , Febre Familiar do Mediterrâneo/sangue , Feminino , Heterozigoto , Humanos , Interleucina-18/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteína S100A12/sangue , Adulto JovemRESUMO
OBJECTIVE: To systematically analyze soluble interleukin-2 receptor (sIL-2R) in CSF as a diagnostic and disease activity biomarker in patients with sarcoidosis involving the CNS (neurosarcoidosis). METHODS: sIL-2R was determined by chemiluminescent immunoassays in CSF/serum samples from patients with neurosarcoidosis (n = 23), MS (n = 19), neurotuberculosis (n = 8), viral (n = 18) and bacterial (n = 9) meningitis, cerebral lymphoma (n = 15), Guillain-Barré syndrome (n = 8), and 115 patients with noninflammatory neurologic diseases (NINDs) as controls. The sIL-2R index was calculated by dividing the CSF/serum sIL-2R quotient (QsIL-2R) through the CSF/serum albumin quotient (QAlb). sIL-2R quotient diagrams were established by plotting QsIL-2R against QAlb. sIL-2R levels were correlated with clinical, MRI, and CSF disease activity markers of neurosarcoidosis. RESULTS: Patients with neurosarcoidosis had higher CSF sIL-2R, QsIL-2R, and sIL-2R index values than patients with NINDs (p < 0.0001 for all pairwise group comparisons). sIL-2R quotient diagrams demonstrated an intrathecal sIL-2R synthesis in >50% of neurosarcoidosis samples. Similar findings were observed in viral/bacterial meningitis, CNS lymphoma, and, most pronounced, in neurotuberculosis, but not in patients with MS. CSF sIL-2R parameters were associated with clinical disease activity, leptomeningeal gadolinium enhancement, and the CSF white cell count in patients with neurosarcoidosis. CONCLUSIONS: CSF sIL-2R parameters are elevated in patients with neurosarcoidosis, but this finding is not specific for neurosarcoidosis. Nevertheless, CSF sIL-2R parameters may help distinguishing neurosarcoidosis from MS and are associated with clinical, radiologic, and CSF disease activity markers of neurosarcoidosis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF sIL-2R parameters distinguish neurosarcoidosis from NINDs and MS.
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Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/diagnóstico , Receptores de Interleucina-2/metabolismo , Sarcoidose/líquido cefalorraquidiano , Sarcoidose/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/sangue , Receptores de Interleucina-2/sangue , Estudos Retrospectivos , Sarcoidose/sangue , Adulto JovemRESUMO
PURPOSE: NEMO-deficient patients present with variable degrees of immunodeficiency. Accordingly, treatment ranges from antibiotic prophylaxis and/or IgG-substitution to allogenic hematopoietic stem cell transplantation (HSCT). The correct estimation of the immunodeficiency is essential to avoid over- as well as under-treatment. We compare the immunological phenotype of a NEMO-deficient patient with a newly-described splice site mutation that causes truncation of the NEMO zinc-finger (ZF) domain and a severe clinical course with the immunological phenotype of three NEMO-deficient patients with missense mutations and milder clinical courses and all previously published patients. METHODS: Lymphocyte subsets, proliferation, and intracellular NEMO-expression were assessed by FACS. NF-κB signal transduction was determined by measuring IκBα-degradation and the production of cytokines upon stimulation with TNF-α, IL-1ß, and TLR-agonists in immortalized fibroblasts and whole blood, respectively. RESULTS: The patient with truncated ZF-domain of NEMO showed low levels of IgM and IgG, reduced class-switched memory B cells, almost complete skewing towards naïve CD45RA+ T cells, impaired T cell proliferation as well as cytokine production upon stimulation with TNF-α, IL-1ß, and TLR-agonists. He suffered from severe infections (sepsis, pneumonia, osteomyelitis) during infancy. In contrast, three patients with missense mutations in IKBKG presented neither skewing of T cells towards naïvety nor impaired T cell proliferation. They are stable on prophylactic IgG-substitution or even off any prophylactic treatment. CONCLUSION: The loss of the ZF-domain and the impaired T cell proliferation accompanied by almost complete persistence of naïve T cells despite severe infections are suggestive for a profound immunodeficiency. Allogenic HSCT should be considered early for these patients before chronic sequelae occur.
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Genótipo , Quinase I-kappa B/genética , Síndromes de Imunodeficiência/imunologia , Deleção de Sequência/genética , Linfócitos T/imunologia , Adulto , Proliferação de Células , Células Cultivadas , Pré-Escolar , Feminino , Humanos , Imunoglobulina G/metabolismo , Síndromes de Imunodeficiência/genética , Memória Imunológica , Lactente , Masculino , Linhagem , Fenótipo , PrognósticoRESUMO
INTRODUCTION: Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated. METHODS AND ANALYSIS: The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité - Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 µg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine. ETHICS AND DISSEMINATION: The institutional ethics committee approved this study on 1 August 2018 (Ethics Committee of Charité - Universitätsmedizin Berlin, EA4/006/18). The results of the study will be disseminated in an international peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT03510650.
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Unidades de Terapia Intensiva/estatística & dados numéricos , Linfo-Histiocitose Hemofagocítica/epidemiologia , Adulto , Berlim/epidemiologia , Biomarcadores/sangue , Feminino , Humanos , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Estudos Observacionais como Assunto , Estudos ProspectivosRESUMO
Chronic fatigue syndrome (CFS) is a severe disease characterized by various symptoms of immune dysfunction. CFS onset is typically with an infection and many patients suffer from frequently recurrent viral or bacterial infections. Immunoglobulin and mannose binding lectin (MBL) deficiency are frequent causes for increased susceptibility to infections. In this study we retrospectively analysed 300 patients with CFS for immunoglobulin and MBL levels, and B-cell subset frequencies. 25% of the CFS patients had decreased serum levels of at least one antibody class or subclass with IgG3 and IgG4 subclass deficiencies as most common phenotypes. However, we found elevated immunoglobulin levels with an excess of IgM and IgG2 in particular in another 25% of patients. No major alteration in numbers of B cells and B-cell subsets was seen. Deficiency of MBL was found in 15% of the CFS patients in contrast to 6% in a historical control group. In a 2nd cohort of 168 patients similar frequencies of IgG subclass and MBL deficiency were found. Thus, humoral immune defects are frequent in CFS patients and are associated with infections of the respiratory tract.
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Síndrome de Fadiga Crônica/imunologia , Imunoglobulina G/genética , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo/imunologia , Infecções Respiratórias/imunologia , Adulto , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Suscetibilidade a Doenças , Síndrome de Fadiga Crônica/sangue , Síndrome de Fadiga Crônica/genética , Síndrome de Fadiga Crônica/patologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Imunoglobulina M/genética , Masculino , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/imunologia , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/patologia , Pessoa de Meia-Idade , Fenótipo , Recidiva , Infecções Respiratórias/sangue , Infecções Respiratórias/genética , Infecções Respiratórias/patologia , Estudos RetrospectivosRESUMO
Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported. In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4(+) and CD8(+) T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication. Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.
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Linfócitos B/imunologia , Síndrome de Fadiga Crônica/imunologia , Herpesvirus Humano 4/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Anticorpos Antivirais/sangue , Sequência de Bases , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Síndrome de Fadiga Crônica/virologia , Feminino , Citometria de Fluxo , Herpesvirus Humano 4/fisiologia , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Subpopulações de Linfócitos T , Replicação ViralRESUMO
BACKGROUND: Infections are the leading cause of death in the acute phase following spinal cord injury and qualify as independent risk factor for poor neurological outcome ("disease modifying factor"). The enhanced susceptibility for infections is not stringently explained by the increased risk of aspiration in tetraplegic patients, neurogenic bladder dysfunction, or by high-dose methylprednisolone treatment. Experimental and clinical pilot data suggest that spinal cord injury disrupts the balanced interplay between the central nervous system and the immune system. The primary hypothesis is that the Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS) is 'neurogenic' including deactivation of adaptive and innate immunity with decreased HLA-DR expression on monocytes as a key surrogate parameter. Secondary hypotheses are that the Immune Depression Syndrome is i) injury level- and ii) severity-dependent, iii) triggers transient lymphopenia, and iv) causes qualitative functional leukocyte deficits, which may endure the post-acute phase after spinal cord injury. METHODS/DESIGN: SCIentinel is a prospective, international, multicenter study aiming to recruit about 118 patients with acute spinal cord injury or control patients with acute vertebral fracture without neurological deficits scheduled for spinal surgery. The assessment points are: i) <31 hours, ii) 31-55 hours, iii) 7 days, iv) 14 days, and v) 10 weeks post-trauma. Assessment includes infections, concomitant injury, medication and neurological classification using American Spinal Injury Association impairment scale (AIS) and neurological level. Laboratory analyses comprise haematological profiling, immunophenotyping, including HLA-DR expression on monocytes, cytokines and gene expression of immune modulators. We provide an administrative interim analysis of the recruitment schedule of the trial. DISCUSSION: The objectives are to characterize the dysfunction of the innate and adaptive immune system after spinal cord injury and to explore its proposed 'neurogenic' origin by analyzing its correlation with lesion height and severity. The trial protocol considers difficulties of enrolment in an acute setting, and loss to follow up. The administrative interim analysis confirmed the feasibility of the protocol. Better understanding of the SCI-IDS is crucial to reduce co-morbidities and thereby to attenuate the impact of disease modifying factors to protect neurological "outcome at risk". This putatively results in improved spinal cord injury medical care. TRIAL REGISTRATION DRKS-ID: DRKS00000122 (German Clinical Trials Registry).
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Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/epidemiologia , Bases de Dados Factuais , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/epidemiologia , Estudos de Viabilidade , Humanos , Internacionalidade , Estudos Longitudinais , Estudos ProspectivosRESUMO
There is growing evidence that adaptive immunity contributes to endogenous regeneration processes: For example, endogenous bone fracture repair is modulated by T cells even in the absence of infection. Because delayed or incomplete fracture healing is associated with poor long-term outcomes and high socioeconomic costs, we investigated the relationship between an individual's immune reactivity and healing outcome. Our study revealed that delayed fracture healing significantly correlated with enhanced levels of terminally differentiated CD8(+) effector memory T (TEMRA) cells (CD3(+)CD8(+)CD11a(++)CD28(-)CD57(+) T cells) in peripheral blood. This difference was long lasting, reflecting rather the individual's immune profile in response to lifelong antigen exposure than a post-fracture reaction. Moreover, CD8(+) TEMRA cells were enriched in fracture hematoma; these cells were the major producers of interferon-γ/tumor necrosis factor-α, which inhibit osteogenic differentiation and survival of human mesenchymal stromal cells. Accordingly, depletion of CD8(+) T cells in a mouse osteotomy model resulted in enhanced endogenous fracture regeneration, whereas a transfer of CD8(+) T cells impaired the healing process. Our data demonstrate the high impact of the individual adaptive immune profile on endogenous bone regeneration. Quantification of CD8(+) TEMRA cells represents a potential marker for the prognosis of the healing outcome and opens new opportunities for early and targeted intervention strategies.
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Regeneração Óssea/imunologia , Regeneração Óssea/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Adulto , Diferenciação Celular/fisiologia , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Major abdominal procedures are strongly associated with postoperative immunosuppression and subsequent increased patient morbidity. It is believed that laparoscopic surgery causes less depletion of the systemic immune function because of the reduced tissue trauma. Various cytokines and monocytic HLA-DR expression have been successfully implemented to assess postoperative immune function. The aim of our study was to show the difference in immunologic profiles after minimally invasive versus conventional liver resection. METHODS: Ten animals underwent either laparoscopic or conventional open left lateral liver resection. Flow cytometric characteristics of HLA-DR expression on monocytes and lipopolysaccharide-stimulated cellular secretion of tumor necrosis factor α, interferon γ, interleukin 6, and interleukin 8 were measured and analyzed in ex vivo whole blood samples. Intraoperative and postoperative clinical outcome parameters were also documented and evaluated. RESULTS: All animals survived the procedures. Postoperative complications were fever (n = 3), wound infections (n = 2), and biloma (n = 1). Open surgery showed a morbidity rate of 80% compared with 40% after laparoscopic surgery. Laparoscopic liver resection showed no postoperative immunoparalysis. Major histocompatibility complex class II expression in this group was elevated, whereas the open surgery group showed decreased major histocompatibility complex class II expression on postoperative day 1. Postoperative secretion of tumor necrosis factor , interleukin 6, and interferon was lower in the open surgery group. Elevated transaminase levels after laparoscopy might have resulted from an ischemia/reperfusion injury caused by the capnoperitoneum. CONCLUSION: Major immunoparalysis depression was not observed in either group. Laparoscopic surgery shows a tendency to improve immunologic recovery after liver resection.
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Citocinas/imunologia , Antígenos HLA-DR/imunologia , Hepatectomia/métodos , Tolerância Imunológica , Imunidade Celular , Laparoscopia , Monócitos/imunologia , Animais , Feminino , Antígenos HLA-DR/biossíntese , Fígado , Monócitos/metabolismo , Suínos , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Polyomavirus associated nephropathy (PVAN) affects up to 10% of kidney transplant recipients and is a major risk factor for graft loss. Mannose-binding lectin (MBL) is an important recognition molecule of the innate immune system, and its deficiency has been associated with susceptibility to various infections. In transplantation, on the other hand, high MBL levels have been associated with increased tissue damage in ischemia-reperfusion models and poorer graft and patient survival in solid organ transplant patients. To investigate the relation between MBL and BK virus infection, post-transplant (post-Tx) MBL levels were determined in a cohort of de novo kidney transplant patients with and without BK viremia. PATIENTS AND METHODS: 41 de novo kidney transplant patients with high (n=16, group 1) or low level BK viremia (n=25, group 2) and 64 patients without BK viremia (group 3) were included. In every patient, functional MBL levels were determined at 1-3 time points (days 30, 90 or 180) post-Tx using an MBL oligomer ELISA. RESULTS: MBL levels remained unchanged between days 30 and 180 post-Tx independent of BKV viremia. Frequencies of MBL deficiency (<500 ng/mL) and MBL levels were not significantly different between the 3 groups. However, group 2 patients showed a trend towards lower MBL serum levels compared to group 1 patients, notably in patients without acute rejection (p=0.076). CONCLUSION: MBL deficiency was not associated with higher risk for BK viremia. In contrast, we hypothesize that BK virus replication in patients with low MBL levels might imply lower risk for progression towards PVAN compared to patients with high MBL levels. This view is supported by recent data demonstrating local complement activation in BK nephropathy.
Assuntos
Vírus BK , Nefropatias/sangue , Nefropatias/virologia , Transplante de Rim , Lectina de Ligação a Manose/sangue , Infecções por Polyomavirus/sangue , Adulto , Ativação do Complemento/imunologia , Feminino , Humanos , Nefropatias/imunologia , Masculino , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Infecções por Polyomavirus/imunologia , Fatores de Risco , Viremia/imunologia , Viremia/virologiaRESUMO
BACKGROUND: High-mobility group box-1 (HMGB-1) protein is released during "late sepsis" by activated monocytes. We investigated whether systemic HMGB-1 levels are associated with indices of monocytic activation/function in patients with sepsis-induced immunosuppression. METHODOLOGY: 36 patients (31 male, 64 +/- 14 years) with severe sepsis/septic shock and monocytic deactivation (reduced mHLA-DR expression and TNF-alpha release) were assessed in a subanalysis of a placebo-controlled immunostimulatory trial using GM-CSF. HMGB-1 levels were assessed over a 9-day treatment interval. Data were compared to standardized biomarkers of monocytic immunity (mHLA-DR expression, TNF-alpha release). PRINCIPLE FINDINGS: HMGB-1 levels were enhanced in sepsis but did not differ between treatment and placebo groups at baseline (14.6 +/- 13.5 versus 12.5 +/- 11.5 ng/ml, P = .62). When compared to controls, HMGB-1 level increased transiently in treated patients at day 5 (27.8 +/- 21.7 versus 11.0 +/- 14.9, P = .01). Between group differences were not noted at any other point of assessment. HMGB-1 levels were not associated with markers of monocytic function or clinical disease severity. CONCLUSIONS: GM-CSF treatment for sepsis-induced immunosuppression induces a moderate but only transient increase in systemic HMGB-1 levels. HMGB-1 levels should not be used for monitoring of monocytic function in immunostimulatory trials as they do not adequately portray contemporary changes in monocytic immunity.