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1.
Emerg Infect Dis ; 25(7): 1304-1313, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31211667

RESUMO

Bourbon virus (BRBV) is a recently discovered tick-transmitted viral pathogen that is prevalent in the Midwest and southern United States. Since 2014, zoonotic BRBV infections have been verified in several human cases of severe febrile illness, occasionally with fatal outcomes, indicating a possible public health threat. We analyzed the pathology of BRBV infection in mice and found a high sensitivity of the virus to the host interferon system. Infected standard laboratory mice did not show clinical signs or virus replication. However, in mice carrying defects in the type I and type II interferon system, the virus grew to high titers and caused severe pathology. In cell culture, BRBV was blocked by antiviral agents like ribavirin and favipiravir (T705). Our data suggest that persons having severe BRBV infection might have a deficiency in their innate immunity and could benefit from an already approved antiviral treatment.

2.
Front Immunol ; 10: 951, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114586

RESUMO

The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic Fas mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.

3.
Front Immunol ; 10: 297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941118

RESUMO

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

4.
Hemodial Int ; 23(2): E59-E64, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30548910

RESUMO

Despite substantial improvements following the introduction of novel agents and antibodies, amyloid light-chain (AL)-amyloidosis still carries a grim prognosis. Here, we report on the case of a severely frail 86-year-old patient suffering from monoclonal gammopathy of renal significance (MGRS)-associated AL-amyloidosis with a diuretic-refractory nephrotic syndrome. In this patient, treatment with bortezomib-dexamethasone effectively induced a serological response, but was unfortunately poorly tolerated and failed to promote renal recovery fast enough to prevent secondary complications. Facing ongoing nephrotic syndrome, we performed unilateral kidney embolization and observed a substantial improvement of hypoalbuminemia accompanied by a significant gain in overall quality of life despite the necessity for thrice weekly dialysis. It can be concluded that systemic drugs in MGRS typically do not lead to instantaneous organ recovery but may initially rather be associated with substantial treatment-related morbidity. In this setting, unilateral renal artery embolization is effective to treat nephrotic syndrome and its secondary complications. The risk of potentially adverse effects, including post-embolization syndrome, can be minimized by unilateral embolization, still noting that also one-sided renal ablation has to be balanced against the requirement for life-long renal replacement therapy. Prospective controlled trials in a more comprehensive cohort will be needed to estimate the overall benefit of kidney embolization relative to novel agent therapies in frail patients with MGRS-related AL-amyloidosis.

6.
Eur J Immunol ; 48(12): 1975-1988, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30315710

RESUMO

The autosomal-dominant hyper-IgE syndrome (HIES), caused by mutations in STAT3, is a rare primary immunodeficiency that predisposes to mucocutaneous candidiasis and staphylococcal skin and lung infections. This infection phenotype is suggestive of defects in neutrophils, but data on neutrophil functions in HIES are inconsistent. This study was undertaken to functionally characterize neutrophils in STAT3-deficient HIES patients and to analyze whether the patients` eosinophilia affects the neutrophil phenotype in S. aureus infection. Neutrophil functions and cell death kinetics were studied in eight STAT3-deficient patients. Moreover, the response of STAT3-deficient neutrophils to S. aureus and the impact of autologous eosinophils on pathogen-induced cell death were analyzed. No specific aberrations in neutrophil functions were detected within this cohort. However, the half-life of STAT3-deficient neutrophils ex vivo was reduced, which was partially attributable to the presence of eosinophils. Increased S. aureus-induced cell lysis, dependent on the staphylococcal virulence controlling accessory gene regulator (agr)-locus, was observed in STAT3-deficient neutrophils and upon addition of eosinophils. Accelerated neutrophil cell death kinetics may underlie the reported variability in neutrophil function testing in HIES. Increased S. aureus-induced lysis of STAT3-deficient neutrophils might affect pathogen control and contribute to tissue destruction during staphylococcal infections in HIES.

7.
Front Immunol ; 9: 2012, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250467

RESUMO

Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30019536

RESUMO

Chronic kidney disease (CKD) is characterized by the loss of nephrons and worsening organ-fibrosis that leads to deterioration and ultimately the total breakdown of kidney function. Renal fibrosis has become a major public health problem worldwide and necessitates hemodialysis and kidney transplantation in affected patients. CKD is mainly characterized by the activation and proliferation of interstitial fibroblasts and by excessive synthesis and accumulation of extracellular matrix components, causing the disruption of the normal tissue architecture of the kidney. Septins are GTPase proteins associated with membranes, actin filaments, and microtubules and are undoubtedly crucial for cytoskeleton organization. Although some septins are involved in liver fibrosis, they have not been investigated in the context of renal fibrosis. Here, we show that numerous septins are expressed in the healthy kidney and demonstrate in fibrotic mouse kidneys that various septins are remarkably up-regulated in the tubulointerstitium compared to contralateral control kidneys. We observed the same findings in human fibrotic kidneys. In both healthy and fibrotic kidneys, septins are coexpressed with extracellular matrix components, reinforcing the structural function of septins as cytoskeletal components. Furthermore, we could show in septin 8-deficient mice that septin 8 is dispensable for the formation of renal fibrosis, and that no other septin was compensatory changed in kidneys compared to wild-type mice.

11.
Artigo em Inglês | MEDLINE | ID: mdl-29729943

RESUMO

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

12.
Pediatr Transplant ; 22(4): e13195, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29665156

RESUMO

HEV infection can lead to chronic hepatitis in immunosuppressed patients; extrahepatic manifestations are rarely seen. Here, we report a 13-year-old renal transplant patient with chronic hepatitis E and renal involvement. Ribavirin therapy led to temporary virus clearance and amelioration of kidney function. However, ribavirin therapy caused severe hyporegenerative anemia, which has so far only been reported in patients treated with a combination of ribavirin and interferon alpha.


Assuntos
Anemia/induzido quimicamente , Antivirais/efeitos adversos , Hepatite E/tratamento farmacológico , Transplante de Rim , Complicações Pós-Operatórias/tratamento farmacológico , Ribavirina/efeitos adversos , Adolescente , Anemia/diagnóstico , Antivirais/uso terapêutico , Doença Crônica , Feminino , Hepatite E/etiologia , Humanos , Ribavirina/uso terapêutico
13.
Sci Rep ; 8(1): 5321, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29593307

RESUMO

Cancer research of immune-modulating mechanisms mainly addresses the role of tumor-infiltrating immune cells. Mechanisms modulating the adaptive immune system at the primary activation site - the draining lymph node (LN) - are less investigated. Here we present tumor-caused histomorphological changes in tumor draining LNs of breast cancer patients, dependent on the localization (sentinel LN vs. non-sentinel LN), the tumor size, the intrinsic subtype and nodal metastatic status. The quantitative morphological study was conducted in breast cancer patients with at least one sentinel LN and no neoadjuvant therapy. All LNs were annotated considering to their topographical location, stained for IgD/H&E, digitized and quantitatively analyzed. In 206 patients, 394 sentinels and 940 non-sentinel LNs were categorized, comprising 40758 follicles and 7074 germinal centers. Subtype specific immunomorphological patterns were detectable: Follicular density was higher in LNs of Her2 enriched hormone receptor positive and triple-negative breast cancers whereas hormone receptor positive breast cancers showed more macrophage infiltrations in the LN cortex. Follicles are rounder in metastatic LNs and non-sentinel LNs. The identified immunomorphological changes reflect different underlying immunomodulations taking place in the tumor-draining LNs and should therefore be considered as possible prognostic and predictive markers for LN metastasis and therapy associated immunomodulation.

14.
BMC Nephrol ; 19(1): 7, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29329521

RESUMO

BACKGROUND: C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown. METHODS: Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time. RESULTS: After treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab. CONCLUSIONS: Eculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C3/metabolismo , Glomerulonefrite/sangue , Glomerulonefrite/tratamento farmacológico , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
15.
World J Urol ; 36(4): 673-680, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29368229

RESUMO

PURPOSE: To evaluate the viability and biocompatibility of a novel, patented bioadhesive system for intrarenal embedding and retrieval of residual fragments after endoscopic lithotripsy. Complete stone clearance via active removal of residual fragments (RF) after intracorporeal laser lithotripsy may be time-consuming and fail in many cases. Therefore, the novel adhesive has been developed and evaluated for the first time in an in vivo pig model in the present work. METHODS: Four female domestic pigs underwent flexible ureteroscopy (RIRS) or percutaneous nephrolithotomy (PNL) under general anesthesia (8 kidneys, 4 × RIRS, 4 × PNL) evaluating the bioadhesive system. INTERVENTIONS: RIRS without adhesive system (sham procedure, kidney I); 3 × RIRS using the bioadhesive system (kidneys II-IV); and 4 × PNL using the bioadhesive system (V-VIII). We endoscopically inserted standardized human stone probes followed by comminution using Ho:YAG lithotripsy. The bioadhesive (kidney II-VIII) was then applied and the adhesive-stone fragment complex extracted. After nephrectomy, all kidneys were evaluated by two independent, blinded pathologists. Endpoints were the procedure's safety and adhesive system's biocompatibility. RESULTS: We observed no substantial toxic effects. We were able to embed and remove 80-90% of fragments. However, because of the pig's hampering pyelocaliceal anatomy, a quantified, proportional assessment of the embedded fragments was compromised. CONCLUSIONS: For the first time, we demonstrated the proven feasibility and safety of this novel bioadhesive system for embedding and endoscopically removing small RF in conjunction with a lack of organ toxicity in vivo.


Assuntos
Adesivos/uso terapêutico , Litotripsia/efeitos adversos , Ureteroscopia/métodos , Animais , Materiais Biocompatíveis/uso terapêutico , Modelos Animais de Doenças , Endoscopia/métodos , Feminino , Litotripsia/métodos , Nefrolitotomia Percutânea/métodos , Reoperação/métodos , Suínos , Resultado do Tratamento
16.
J Allergy Clin Immunol ; 141(2): 730-740, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28554560

RESUMO

BACKGROUND: A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. OBJECTIVES: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. METHODS: We quantified TH1/TH2/TH17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. RESULTS: Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3+CCR6- TH1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)+ B cells in lymph nodes, and an accumulation of T-bet+CD21low B cells in peripheral blood of affected patients. CONCLUSION: Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21low B cells might serve as a marker of this IFN-γ-associated dysregulation.

18.
EMBO Rep ; 18(12): 2144-2159, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29097394

RESUMO

Immunity to mycobacteria involves the formation of granulomas, characterized by a unique macrophage (MΦ) species, so-called multinucleated giant cells (MGC). It remains unresolved whether MGC are beneficial to the host, that is, by prevention of bacterial spread, or whether they promote mycobacterial persistence. Here, we show that the prototypical antimycobacterial molecule nitric oxide (NO), which is produced by MGC in excessive amounts, is a double-edged sword. Next to its antibacterial capacity, NO propagates the transformation of MΦ into MGC, which are relatively permissive for mycobacterial persistence. The mechanism underlying MGC formation involves NO-induced DNA damage and impairment of p53 function. Moreover, MGC have an unsurpassed potential to engulf mycobacteria-infected apoptotic cells, which adds a further burden to their antimycobacterial capacity. Accordingly, mycobacteria take paradoxical advantage of antimicrobial cellular efforts by driving effector MΦ into a permissive MGC state.


Assuntos
Células Gigantes/microbiologia , Macrófagos/fisiologia , Mycobacterium/metabolismo , Óxido Nítrico/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Dano ao DNA , Genes p53/fisiologia , Células Gigantes/metabolismo , Humanos , Macrófagos/microbiologia , Camundongos , Mycobacterium/imunologia , Óxido Nítrico/biossíntese
20.
Nat Immunol ; 18(10): 1150-1159, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28805811

RESUMO

Caveolin-1 (Cav1) regulates the nanoscale organization and compartmentalization of the plasma membrane. Here we found that Cav1 controlled the distribution of nanoclusters of isotype-specific B cell antigen receptors (BCRs) on the surface of B cells. In mature B cells stimulated with antigen, the immunoglobulin M BCR (IgM-BCR) gained access to lipid domains enriched for GM1 glycolipids, by a process that was dependent on the phosphorylation of Cav1 by the Src family of kinases. Antigen-induced reorganization of nanoclusters of IgM-BCRs and IgD-BCRs regulated BCR signaling in vivo. In immature Cav1-deficient B cells, altered nanoscale organization of IgM-BCRs resulted in a failure of receptor editing and a skewed repertoire of B cells expressing immunoglobulin-µ heavy chains with hallmarks of poly- and auto-reactivity, which ultimately led to autoimmunity in mice. Thus, Cav1 emerges as a cell-intrinsic regulator that prevents B cell-induced autoimmunity by means of its role in plasma-membrane organization.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Caveolina 1/metabolismo , Tolerância Imunológica , Receptores de Antígenos de Linfócitos B/metabolismo , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Caveolina 1/genética , Expressão Gênica , Tolerância Imunológica/genética , Imunoglobulina D/imunologia , Imunoglobulina D/metabolismo , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fosforilação , Ligação Proteica , Receptores de Antígenos de Linfócitos B/genética
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