Publications by authors named "Martina Sester"

105 Publications

The future of SARS-CoV-2 vaccines in transplant recipients: To be determined.

Am J Transplant 2021 Apr 8. Epub 2021 Apr 8.

Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.1111/ajt.16598DOI Listing
April 2021

Diversity of antibody responses after influenza infection or vaccination-Needed or nice to have?

Am J Transplant 2021 Feb 27. Epub 2021 Feb 27.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

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http://dx.doi.org/10.1111/ajt.16554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014159PMC
February 2021

Case Report: Management of a Multidrug-Resistant CMV-Strain in a Renal Transplant Recipient by High-Dose CMV-Specific Immunoglobulins, Modulation in Immunosuppression, and Induction of CMV-Specific Cellular Immunity.

Front Immunol 2020 25;11:623178. Epub 2021 Jan 25.

Transplant Nephrology/Department of Internal Medicine D, University Hospital Münster, Westphalian Wilhelm's University Münster, Münster, Germany.

The management of multidrug-resistant strains of cytomegalovirus after solid organ transplantation is challenging. This case report demonstrates the successful treatment of a multidrug-resistant strain of cytomegalovirus that may represent a valuable option for problematic cases. This report illustrates the emergence of a multidrug-resistant cytomegalovirus (CMV) UL54 mutant strain in a renal transplant recipient with severe lymphopenia and thrombocytopenia. We show that the combined treatment with high-dose intravenous cytomegalovirus-specific immunoglobulins (CMV-IVIG) after the switch to a mammalian target of rapamycin (mTOR)-inhibitor and cyclosporine A was a successful treatment alternative to direct antiviral treatment with high-dose ganciclovir and foscarnet. This treatment was associated with a quantitative induction of CMV-specific CD4 and CD8 T cells that showed maturation in phenotype and functionality with decreasing viral load. Our case report illustrates that high-dose CMV-IVIG and conversion of immunosuppressive drugs to mTOR inhibitors and cyclosporine A can be a successful treatment in a situation where the use of direct antiviral drugs was considered insufficient.
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http://dx.doi.org/10.3389/fimmu.2020.623178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868410PMC
June 2021

Impact of COVID-19 in solid organ transplant recipients.

Am J Transplant 2021 03 26;21(3):925-937. Epub 2021 Feb 26.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exploded onto the world stage in early 2020. The impact on solid organ transplantation (SOT) has been profound affecting potential donors, candidates, and recipients. Importantly, decreased donations and the pressure of limited resources placed on health care by the pandemic also disrupted transplant systems. We address the impact of COVID-19 on organ transplantation globally and review current understanding of the epidemiology, outcomes, diagnosis, and treatment of COVID-19 in SOT recipients.
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http://dx.doi.org/10.1111/ajt.16449DOI Listing
March 2021

Effect of everolimus-based drug regimens on CMV-specific T-cell functionality after renal transplantation: 12-month ATHENA subcohort-study results.

Eur J Immunol 2021 Apr 28;51(4):943-955. Epub 2020 Dec 28.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections.
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http://dx.doi.org/10.1002/eji.202048855DOI Listing
April 2021

Wrinkle in the plan: miR-34a-5p impacts chemokine signaling by modulating CXCL10/CXCL11/CXCR3-axis in CD4, CD8 T cells, and M1 macrophages.

J Immunother Cancer 2020 11;8(2)

Institute of Human Genetics, Saarland University, 66421 Homburg, Germany.

Background: In 2016 the first-in-human phase I study of a miRNA-based cancer therapy with a liposomal mimic of microRNA-34a-5p (miR-34a-5p) was closed due to five immune related serious adverse events (SAEs) resulting in four patient deaths. For future applications of miRNA mimics in cancer therapy it is mandatory to unravel the miRNA effects both on the tumor tissue and on immune cells. Here, we set out to analyze the impact of miR-34a-5p over-expression on the CXCL10/CXCL11/CXCR3 axis, which is central for the development of an effective cancer control.

Methods: We performed a whole genome expression analysis of miR-34a-5p transfected M1 macrophages followed by an over-representation and a protein-protein network analysis. In-silico miRNA target prediction and dual luciferase assays were used for target identification and verification. Target genes involved in chemokine signaling were functionally analyzed in M1 macrophages, CD4 and CD8 T cells.

Results: A whole genome expression analysis of M1 macrophages with induced miR-34a-5p over-expression revealed an interaction network of downregulated target mRNAs including and In-silico target prediction in combination with dual luciferase assays identified direct binding of miR-34a-5p to the 3'UTRs of and . Decreased CXCL10 and CXCL11 secretion was shown on the endogenous protein level and in the supernatant of miR-34a-5p transfected and activated M1 macrophages. To complete the analysis of the CXCL10/CXCL11/CXCR3 axis, we activated miR-34a-5p transfected CD4 and CD8 T cells by PMA/Ionomycin and found reduced levels of endogenous CXCR3 and CXCR3 on the cell surface.

Conclusions: MiR-34a-5p mimic administered by intravenous administration will likely not only be up-taken by the tumor cells but also by the immune cells. Our results indicate that miR-34a-5p over-expression leads in M1 macrophages to a reduced secretion of CXCL10 and CXCL11 chemokines and in CD4 and CD8 T cells to a reduced expression of CXCR3. As a result, less immune cells will be attracted to the tumor site. Furthermore, high levels of miR-34a-5p in naive CD4 T cells can in turn hinder Th1 cell polarization through the downregulation of CXCR3 leading to a less pronounced activation of cytotoxic T lymphocytes, natural killer, and natural killer T cells and possibly contributing to lymphocytopenia.
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http://dx.doi.org/10.1136/jitc-2020-001617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684812PMC
November 2020

Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings.

Nat Med 2020 12 19;26(12):1941-1949. Epub 2020 Oct 19.

Tuberculosis Network European Trials Group (TBnet), Borstel, Germany.

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.
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http://dx.doi.org/10.1038/s41591-020-1076-0DOI Listing
December 2020

Quantitative and time-resolved miRNA pattern of early human T cell activation.

Nucleic Acids Res 2020 10;48(18):10164-10183

Institute of Human Genetics, Saarland University, 66421 Homburg, Germany.

T cells are central to the immune response against various pathogens and cancer cells. Complex networks of transcriptional and post-transcriptional regulators, including microRNAs (miRNAs), coordinate the T cell activation process. Available miRNA datasets, however, do not sufficiently dissolve the dynamic changes of miRNA controlled networks upon T cell activation. Here, we established a quantitative and time-resolved expression pattern for the entire miRNome over a period of 24 h upon human T-cell activation. Based on our time-resolved datasets, we identified central miRNAs and specified common miRNA expression profiles. We found the most prominent quantitative expression changes for miR-155-5p with a range from initially 40 molecules/cell to 1600 molecules/cell upon T-cell activation. We established a comprehensive dynamic regulatory network of both the up- and downstream regulation of miR-155. Upstream, we highlight IRF4 and its complexes with SPI1 and BATF as central for the transcriptional regulation of miR-155. Downstream of miR-155-5p, we verified 17 of its target genes by the time-resolved data recorded after T cell activation. Our data provide comprehensive insights into the range of stimulus induced miRNA abundance changes and lay the ground to identify efficient points of intervention for modifying the T cell response.
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http://dx.doi.org/10.1093/nar/gkaa788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544210PMC
October 2020

Prolonged Course of COVID-19-Associated Pneumonia in a B-Cell Depleted Patient After Rituximab.

Front Oncol 2020 2;10:1578. Epub 2020 Sep 2.

Department of Hematology, Oncology, Clinical Immunology, Rheumatology, Saarland University, Homburg, Germany.

Patients with pre-existing comorbidities and immunosuppression are at greater risk for SARS-CoV-2 infection and severe manifestations of COVID-19. This also includes cancer patients, who are shown to have a poor prognosis after infection. Here, we describe the case of a 72-year old male patient with B-cell depletion after maintenance treatment with rituximab for non-Hodgkin-lymphoma who had a prolonged COVID-19 course and initial false negative test results. Our case highlights the diagnostic pitfalls in diagnosing COVID-19 in B-cell depleted patients and discuss the role of B-cell depletion in the course and treatment of COVID-19. Furthermore, we investigated peripheral blood monocytes and SARS-CoV-2 specific T cells in our patient. In conclusion, our case report can help physicians to avoid diagnostic pitfalls for COVID-19 in hemato-oncological patients under chemoimmunotherapy and tries to explain the role of B-cell depletion and SARS-CoV-2 specific T cells in this context.
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http://dx.doi.org/10.3389/fonc.2020.01578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493633PMC
September 2020

High levels of SARS-CoV-2-specific T cells with restricted functionality in severe courses of COVID-19.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

Department of Transplant and Infection Immunology.

BACKGROUNDPatients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ in the severity of disease. We hypothesized that characteristics of SARS-CoV-2-specific immunity correlate with disease severity.METHODSIn this study, SARS-CoV-2-specific T cells and antibodies were characterized in uninfected controls and patients with different coronavirus disease 2019 (COVID-19) disease severity. SARS-CoV-2-specific T cells were flow cytometrically quantified after stimulation with SARS-CoV-2 peptide pools and analyzed for expression of cytokines (IFN-γ, IL-2, and TNF-α) and markers for activation, proliferation, and functional anergy. SARS-CoV-2-specific IgG and IgA antibodies were quantified using ELISA. Moreover, global characteristics of lymphocyte subpopulations were compared between patient groups and uninfected controls.RESULTSDespite severe lymphopenia affecting all major lymphocyte subpopulations, patients with severe disease mounted significantly higher levels of SARS-CoV-2-specific T cells as compared with convalescent individuals. SARS-CoV-2-specific CD4+ T cells dominated over CD8+ T cells and closely correlated with the number of plasmablasts and SARS-CoV-2-specific IgA and IgG levels. Unlike in convalescent patients, SARS-CoV-2-specific T cells in patients with severe disease showed marked alterations in phenotypical and functional properties, which also extended to CD4+ and CD8+ T cells in general.CONCLUSIONGiven the strong induction of specific immunity to control viral replication in patients with severe disease, the functionally altered characteristics may result from the need for contraction of specific and general immunity to counteract excessive immunopathology in the lung.FUNDINGThe study was supported by institutional funds to MS and in part by grants of Saarland University, the State of Saarland, and the Rolf M. Schwiete Stiftung.
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http://dx.doi.org/10.1172/jci.insight.142167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605520PMC
October 2020

High-dose intranasal application of titanium dioxide nanoparticles induces the systemic uptakes and allergic airway inflammation in asthmatic mice.

Respir Res 2020 Jul 2;21(1):168. Epub 2020 Jul 2.

Department of Experimental Pneumology and Allergology, Faculty of Medicine, Saarland University, Homburg, Germany.

Background: Titanium dioxide nanoparticles (TiO NPs) have a wide range of applications in several industrial and biomedical domains. Based on the evidence, the workers exposed to inhaled nanosized TiO powder are more susceptible to the risks of developing respiratory diseases. Accordingly, this issue has increasingly attracted the researchers' interest in understanding the consequences of TiO NPs exposure. Regarding this, the present study was conducted to analyze the local effects of TiO NPs on allergic airway inflammation and their uptake in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation.

Methods: For the purpose of the study, female BALB/c mice with or without asthma were intranasally administered with TiO NPs. The mice were subjected to histological assessment, lung function testing, scanning electron microscopy (SEM), inductively coupled plasma mass spectrometry (ICP-MS), and NP uptake measurement. In addition, T helper (Th) 1/Th2 cytokines were evaluated in the lung homogenate using the enzyme-linked immunosorbent assay.

Results: According to the results, the mice receiving OVA alone or OVA plus TiO NPs showed eosinophilic infiltrates and mucus overproduction in the lung tissues, compared to the controls. Furthermore, a significant elevation was observed in the circulating Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13 after NP exposure. The TiO NPs were taken up by alveolar macrophages at different time points. As the results of the SEM and ICP-MS indicated, TiO NPs were present in most of the organs in both asthmatic and non-asthmatic mice.

Conclusion: Based on the findings of the current study, intranasally or inhalation exposure to high-dose nanosized TiO particles appears to exacerbate the allergic airway inflammation and lead to systemic uptake in extrapulmonary organs. These results indicate the very important need to investigate the upper limit of intranasally or inhalation exposure to nanosized TiO particles in occupational and environmental health policy.
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http://dx.doi.org/10.1186/s12931-020-01386-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331175PMC
July 2020

A Polyclonal Immune Function Assay Allows Dose-Dependent Characterization of Immunosuppressive Drug Effects but Has Limited Clinical Utility for Predicting Infection on an Individual Basis.

Front Immunol 2020 15;11:916. Epub 2020 May 15.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

Dosage of immunosuppressive drugs after transplantation critically determines rejection and infection episodes. In this study, a global immune function assay was characterized among controls, dialysis-patients, and transplant-recipients to evaluate its utility for pharmacodynamic monitoring of immunosuppressive drugs and for predicting infections. Whole-blood samples were stimulated with anti-CD3/toll-like-receptor (TLR7/8)-agonist in the presence or absence of drugs and IFN-γ secretion was measured by ELISA. Additional stimulation-induced cytokines were characterized among T-, B-, and NK-cells using flow-cytometry. Cytokine-secretion was dominated by IFN-γ, and mainly observed in CD4, CD8, and NK-cells. Intra-assay variability was low (CV = 10.4 ± 6.2%), whereas variability over time was high, even in the absence of clinical events (CV = 65.0 ± 35.7%). Cyclosporine A, tacrolimus and steroids dose-dependently inhibited IFN-γ secretion, and reactivity was further reduced when calcineurin inhibitors were combined with steroids. Moreover, IFN-γ levels significantly differed between controls, dialysis-patients, and transplant-recipients, with lowest IFN-γ levels early after transplantation ( < 0.001). However, a single test had limited ability to predict infectious episodes. In conclusion, the assay may have potential for basic pharmacodynamic characterization of immunosuppressive drugs and their combinations, and for assessing loss of global immunocompetence after transplantation, but its application to guide drug-dosing and to predict infectious on an individual basis is limited.
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http://dx.doi.org/10.3389/fimmu.2020.00916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243819PMC
April 2021

BK Polyomavirus-specific T Cells as a Diagnostic and Prognostic Marker for BK Polyomavirus Infections After Pediatric Kidney Transplantation.

Transplantation 2020 11;104(11):2393-2402

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.

Background: After kidney transplantation, uncontrolled BK polyomavirus (BKPyV) replication causes kidney graft failure through BKPyV-associated nephropathy (BKPyVAN), but markers predicting outcome are missing. BKPyV-specific T cells may serve as a predictive marker to identify patients at risk of persistent DNAemia and BKPyVAN.

Methods: Out of a total of 114 pediatric kidney recipients transplanted between 2008 and 2018, 36 children with posttransplant BKPyV-DNAemia were identified. In a prospective noninterventional study, BKPyV-specific CD4 and CD8 T cells were measured in 32 of 36 viremic pediatric kidney recipients using intracellular cytokine staining and flow cytometry. The course of the BKPyV replication was monitored with regard to duration of BKPyV-DNAemia and need of therapeutic intervention and diagnosis of proven BKPyVAN.

Results: Levels of BKPyV-specific T cells negatively correlated with subsequent duration of BKPyV-DNAemia. Patients with BKPyV-specific CD4 T cells ≥0.5 cells/µL and/or BKPyV-specific CD8 T cells ≥0.1 cells/µL had transient, self-limiting DNAemia (PPV 1.0, NPV 0.86). BKPyV-specific CD4 and CD8 T cells below these thresholds were found in children with persistent BKPyV-DNAemia and biopsy-proven BKPyVAN with need for therapeutic intervention. After reducing immunosuppressive therapy, levels of BKPyV-specific CD4 T cells increased while plasma BKPyV-DNAemia declined.

Conclusions: This study found that BKPyV-specific T cell levels may help to distinguish patients with transient, self-limiting BKPyV-DNAemia from those with persisting BKPyV-DNAemia and biopsy-proven BKPyVAN, who would benefit from individualized therapeutic interventions such as reduced immunosuppression. Thereby the risk for rejection because of unnecessary reduction of immunosuppression in case of self-limiting BKPyV-DNAemia can be minimized.
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http://dx.doi.org/10.1097/TP.0000000000003133DOI Listing
November 2020

Timing of Vaccination after Training: Immune Response and Side Effects in Athletes.

Med Sci Sports Exerc 2020 07;52(7):1603-1609

Institute of Sports and Preventive Medicine, Saarland University, Saarbrücken, GERMANY.

Objectives: Influenza vaccination was used to assess whether induction of immunity or side effects are influenced by the timing of the last training session before vaccination.

Methods: Forty-five healthy athletes (36 male, 23 ± 8 yr, ≥5 training sessions per week, predominantly national competition level) were vaccinated with the tetravalent influenza vaccine; blood samples were collected immediately before and 1, 2, and 26 wk after vaccination. Athletes were randomly assigned to vaccination within 2 h after the last training session versus after 24-26 h. Influenza-specific T cells were quantified after stimulation with the vaccine based on intracellular cytokine staining. Antibodies (IgA, IgG, IgM) were quantified by enzyme-linked immunosorbent assay and neutralization assay. Participants documented resulting side effects and training restrictions using a standardized diary.

Results: Both groups showed an increase in influenza-reactive CD4 T-cell levels, which peaked 1 wk after vaccination (fold changes to baseline; median (interquartile range), 3.7 (3.0-5.4; P < 0.001) in the 2-h group; 4.6 (2.8-7.4; P < 0.001) in the 26-h group) with no difference between groups (P = 0.52). Influenza-specific antibodies showed a significant increase after vaccination in both groups (at least 1.4-fold, each P < 0.001, no group differences; P = 0.24-0.97 for different antibody types). Only antibodies toward the Brisbane strain showed a trend toward significant differences in neutralization titers between groups (4-fold (2-17.8) in the 2-h group, 16-fold (4-32.9) in the 26-h group; P = 0.06), whereas other specificities did not differ (P = 0.16-0.72). No intergroup differences were found for side effects; no athlete reported a loss of training time due to the vaccination or its side effects.

Conclusion: Infection prophylaxis in elite athletes by influenza vaccination seems to be effective and safe. Timing of vaccination after prior training does not seem to require specific constraints.
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http://dx.doi.org/10.1249/MSS.0000000000002278DOI Listing
July 2020

Novel human sex-typing strategies based on the autism candidate gene NLGN4X and its male-specific gametologue NLGN4Y.

Biol Sex Differ 2019 12 18;10(1):62. Epub 2019 Dec 18.

Institute of Anatomy and Cell Biology, Saarland University, Homburg, Germany.

Background: Since the early days of PCR techniques, sex identification, "sex-typing," of genomic DNA samples has been a fundamental part of human forensic analysis but also in animal genetics aiming at strategic livestock breeding. Most analyses are employing the AMELX/AMELY gene loci on the X and Y chromosomes present in most mammals. We hypothesize that sex-typing in humans is also possible based on the genes NLGN4X and NLGN4Y, which represent X and Y chromosome-specific copies of a common ancestral neuroligin-4 orthologue.

Methods: Genomic DNA was isolated from human blood and buccal cell samples (total n = 111) and submitted to two different strategies: (a) a traditional two-primer PCR approach detecting an insertion/deletion (indel) polymorphism immediately upstream of the translational start on exon 1 and (b) detection of a single nucleotide polymorphism, SNP, on the translational stop carrying exon 7. The SNP detection was based on a quantitative PCR approach (rhAMP genotyping) employing DNA/RNA hybrid oligonucleotides that were blocked and which could only be activated upon perfect annealing to the target DNA sequence.

Results: All indel PCR-tested human DNA samples showed two bands for males representing X- and Y-specific copies of NLGN4 and a single band for female samples, i.e., homozygosity of NLGN4X and absence of NLGN4Y, in accordance with the self-reported sex of the donors. These results were in perfect agreement with the results of the rhAMP-based SNP-detection method: all males were consequently positive for both alleles, representing either SNP variant, and females were interpreted as homozygous regarding the SNP variant found in NLGN4X. Both methods have shown reliable and consistent results that enabled us to infer the sex of donor DNA samples across different ethnicities.

Conclusions: These results indicate that the detection of human NLGN4X/Y is a suitable alternative to previously reported methods employing gene loci such as AMELX/Y. Furthermore, this is the first report applying successfully the rhAMP-genotyping strategy as a means for SNP-based sex-typing, which consequently will be applicable to other gene loci or different species as well.
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http://dx.doi.org/10.1186/s13293-019-0279-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921425PMC
December 2019

Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.

Nat Immunol 2020 01 9;21(1):30-41. Epub 2019 Dec 9.

Institute of Molecular Health Science, ETH, Zurich, Switzerland.

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.
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http://dx.doi.org/10.1038/s41590-019-0548-1DOI Listing
January 2020

Elite athletes on regular training show more pronounced induction of vaccine-specific T-cells and antibodies after tetravalent influenza vaccination than controls.

Brain Behav Immun 2020 01 30;83:135-145. Epub 2019 Sep 30.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany. Electronic address:

Compliance of elite athletes with vaccination recommendations is low mainly based on concerns about side-effects and perceived poor vaccine efficacy due to continued physical training. We therefore employed seasonal influenza vaccination to investigate the effect of regular physical training on vaccine-induced cellular and humoral immunity in elite athletes and controls. Lymphocyte subpopulations and vaccine-specific T-cells were quantified and functionally characterized from 45 athletes and 25 controls before, and 1, 2 and 26 weeks after vaccination. Moreover, influenza-specific antibodies and their neutralizing function were quantified. Both groups showed a significant increase in vaccine-reactive CD4 T-cell levels which peaked one week after vaccination (p < 0.0001). The increase was significantly more pronounced in athletes (4.1-fold) compared to controls (2.3-fold; p = 0.0007). The cytokine profile changed from multifunctional T-cells co-producing IFNγ, IL-2 and TNFα to cells with restricted cytokine expression. This change in functionality was associated with a significant increase in CTLA-4 expression (p < 0.0001), which again was more pronounced in athletes. Likewise, the increase in neutralizing antibodies was stronger in athletes (p = 0.004 for H1N1; p = 0.032 for H3N2). In conclusion, both groups mounted a strong vaccine-specific cellular and humoral immunity after standard vaccination. The more pronounced increase in specific T-cells and neutralizing antibodies indicates that high frequency and intensity of training enhance vaccine-responses in elite athletes.
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http://dx.doi.org/10.1016/j.bbi.2019.09.024DOI Listing
January 2020

miR-34a as hub of T cell regulation networks.

J Immunother Cancer 2019 07 16;7(1):187. Epub 2019 Jul 16.

Institute of Human Genetics, Saarland University, Building 60, 66421, Homburg, Germany.

Background: Micro(mi)RNAs are increasingly recognized as central regulators of immune cell function. While it has been predicted that miRNAs have multiple targets, the majority of these predictions still await experimental confirmation. Here, miR-34a, a well-known tumor suppressor, is analyzed for targeting genes involved in immune system processes of leucocytes.

Methods: Using an in-silico approach, we combined miRNA target prediction with GeneTrail2, a web tool for Multi-omics enrichment analysis, to identify miR-34a target genes, which are involved in the immune system process subcategory of Gene Ontology.

Results: Out of the 193 predicted target genes in this subcategory we experimentally tested 22 target genes and confirmed binding of miR-34a to 14 target genes including VAMP2, IKBKE, MYH9, MARCH8, KLRK1, CD11A, TRAFD1, CCR1, PYDC1, PRF1, PIK3R2, PIK3CD, AP1B1, and ADAM10 by dual luciferase assays. By transfecting Jurkat, primary CD4 and CD8 T cells with miR-34a, we demonstrated that ectopic expression of miR-34a leads to reduced levels of endogenous VAMP2 and CD11A, which are central to the analyzed subcategories. Functional downstream analysis of miR-34a over-expression in activated CD8 T cells exhibits a distinct decrease of PRF1 secretion.

Conclusions: By simultaneous targeting of 14 mRNAs miR-34a acts as major hub of T cell regulatory networks suggesting to utilize miR-34a as target of intervention towards a modulation of the immune responsiveness of T-cells in a broad tumor context.
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http://dx.doi.org/10.1186/s40425-019-0670-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636054PMC
July 2019

CMV-specific T-cells and CD27-CD28-CD4+ T-cells for assignment of cytomegalovirus (CMV) status in adults awaiting organ transplant.

J Clin Virol 2019 06 25;115:37-42. Epub 2019 Mar 25.

Department of Medicine, University of Alberta, Edmonton T6G 2B7, Canada.

Background/objectives: Determination of Cytomegalovirus (CMV) status in solid organ transplant (SOT) candidates is essential to stratify risk of post-transplant CMV disease. Passive transfusion-acquired antibodies can make serologic determination of CMV status unreliable. We evaluated 3 assays, not affected by passive antibodies (PA), in assignment of CMV status: quantification of CMV-specific CD4 + T-cells (CMV-TC) and exhausted CD27-CD28- CD4 + T-cells, and detection of CMV DNA with Nucleic Acid Amplification Testing (NAAT).

Study Design: We enrolled 50 adults awaiting SOT and 50 immunocompetent age-matched controls, and collected a throat swab, urine, saliva and blood sample on each. Using flow cytometry CD4 + T-cells were phenotypically analyzed for expression of CD27 and CD28 and CMV-specific CD4 + T-cells were identified by CD69 expression and intracellular IFN-γ quantification after stimulation with CMV-antigen lysate. CMV NAAT was performed on all specimens using real-time PCR. CMV serology (CMV IgG) was determined by enzyme immunoassay. Subjects were considered to have potential PA if they received blood products within 2 months of collection.

Results: The CMV-TC assay discriminated between CMV-seropositive and seronegative SOT candidates without PA well (sensitivity 79%, specificity 93%) while the CD27-CD28-CD4 + T-cell assay had good sensitivity (86%) but specificity of 74%. Detection of CMV DNA was uncommon in CMV-seropositive SOT candidates (2/21).

Conclusions: Given its high specificity, the CMV-TC assay is valuable in confirming true-positive CMV status in seropositive SOT candidates with PA, while use of CD27-CD28-CD4 + T-cell analysis is limited by moderate specificity. Detection of CMV DNA is of limited value in assignment of CMV status in adults.
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http://dx.doi.org/10.1016/j.jcv.2019.03.014DOI Listing
June 2019

miR-34a: a new player in the regulation of T cell function by modulation of NF-κB signaling.

Cell Death Dis 2019 01 18;10(2):46. Epub 2019 Jan 18.

Institute of Human Genetics, Saarland University, 66421, Homburg, Germany.

NF-κB functions as modulator of T cell receptor-mediated signaling and transcriptional regulator of miR-34a. Our in silico analysis revealed that miR-34a impacts the NF-κB signalosome with miR-34a binding sites in 14 key members of the NF-κB signaling pathway. Functional analysis identified five target genes of miR-34a including PLCG1, CD3E, PIK3CB, TAB2, and NFΚBIA. Overexpression of miR-34a in CD4 and CD8 T cells led to a significant decrease of NFΚBIA as the most downstream cytoplasmic NF-κB member, a reduced cell surface abundance of TCRA and CD3E, and to a reduction of T cell killing capacity. Inhibition of miR-34a caused an increase of NFΚBIA, TCRA, and CD3E. Notably, activation of CD4 and CD8 T cells entrails a gradual increase of miR-34a. Our results lend further support to a model with miR-34a as a central NF-κB regulator in T cells.
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http://dx.doi.org/10.1038/s41419-018-1295-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362007PMC
January 2019

VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs.

Arthritis Res Ther 2018 Nov 9;20(1):252. Epub 2018 Nov 9.

Department of Transplant and Infection Immunology, Saarland University, 66421, Homburg, Germany.

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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http://dx.doi.org/10.1186/s13075-018-1742-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235212PMC
November 2018

Robust method for isolation of tumor infiltrating lymphocytes with a high vital cell yield from small samples of renal cell carcinomas by a new collagenase-free mechanical procedure.

Urol Oncol 2018 09 30;36(9):402.e1-402.e10. Epub 2018 Jul 30.

Department of Urology and Pediatric Urology, Saarland University, Homburg (Saar), Germany; Department of Transplant and Infection Immunology, Saarland University, Homburg (Saar), Germany. Electronic address:

Background: Tumor-infiltrating lymphocytes (TIL) play an important role in the pathogenesis of renal cell carcinoma. Characterization of TIL requires efficient isolation procedures, especially in early stage disease when the tumor is of small in size. Conventional methods for isolating TIL are based on enzymatic tissue digestion, most frequently with collagenase. Collagenase isolation is limited by poor cell recovery, altered expression of cell-surface molecules, and impaired TIL-functionality. To overcome these limitations, we developed and optimized conditions for a robust collagenase-free mechanical procedure for improved isolation of TIL from renal cell carcinoma samples.

Methods: TIL from tumor samples and T cells from peripheral blood were collected from 12 patients undergoing partial or radical nephrectomy. Samples were subjected to an enzymatic reference protocol and to a newly established mechanical isolation protocol. After viability staining, TIL-subpopulations were quantified and phenotyped by immunohistochemistry and flow-cytometric analysis, and were compared to characteristics of peripheral blood T cells. As a marker for TIL-functionality, T-cell cytokine induction was quantified after polyclonal stimulation.

Results: We show that this new technique is rapid and allows identification of CD4 and CD8 T-cell subpopulations including CD4, CD8, and regulatory T cells expressing anergy markers such as programmed death-1 (PD-1) or B- and T-lymphocyte attenuator. When compared to the reference protocol involving collagenase digestion, the yield of TIL after mechanical isolation was higher and the expression of cell-surface markers was better preserved. Moreover, although antitumor activity was not assessed, mechanically isolated TIL are at least equally functional as T cells from peripheral blood, as polyclonal stimulation induced cytokines such as interferon-γ and tumor necrosis factor-α in both TIL and T cells from peripheral blood.

Conclusion: The mechanical procedure may be applied as a robust and rapid alternative to collagenase digestion for isolation of high amounts of phenotypically and functionally intact TIL from fresh tumor samples.
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http://dx.doi.org/10.1016/j.urolonc.2018.06.002DOI Listing
September 2018

Testing for LTBI: more of the same or a step forward?

Int J Tuberc Lung Dis 2018 06;22(6):591

Department of Transplant and Infection Immunology, Saarland University Homburg, Germany , Email:

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http://dx.doi.org/10.5588/ijtld.18.0267DOI Listing
June 2018

Assigning Cytomegalovirus Status in Children Awaiting Organ Transplant: Viral Shedding, CMV-Specific T Cells, and CD27-CD28-CD4+ T Cells.

J Infect Dis 2018 09;218(8):1205-1209

Department of Pediatrics, University of Alberta, Edmonton, Canada.

Passive antibodies, maternal or transfusion-acquired, make serologic determination of pretransplant cytomegalovirus (CMV) status unreliable. We evaluated 3 assays unaffected by passive antibodies, in assignment of CMV infection status in children awaiting solid organ transplant and in controls: (1) CMV nucleic acid amplification testing (NAAT), (2) quantification of CMV-specific CD4+ T cells, and (3) quantification of CD27-CD28-CD4+ T cells. Our results highlight that CMV NAAT, from urine and oropharynx, is useful in confirming positive CMV status. Detection of CMV-specific CD4+ T cells was sensitive and specific in children >18 months but was less sensitive in children <12 months. CD27-CD28-CD4+ T cells are not likely useful in CMV risk stratification in children.
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http://dx.doi.org/10.1093/infdis/jiy309DOI Listing
September 2018

Quantity, quality, and functionality of peripheral blood cells derived from residual blood of different apheresis kits.

Transfusion 2018 06 6;58(6):1516-1526. Epub 2018 May 6.

Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Homburg, Germany.

Background: Research with primary human white blood cell (WBC) subpopulations requires high quantity, quality, and functionality of peripheral blood mononuclear cells (PBMCs) as a source to further characterize cellular subpopulations such as T and B lymphocytes, monocytes, or natural killer cells. Apart from buffy coats derived from whole blood, residual blood from preparative hemapheresis kits are used as a source for PBMCs, but knowledge on the yield and functionality of cells from different devices is limited.

Study Design And Methods: We evaluated quantity and quality of PBMCs isolated from apheresis kits of two apheresis devices (AMICUS, Fenwal; and Trima Accel, Terumo BCT), the latter being our standard source for many years. PBMCs derived from Trima or AMICUS were tested for yield and subtype composition by flow cytometry. Functionality was assessed by cytokine induction of CD4 and CD8 T cells and by degranulation. Moreover, cytotoxic activity of natural killer cells was quantified by a real-time killing assay.

Results: Mean numbers of isolated cells were 5.5 ± 2.4 × 10 for AMICUS, and 10.3 ± 6.4 × 10 for Trima Accel, respectively. The proportion of WBC subtypes corresponded to well-known numbers from whole blood, with minor differences between the two apheresis systems. Likewise, minor differences in cytokine induction were found in stimulated CD4 or CD8 T cells. Finally, PBMCs derived from the two systems showed comparable cytotoxic activity.

Conclusion: PBMC derived from residual blood of the AMICUS and Trima Accel apheresis devices serve as an economic and easily accessible source for functional PBMCs with comparable quantity and quality to PBMCs derived from whole blood.
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http://dx.doi.org/10.1111/trf.14616DOI Listing
June 2018

Decreased Migration of Dendritic Cells into the Jugular-Nodose Ganglia by the CXCL12 Neutraligand Chalcone 4 in Ovalbumin-Sensitized Asthmatic Mice.

Neuroimmunomodulation 2017 20;24(6):331-340. Epub 2018 Apr 20.

Department of Experimental Pneumology and Allergology, Internal Medicine V, Faculty of Medicine, Saarland University, Homburg, Germany.

Objective: The chemokine CXCL12 interacting with the CXC receptor 4 (CXCR4) has been reported to play a role in the development and progression of bronchial asthma, but its mechanism of action is still unknown. The objective of this study was to assess the effect of the CXCL12 neutraligand chalcone 4 on the migration of dendritic cells (DCs) in a murine model of allergic airway inflammation.

Methods: A 21-day ovalbumin (OVA)-induced allergic-airway TH2 inflammation model in BALB/c mice was used. Four groups were sensitized with OVA adsorbed on alum and challenged either with OVA or saline for 4 days. Mice were treated intranasally with chalcone 4 (300 nmol/kg body weight) or solvent 2 h before each OVA or saline challenge; 24 h after the last challenge, CD11c+F4/80- DCs were counted in the bronchoalveolar lavage. Jugular-nodose ganglion complex (JNC) sections were sampled, and for immunofluorescence staining, cryocut sections were prepared. MHC II+F4/80- DCs as well as calcitonin gene-related peptide (CGRP)- and substance P (SP)-positive neuronal cell bodies were analyzed.

Results: In OVA-challenged mice, chalcone 4 caused a significantly decreased DC/neuron ratio in the JNC from 51.7% in solvent-treated to 32.6% in chalcone 4-treated mice. In parallel, chalcone 4 also decreased the DC population in BALF from 11.5 × 103 cells in solvent to 4.5 × 103 cells in chalcone 4-treated mice. By contrast, chalcone 4 had no effect on the expression of the neuropeptides CGRP and SP in JNC.

Conclusion: This study reported the CXCL12 neutraligand chalcone 4 to affect DC infiltration into the airways and airway ganglia as well as to decrease airway eosinophilic inflammation and, therefore, validated CXCL12 as a new target in allergic disease models of asthma.
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http://dx.doi.org/10.1159/000487140DOI Listing
January 2019

Rapid reconstitution of CMV-specific T-cells after stem-cell transplantation.

Eur J Haematol 2018 Jul 17;101(1):38-47. Epub 2018 May 17.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

Objective: As reconstitution of virus-specific T-cells is critical to control cytomegalovirus (CMV)-viremia following stem-cell transplantation (SCT), we characterized the dynamics in CMV-specific T-cell reconstitution after SCT.

Methods: Cytomegalovirus-specific T-cells from 51 SCT-recipients were prospectively quantified and phenotypically characterised by intracellular cytokine-staining after specific stimulation and HLA class-I-specific pentamers using flow cytometry.

Results: Cytomegalovirus-specific CD4 T-cells reconstituted after a median of 2.3 (IQR, 2.0-3.0) weeks following autografting, and 4.0 (IQR, 3.0-5.6) weeks after allografting, with CMV-specific T-cells originating from donors and/or recipients. The time for reconstitution of CMV-specific CD4 and CD8 T-cells did not differ (P = .58). Factors delaying the time to initial reconstitution of CMV-specific CD4 T-cells included a negative recipient serostatus (P = .016) and CMV-viremia (P = .026). Percentages of CMV-specific CD4 T-cells significantly increased over time and reached a plateau after 90 days (P = .043). Relative CMV-specific CD4 T-cell levels remained higher in long-term transplant recipients compared with those in controls (P < .0001). However, due to persisting lymphopenia, absolute numbers of CMV-specific T-cells were similar as in controls.

Conclusion: Cytomegalovirus-specific T-cells rapidly reconstitute after SCT and their percentages remain high in the long term. In the face of persistent lymphopenia, this results in similar absolute numbers of CMV-specific T-cells as in controls to ensure sufficient pathogen control.
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http://dx.doi.org/10.1111/ejh.13077DOI Listing
July 2018

Assay for improved detection of antigen-specific immune cells from extrasanguinous fluids.

Eur J Immunol 2018 08 23;48(8):1412-1414. Epub 2018 Apr 23.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

In this approach, pre-stained cells from extrasanguinous fluids (ESFs) are stimulated in the presence of blood from the same individual. Thus, blood-derived antigen-presenting cells enable stimulation of both ESF- and blood T cells. Pre-staining allows distinction of T cells from ESF and blood, and simultaneous analysis of antigen-specific T cells in both compartments.
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http://dx.doi.org/10.1002/eji.201847490DOI Listing
August 2018

CTLA-4-expression on VZV-specific T cells in CSF and blood is specifically increased in patients with VZV related central nervous system infections.

Eur J Immunol 2018 01 14;48(1):151-160. Epub 2017 Sep 14.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

VZV-reactivation may lead to symptomatic central nervous system (CNS) diseases, but identification of VZV as causative pathogen of CNS-diseases is challenging. This study was performed to characterize VZV-specific T cells from cerebrospinal fluid (CSF) and blood of patients with active CNS-disease and to determine whether this may improve differential diagnosis. 27 patients with pleocytosis in the CSF were recruited and classified into three groups (10 VZV-related, 10 non-VZV-related, 7 unclear). VZV-specific CD4 T cells were quantified in CSF and blood after simultaneous stimulation with a VZV-antigen lysate and detection of cytokines (IFN-γ, IL-2, TNF-α) and CTLA-4. Polyclonal stimulation served as positive control. VZV-specific CD4 T-cell frequencies were highest in both CSF (p = 0.0001) and blood (p = 0.011) of patients with VZV-infection, and were enriched at the site of infection (p = 0.002). While cytokine-expression profiles only showed minor differences between the groups, CTLA-4-expression levels on VZV-specific T cells from CSF and blood were significantly increased in VZV-related CNS-infections (p = 0.0002 and p<0.0001) and clearly identified VZV-related CNS-diseases (100% sensitivity and 100% specificity). Polyclonally stimulated T cells did not show any quantitative and phenotypical differences between the groups. Increased frequency and CTLA-4-expression of VZV-specific T cells from CSF or blood are specifically found in patients with VZV-related CNS-infection.
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http://dx.doi.org/10.1002/eji.201747079DOI Listing
January 2018