TY - JOUR A1 - Lenz, Dominic A1 - Pahl, Jens A1 - Hauck, Fabian A1 - Alameer, Seham A1 - Balasubramanian, Meena A1 - Baric, Ivo A1 - Boy, Nikolas A1 - Church, Joseph A. A1 - Crushell, Ellen A1 - Dick, Anke A1 - Distelmaier, Felix A1 - Gujar, Jidnyasa A1 - Indolfi, Giuseppe A1 - Lurz, Eberhard A1 - Peters, Bianca A1 - Schwerd, Tobias A1 - Serranti, Daniele A1 - Kölker, Stefan A1 - Klein, Christoph A1 - Hoffmann, Georg F. A1 - Prokisch, Holger A1 - Greil, Johann A1 - Cerwenka, Adelheid A1 - Giese, Thomas A1 - Staufner, Christian T1 - NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency JF - Journal of Clinical Immunology N2 - Purpose Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. Methods Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. Results Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. Conclusion In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity. KW - NBAS KW - inborn error of immunity KW - NK cell deficiency KW - B cell deficiency KW - vesicle trafficking KW - familial hemophagocytic lymphohistiocytosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308362 SN - 0271-9142 SN - 1573-2592 VL - 41 IS - 8 ER - TY - JOUR A1 - Dirks, Johannes A1 - Andres, Oliver A1 - Paul, Luisa A1 - Manukjan, Georgi A1 - Schulze, Harald A1 - Morbach, Henner T1 - IgD shapes the pre-immune naïve B cell compartment in humans JF - Frontiers in Immunology N2 - B cell maturation and immunoglobulin (Ig) repertoire selection are governed by expression of a functional B cell receptor (BCR). Naïve B cells co-express their BCR as IgM and IgD isotype. However, the role of the additionally expressed IgD on naïve B cells is not known. Here we assessed the impact of IgD on naïve B cell maturation and Ig repertoire selection in 8 individuals from 3 different families with heterozygous loss-of-function or loss-of expression mutations in IGHD. Although naïve B cells from these individuals expressed IgM on their surface, the IGHD variant in heterozygous state entailed a chimeric situation by allelic exclusion with almost half of the naïve B cell population lacking surface IgD expression. Flow cytometric analyses revealed a distinct phenotype of IgD-negative naïve B cells with decreased expression of CD19, CD20 and CD21 as well as lower BAFF-R and integrin-β7 expression. IgD-negative B cells were less responsive in vitro after engaging the IgM-BCR, TLR7/9 or CD40 pathway. Additionally, a selective disadvantage of IgD-negative B cells within the T2 transitional and mature naïve B cell compartment as well as reduced frequencies of IgMlo/- B cells within the mature naïve B cell compartment lacking IgD were evident. RNA-Ig-seq of bulk sorted B cell populations showed an altered selection of distinct VH segments in the IgD-negative mature naïve B cell population. We conclude that IgD expression on human naïve B cells is redundant for generation of naïve B cells in general, but further shapes the naive B cell compartment starting from T2 transitional B cells. Our observations suggest an unexpected role of IgD expression to be critical for selection of distinct Ig VH segments into the pre-immune Ig repertoire and for the survival of IgMlo/- naïve B cells known to be enriched in poly-/autoreactive B cell clones. KW - B cell KW - IgD KW - IgM KW - immunoglobulin repertoire KW - B cell maturation KW - B cell receptor Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304758 VL - 14 ER - TY - JOUR A1 - Heinemann, Anna Sophie A1 - Stalp, Jan Lennart A1 - Bonifacio, João Pedro Pereira A1 - Silva, Filo A1 - Willers, Maike A1 - Heckmann, Julia A1 - Fehlhaber, Beate A1 - Völlger, Lena A1 - Raafat, Dina A1 - Normann, Nicole A1 - Klos, Andreas A1 - Hansen, Gesine A1 - Schmolke, Mirco A1 - Viemann, Dorothee T1 - Silent neonatal influenza A virus infection primes systemic antimicrobial immunity JF - Frontiers in Immunology N2 - Infections with influenza A viruses (IAV) cause seasonal epidemics and global pandemics. The majority of these infections remain asymptomatic, especially among children below five years of age. Importantly, this is a time, when immunological imprinting takes place. Whether early-life infections with IAV affect the development of antimicrobial immunity is unknown. Using a preclinical mouse model, we demonstrate here that silent neonatal influenza infections have a remote beneficial impact on the later control of systemic juvenile-onset and adult-onset infections with an unrelated pathogen, Staphylococcus aureus, due to improved pathogen clearance and clinical resolution. Strategic vaccination with a live attenuated IAV vaccine elicited a similar protection phenotype. Mechanistically, the IAV priming effect primarily targets antimicrobial functions of the developing innate immune system including increased antimicrobial plasma activity and enhanced phagocyte functions and antigen-presenting properties at mucosal sites. Our results suggest a long-term benefit from an exposure to IAV during the neonatal phase, which might be exploited by strategic vaccination against influenza early in life to enforce the host’s resistance to later bacterial infections. KW - neonate KW - influenza A virus KW - influenza vaccination KW - innate immunity training KW - antimicrobial immunity KW - Staphylococcus aureus KW - sepsis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304782 VL - 14 ER - TY - JOUR A1 - Giansanti, Manuela A1 - Theinert, Tobias A1 - Boeing, Sarah Katharina A1 - Haas, Dorothee A1 - Schlegel, Paul-Gerhardt A1 - Vacca, Paola A1 - Nazio, Francesca A1 - Caruana, Ignazio T1 - Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies JF - Molecular Cancer N2 - Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer. KW - autophagy KW - effector cells KW - mitophagy KW - metabolism KW - T and NK development Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357515 VL - 22 ER - TY - JOUR A1 - Haake, Markus A1 - Haack, Beatrice A1 - Schäfer, Tina A1 - Harter, Patrick N. A1 - Mattavelli, Greta A1 - Eiring, Patrick A1 - Vashist, Neha A1 - Wedekink, Florian A1 - Genssler, Sabrina A1 - Fischer, Birgitt A1 - Dahlhoff, Julia A1 - Mokhtari, Fatemeh A1 - Kuzkina, Anastasia A1 - Welters, Marij J. P. A1 - Benz, Tamara M. A1 - Sorger, Lena A1 - Thiemann, Vincent A1 - Almanzar, Giovanni A1 - Selle, Martina A1 - Thein, Klara A1 - Späth, Jacob A1 - Gonzalez, Maria Cecilia A1 - Reitinger, Carmen A1 - Ipsen-Escobedo, Andrea A1 - Wistuba-Hamprecht, Kilian A1 - Eichler, Kristin A1 - Filipski, Katharina A1 - Zeiner, Pia S. A1 - Beschorner, Rudi A1 - Goedemans, Renske A1 - Gogolla, Falk Hagen A1 - Hackl, Hubert A1 - Rooswinkel, Rogier W. A1 - Thiem, Alexander A1 - Romer Roche, Paula A1 - Joshi, Hemant A1 - Pühringer, Dirk A1 - Wöckel, Achim A1 - Diessner, Joachim E. A1 - Rüdiger, Manfred A1 - Leo, Eugen A1 - Cheng, Phil F. A1 - Levesque, Mitchell P. A1 - Goebeler, Matthias A1 - Sauer, Markus A1 - Nimmerjahn, Falk A1 - Schuberth-Wagner, Christine A1 - Felten, Stefanie von A1 - Mittelbronn, Michel A1 - Mehling, Matthias A1 - Beilhack, Andreas A1 - van der Burg, Sjoerd H. A1 - Riedel, Angela A1 - Weide, Benjamin A1 - Dummer, Reinhard A1 - Wischhusen, Jörg T1 - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment JF - Nature Communications N2 - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. KW - cancer microenvironment KW - immunotherapy KW - T cells KW - tumour immunology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333 VL - 14 ER - TY - JOUR A1 - Klenke, Daniela A1 - Quast, Anja A1 - Prelog, Martina A1 - Holl-Wieden, Annette A1 - Riekert, Maximilian A1 - Stellzig-Eisenhauer, Angelika A1 - Meyer-Marcotty, Philipp T1 - TMJ pathomorphology in patients with JIA-radiographic parameters for early diagnosis- JF - Head & Face Medicine N2 - Background Juvenile idiopathic arthritis (JIA) is often accompanied by pathomorphological changes to the temporomandibular joint (TMJ). By analyzing orthodontical orthopantomograms of JIA patients the aims of the study were a) classification of condyle changes, b) quantification of bony asymmetries of condylar destruction and c) detection of relationships between disease duration and TMJ-involvement. Patients/Methods 46 caucasian JIA-patients (28 female; 18 male; < 16.0 years) were enrolled, each joint (n = 92) was morphologically assessed by means of orthopantomogram, quantitatively analysed and compared with duration of general disease. Condyle morphology was assessed using the Billiau scale for severity of destruction [1]. The quantitative analysis was based on ratios of condyle, ramus and mandible height. Results Patients were divided into groups (Group I – slightly affected, n = 36; Billiau severity 0–2; condyle findings: X-ray normal, condyle erosions, condylar flattening; Group II – severely affected, N = 10; Billiau severity 3–4; condyle findings: condylar flattenings and erosions, unilateral/bilateral complete loss of condyles), based on morphological analysis of condylar destruction. Duration of disease was significantly longer in Group II (8.9 ± 5.2 years) than in Group I (4.6 ± 4.7 years). Asymmetries of condyle, ramus and mandible height, quantitatively analysed by contralateral comparison, were significantly more marked in patients of Group II than of Group I. Conclusions Orthopantomogram imaging can be used in orthodontics clinical routine to detect TMJ-pathologies and is an important reference for monitoring progression of JIA. Classification into severe and slightly affected TMJ is possible by analysis of condylar pathomorphology. An association between degree of destruction, extent of lower jaw asymmetry and disease duration is suggested by the results. KW - juvenile idiopathic arthritis KW - TMJ KW - OPT KW - asymmetry KW - condyle pathomorphology Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325882 VL - 14 ER - TY - JOUR A1 - Augustin, Anne Marie A1 - Kertels, Olivia A1 - Wiegering, Verena A1 - Thurner, Annette A1 - Kickuth, Ralph T1 - Percutaneous implantation of peripherally inserted totally implantable venous access systems in the forearm in adolescent patients JF - Pediatric Radiology N2 - Background Children with different underlying malignant diseases require long-term central venous access. As for port systems in a pectoral position, peripherally implanted port systems in the forearm revealed high levels of technical and clinical success in adult cohorts. Objective To investigate the technical and clinical outcomes of percutaneous central venous port implantation in the forearm in adolescents. Materials and methods Between April 2010 and August 2020, 32 children ages 9 to 17 years with underlying malignancy received 35 totally implantable venous access ports (TIVAPs) in the forearm. All venous port systems were peripherally inserted under ultrasound guidance. Correct catheter placement was controlled by fluoroscopy. As primary endpoints, the technical success, rate of complications and catheter maintenance were analyzed. Secondary endpoints were the side of implantation, vein of catheter access, laboratory results on the day of the procedure, procedural radiation exposure, amount of contrast agent and reasons for port device removal. Results Percutaneous TIVAP placement under sonographic guidance was technically successful in 34 of 35 procedures (97.1%). Procedure-related complications did not occur. During the follow-up, 13,684 catheter days were analyzed, revealing 11 complications (0.8 per 1,000 catheter-duration days), Of these 11 complications, 7 were major and 10 occurred late. In seven cases, the port device had to be removed; removal-related complications did not occur. Conclusion Peripheral TIVAP placement in the forearms of children is a feasible, effective and safe technique with good midterm outcome. As results are comparable with standard access routes, this technique may be offered as an alternative when intermittent venous access is required. KW - adolescents KW - central venous catheter KW - children KW - forearm KW - interventional radiology KW - totally implantable venous access port KW - vascular access Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324947 VL - 52 IS - 8 ER - TY - JOUR A1 - Nentwich, Julia A1 - Ruf, Katharina A1 - Girschick, Hermann A1 - Holl-Wieden, Annette A1 - Morbach, Henner A1 - Hebestreit, Helge A1 - Hofmann, Christine T1 - Physical activity and health-related quality of life in chronic non-bacterial osteomyelitis JF - Pediatric Rheumatology N2 - Background Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disorder of the skeletal system of yet unknown etiology. Patients present with local bone pain and inflammation and - to our experience - often suffer from functional impairment with significant disabilities of daily life. The objective of this study was to assess physical activity, fitness and health-related quality of life (HRQOL) in adolescents with established diagnosis of CNO versus healthy controls (HC). Methods 15 patients with CNO and 15 age and gender matched HC aged 13–18 years, completed questionnaires, performed an incremental exercise test with gas exchange measures up to voluntary fatigue and wore an accelerometer over 7 days at home to assess physical activity behavior. Results At the time of assessment, 5 CNO patients were in clinical, one in radiological and 5 in clinical and radiological remission. 7 did not receive any therapy at the time of assessment. The results of the exercise test and of the accelerometry did not show any significant difference between CNO and HC. However, reported sports participation was lower in patients with CNO and PedsQL3.0 and 4.0 showed significant lower values in most of the scores indicating reduced HRQOL. Conclusion Although most CNO patients showed a favorable course of disease without any relevant differences in objective measurements of physical activity and fitness versus HC at the time of assessment, questionnaires revealed perceived limitations. Further studies are needed to measure HRQOL and to validate questionnaires in patients with CNO against objective measures including more participants with a higher level of disease activity. KW - chronic non-bacterial osteomyelitis KW - CRMO KW - HRQOL KW - physical activity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323710 VL - 17 ER - TY - JOUR A1 - Hetzer, Benjamin A1 - Orth-Höller, Dorothea A1 - Würzner, Reinhard A1 - Kreidl, Peter A1 - Lackner, Michaela A1 - Müller, Thomas A1 - Knabl, Ludwig A1 - Geisler-Moroder, Daniel Rudolf A1 - Mellmann, Alexander A1 - Sesli, Özcan A1 - Holzknecht, Jeanett A1 - Noce, Damia A1 - Akarathum, Noppadon A1 - Chotinaruemol, Somporn A1 - Prelog, Martina A1 - Oberdorfer, Peninnah T1 - “Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study” JF - Antimicrobial Resistance & Infection Control N2 - Background Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance. KW - Escherichia coli KW - antibiotic resistance KW - multiresistance KW - transmission KW - persistence KW - children KW - neonates Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320284 VL - 8 ER - TY - JOUR A1 - Dirks, Johannes A1 - Haase, Gabriele A1 - Cantaert, Tineke A1 - Frey, Lea A1 - Klaas, Moritz A1 - Rickert, Christian H. A1 - Girschick, Hermann A1 - Meffre, Eric A1 - Morbach, Henner T1 - A novel AICDA splice-site mutation in two siblings with HIGM2 permits somatic hypermutation but abrogates mutational targeting JF - Journal of Clinical Immunology N2 - Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients. KW - hyper-IgM syndrome type 2 (HIGM2) KW - AICDA KW - AID-ΔE4a KW - AD-AID KW - mutational targeting KW - somatic hypermutation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324253 VL - 42 IS - 4 ER -