@article{BadrMcFlederWuetal.2022,
  author    = {Badr, Mohammad and McFleder, Rhonda L. and Wu, Jingjing and Knorr, Susanne and Koprich, James B. and H{\"u}nig, Thomas and Brotchie, Jonathan M. and Volkmann, Jens and Lutz, Manfred B. and Ip, Chi Wang},
  title     = {Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson's disease mice},
  series = {Journal of Neuroinflammation},
  volume    = {19},
  journal   = {Journal of Neuroinflammation},
  doi       = {10.1186/s12974-022-02685-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300580},
  year      = {2022},
  abstract  = {Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson's disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson's disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson's disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson's disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson's disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson's disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson's disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson's disease patients.},
  language  = {en}
}
@article{TappeLauruschkatStrobeletal.2022,
  author    = {Tappe, Beeke and Lauruschkat, Chris D. and Strobel, Lea and Pantale{\´o}n Garc{\´i}a, Jezreel and Kurzai, Oliver and Rebhan, Silke and Kraus, Sabrina and Pfeuffer-Jovic, Elena and Bussemer, Lydia and Possler, Lotte and Held, Matthias and H{\"u}nniger, Kerstin and Kniemeyer, Olaf and Sch{\"a}uble, Sascha and Brakhage, Axel A. and Panagiotou, Gianni and White, P. Lewis and Einsele, Hermann and L{\"o}ffler, J{\"u}rgen and Wurster, Sebastian},
  title     = {COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds},
  series = {Frontiers in Immunology},
  volume    = {13},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2022.954985},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283558},
  year      = {2022},
  abstract  = {Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.},
  language  = {en}
}
@article{GrotemeyerMcFlederWuetal.2022,
  author    = {Grotemeyer, Alexander and McFleder, Rhonda Leah and Wu, Jingjing and Wischhusen, J{\"o}rg and Ip, Chi Wang},
  title     = {Neuroinflammation in Parkinson's disease - putative pathomechanisms and targets for disease-modification},
  series = {Frontiers in Immunology},
  volume    = {13},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2022.878771},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274665},
  year      = {2022},
  abstract  = {Parkinson's disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD.},
  language  = {en}
}
@article{WagnerDrouetTeschnerWolschkeetal.2021,
  author    = {Wagner-Drouet, Eva and Teschner, Daniel and Wolschke, Christine and Sch{\"a}fer-Eckart, Kerstin and G{\"a}rtner, Johannes and Mielke, Stephan and Schreder, Martin and Kobbe, Guido and Hilgendorf, Inken and Klein, Stefan and Verbeek, Mareike and Ditschkowski, Markus and Koch, Martina and Lindemann, Monika and Schmidt, Traudel and Rascle, Anne and Barabas, Sascha and Deml, Ludwig and Wagner, Ralf and Wolff, Daniel},
  title     = {Comparison of cytomegalovirus-specific immune cell response to proteins versus peptides using an IFN-γ ELISpot assay after hematopoietic stem cell transplantation},
  series = {Diagnostics},
  volume    = {11},
  journal   = {Diagnostics},
  number    = {2},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics11020312},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228843},
  year      = {2021},
  abstract  = {Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4\% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8\(^+\) counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients.},
  language  = {en}
}
@article{KaderAzeemJwayedetal.2021,
  author    = {Kader, Hidaya A. and Azeem, Muhammad and Jwayed, Suhib A. and Al-Shehhi, Aaesha and Tabassum, Attia and Ayoub, Mohammed Akli and Hetta, Helal F. and Waheed, Yasir and Iratni, Rabah and Al-Dhaheri, Ahmed and Muhammad, Khalid},
  title     = {Current insights into immunology and novel therapeutics of atopic dermatitis},
  series = {Cells},
  volume    = {10},
  journal   = {Cells},
  number    = {6},
  issn      = {2073-4409},
  doi       = {10.3390/cells10061392},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241008},
  year      = {2021},
  abstract  = {Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.},
  language  = {en}
}
@article{ThomannSchneiderCyranetal.2021,
  author    = {Thomann, Anna Sophie and Schneider, Theresa and Cyran, Laura and Eckert, Ina Nathalie and Kerstan, Andreas and Lutz, Manfred B.},
  title     = {Conversion of Anergic T Cells Into Foxp3\(^-\) IL-10\(^+\) Regulatory T Cells by a Second Antigen Stimulus In Vivo},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.704578},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241429},
  year      = {2021},
  abstract  = {T cell anergy is a common mechanism of T cell tolerance. However, although anergic T cells are retained for longer time periods in their hosts, they remain functionally passive. Here, we describe the induction of anergic CD4\(^+\) T cells in vivo by intravenous application of high doses of antigen and their subsequent conversion into suppressive Foxp3\(^-\) IL-10\(^+\) Tr1 cells but not Foxp3\(^+\) Tregs. We describe the kinetics of up-regulation of several memory-, anergy- and suppression-related markers such as CD44, CD73, FR4, CD25, CD28, PD-1, Egr-2, Foxp3 and CTLA-4 in this process. The conversion into suppressive Tr1 cells correlates with the transient intracellular CTLA-4 expression and required the restimulation of anergic cells in a short-term time window. Restimulation after longer time periods, when CTLA-4 is down-regulated again retains the anergic state but does not lead to the induction of suppressor function. Our data require further functional investigations but at this stage may suggest a role for anergic T cells as a circulating pool of passive cells that may be re-activated into Tr1 cells upon short-term restimulation with high and systemic doses of antigen. It is tentative to speculate that such a scenario may represent cases of allergen responses in non-allergic individuals.},
  language  = {en}
}
@article{KuznetsovAlmuzzainiKritikouetal.2017,
  author    = {Kuznetsov, Nikolai V. and Almuzzaini, Bader and Kritikou, Joanna S. and Baptista, Marisa A. P. and Oliveira, Mariana M. S. and Keszei, Marton and Snapper, Scott B. and Percipalle, Piergiorgio and Westerberg, Lisa S.},
  title     = {Nuclear Wiskott-Aldrich syndrome protein co-regulates T cell factor 1-mediated transcription in T cells},
  series = {Genome Medicine},
  volume    = {9},
  journal   = {Genome Medicine},
  doi       = {10.1186/s13073-017-0481-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173486},
  year      = {2017},
  abstract  = {Background The Wiskott-Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell development remains incompletely defined. Methods We performed WASp chromatin immunoprecipitation and deep sequencing (ChIP-seq) in thymocytes and spleen CD4\(^+\) T cells. Results WASp was enriched at genic and intergenic regions and associated with the transcription start sites of protein-coding genes. Thymocytes and spleen CD4\(^+\) T cells showed 15 common WASp-interacting genes, including the gene encoding T cell factor (TCF)12. WASp KO thymocytes had reduced nuclear TCF12 whereas thymocytes expressing constitutively active WASp\(^{L272P}\) and WASp\(^{I296T}\) had increased nuclear TCF12, suggesting that regulated WASp activity controlled nuclear TCF12. We identify a putative DNA element enriched in WASp ChIP-seq samples identical to a TCF1-binding site and we show that WASp directly interacted with TCF1 in the nucleus. Conclusions These data place nuclear WASp in proximity with TCF1 and TCF12, essential factors for T cell development.},
  language  = {en}
}
@article{Romero‐OlmedoSchulzHuberetal.2021,
  author    = {Romero-Olmedo, Addi J. and Schulz, Axel R. and Huber, Magdalena and Brehm, Corinna U. and Chang, Hyun-Dong and Chiarolla, Cristina M. and Bopp, Tobias and Skevaki, Chrysanthi and Berberich-Siebelt, Friederike and Radbruch, Andreas and Mei, Henrik E. and Lohoff, Michael},
  title     = {Deep phenotypical characterization of human CD3\(^{+}\)CD56\(^{+}\) T cells by mass cytometry},
  series = {European Journal of Immunology},
  volume    = {51},
  journal   = {European Journal of Immunology},
  number    = {3},
  doi       = {10.1002/eji.202048941},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225699},
  pages     = {672 -- 681},
  year      = {2021},
  abstract  = {CD56\(^{+}\) T cells are a group of pro-inflammatory CD3\(^{+}\) lymphocytes with characteristics of natural killer cells, being involved in antimicrobial immune defense. Here, we performed deep phenotypic profiling of CD3\(^{+}\)CD56\(^{+}\) cells in peripheral blood of normal human donors and individuals sensitized to birch-pollen or/and house dust mite by high-dimensional mass cytometry combined with manual and computational data analysis. A co-regulation between major conventional T-cell subsets and their respective CD3\(^{+}\)CD56\(^{+}\) cell counterparts appeared restricted to CD8\(^{+}\), MAIT, and TCRγδ\(^{+}\) T-cell compartments. Interestingly, we find a co-regulation of several CD3\(^{+}\)CD56\(^{+}\) cell subsets in allergic but not in healthy individuals. Moreover, using FlowSOM, we distinguished a variety of CD56\(^{+}\) T-cell phenotypes demonstrating a hitherto underestimated heterogeneity among these cells. The novel CD3\(^{+}\)CD56\(^{+}\) subset description comprises phenotypes superimposed with naive, memory, type 1, 2, and 17 differentiation stages, in part represented by a phenotypical continuum. Frequencies of two out of 19 CD3\(^{+}\)CD56\(^{+}\) FlowSOM clusters were significantly diminished in allergic individuals, demonstrating less frequent presence of cells with cytolytic, presumably protective, capacity in these donors consistent with defective expansion or their recruitment to the affected tissue. Our results contribute to defining specific cell populations to be targeted during therapy for allergic conditions.},
  language  = {en}
}
@article{Prelog2012,
  author    = {Prelog, Martina},
  title     = {Differential Approaches for Vaccination from Childhood to Old Age},
  series = {Gerontology},
  volume    = {59},
  journal   = {Gerontology},
  number    = {3},
  issn      = {0304-324X},
  doi       = {10.1159/000343475},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196602},
  pages     = {230-239},
  year      = {2012},
  abstract  = {Primary prevention strategies, such as vaccinations at the age extremes, in neonates and elderly individuals, demonstrate a challenge to health professionals and public health specialists. The aspects of the differentiation and maturation of the adaptive immune system, the functional implications of immunological immaturity or immunosenescence and its impact on vaccine immunogenicity and efficacy will be highlighted in this review. Several approaches have been undertaken to promote Th1 responses in neonates and to enhance immune functions in elderly, such as conjugation to carrier proteins, addition of adjuvants, concomitant vaccination with other vaccines, change in antigen concentrations or dose intervals or use of different administration routes. Also, early protection by maternal vaccination seems to be beneficial in neonates. However, it also appears necessary to think of other end points than antibody concentrations to assess vaccine efficacy in neonates or elderly, as also the cellular immune response may be impaired by the mechanisms of immaturity, underlying health conditions, immunosuppressive treatments or immunosenescence. Thus, lifespan vaccine programs should be implemented to all individuals on a population level not only to improve herd protection and to maintain protective antibody levels and immune memory, but also to cover all age groups, to protect unvaccinated elderly persons and to provide indirect protection for neonates and small infants.},
  language  = {en}
}
@article{SchmidtEbnerRosenetal.2020,
  author    = {Schmidt, Stefanie and Ebner, Friederike and Rosen, Kerstin and Kniemeyer, Olaf and Brakhage, Axel A. and L{\"o}ffler, J{\"u}rgen and Seif, Michelle and Springer, Jan and Schlosser, Josephine and Scharek-Tedin, Lydia and Scheffold, Alexander and Bacher, Petra and K{\"u}hl, Anja A. and R{\"o}sler, Uwe and Hartmann, Susanne},
  title     = {The domestic pig as human-relevant large animal model to study adaptive antifungal immune responses against airborne Aspergillus fumigatus},
  series = {European Journal of Immunology},
  volume    = {50},
  journal   = {European Journal of Immunology},
  number    = {11},
  doi       = {10.1002/eji.201948524},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216085},
  pages     = {1712 -- 1728},
  year      = {2020},
  abstract  = {Pulmonary mucosal immune response is critical for preventing opportunistic Aspergillus fumigatus infections. Although fungus-specific CD4\(^{+}\) T cells in blood are described to reflect the actual host-pathogen interaction status, little is known about Aspergillus-specific pulmonary T-cell responses. Here, we exploit the domestic pig as human-relevant large animal model and introduce antigen-specific T-cell enrichment in pigs to address Aspergillus-specific T cells in the lung compared to peripheral blood. In healthy, environmentally Aspergillus-exposed pigs, the fungus-specific T cells are detectable in blood in similar frequencies as observed in healthy humans and exhibit a Th1 phenotype. Exposing pigs to 10\(^{6}\) cfu/m\(^{3}\) conidia induces a long-lasting accumulation of Aspergillus-specific Th1 cells locally in the lung and also systemically. Temporary immunosuppression during Aspergillus-exposure showed a drastic reduction in the lung-infiltrating antifungal T-cell responses more than 2 weeks after abrogation of the suppressive treatment. This was reflected in blood, but to a much lesser extent. In conclusion, by using the human-relevant large animal model the pig, this study highlights that the blood clearly reflects the mucosal fungal-specific T-cell reactivity in environmentally exposed as well as experimentally exposed healthy pigs. But, immunosuppression significantly impacts the mucosal site in contrast to the initial systemic immune response.},
  language  = {en}
}