@phdthesis{Palanichamy2007,
  author    = {Palanichamy, Arumugam},
  title     = {Influence of transient B cell depletion on recirculating B cells and plasma cells in rheumatoid arthritis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-25132},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Die zentrale Rolle der B-Zellen in der Pathogenese von Autoimmunerkrankungen hat in den letzten Jahren zu unterschiedlichen therapeutischen Ans{\"a}tzen gef{\"u}hrt, B-Zellen direkt oder indirekt zu targetieren. Ein Beispiel hierf{\"u}r stellt der monoklonale anti-CD20 Antik{\"o}rper Rituximab dar. Derzeit ist wenig {\"u}ber das Regenerationsverhalten von B-Zellen nach Therapie mit Rituximab bekannt. Daher untersuchten wir die fr{\"u}he Regnerationsphase und die Ver{\"a}nderungen des B-Zellrepertoirs. Am Beispiel der VH4 Familie der Immunglobulin schweren Ketten analysierten wir die Modulation des Immunglobulinrezeptor Repertoires durch die passagere B-Zelldepletion. Insgesamt wurden bei 5 Patienten 3 Zeitpunkte analysiert: vor Therapie, in der fr{\"u}hen Regenerationsphase (ERP- early regeneration period, mit einem B-Zellanteil > 1\% im peripheren Blut) und in der sp{\"a}ten Regenerationsphase (LRP- late regeneration period, 2-3 Monate nach der fr{\"u}hen Regenerationsphase). Bei 3 Patienten (A-C) wurden die Ig-VH4 Gene aus genomischer DNA amplifiziert und zu o.g. Zeitpunkten analysiert. Bei weiteren 2 Patienten (D und E) erfolgte die Analyse der Ig Gene in einzelnen B-Zellen mittels Einzelzellsortierung und Einzelzell RT-PCR. Die B-Zellregeneration nach Therapie mit Rituximab zeigte ein charakteristisches Regenerationsmuster mit einer Dominanz von unreifen CD10+ B-Zellen und CD38hi Plasmazellen w{\"a}hrend der fr{\"u}hen Phase der B-Zellrekonstitution. Im weiteren Verlauf kam es zu einer Abnahme dieser Zellen und einem Anstieg von naiven B-Zellen. Auf der molekularen Ebene zeigte sich vor und nach B-Zelldepletion eine unterschiedliche Nutzung der Ig-VH4 Gene. Mini Gene wie VH4-34 und VH4-39, die in Verbindung mit Autoimmunit{\"a}t stehen, waren vor Einleitung der Therapie {\"u}berexprimiert. Durch die Behandlung mit Rituximab kam es zu einer Ver{\"a}nderung des Repertoires der regenerierenden B-Zellen mit einer reduzierten Benutzung der VH4-39 Gene im B-Zellpool. Tief greifende Ver{\"a}nderungen fanden sich im regenerierenden Repertoire, mit einem relativen Anstieg von stark mutierten (>=9 Mutationen / Ig Sequenz) B-Zellen.. Die Immunph{\"a}notypisierung zeigte, dass diese hochmutierten B-Zellen den Ig-klassengeswitchten Ged{\"a}chtnis B-Zellkompartiment, insbesondere den Plasmazellen zugh{\"o}rig sind. Um diese Hypothese zu untermauern, erfolgte bei 2 Patienten eine Einzelzellsortierung dieser Plasmazellen w{\"a}hrend der fr{\"u}hen Regenerationsphase, welche einen vergleichbaren Mutationsstatus zeigte. Da Plasmazellen kein CD20 Molek{\"u}l exprimieren, werden sie durch eine Therapie mit Rituximab nicht direkt eliminiert. Allerdings zirkulieren sie nicht im peripheren Blut w{\"a}hrend der Phase der B-Zelldepletion. W{\"a}hrend der fr{\"u}hen Regenerationsphase (ERP) lassen sie sich in der Peripherie erneut nachweisen. Es wurde deshalb untersucht ob auch Plasmazellen durch die Therapie moduliert werden, obwohl sie nicht direkt durch Rituximab targetiert werden. In diesem Zusammenhang erfolgte eine detaillierte Analyse des Mutationsmusters der Plasmazellen vor Therapie und w{\"a}hrend der fr{\"u}hen Regenerationsphase. Die Analyse der Mutationsh{\"a}ufigkeit in RGYW/WRCY Hotspot Motive (R=purine, Y=pyrimidine, W=A/T) erlaubt Absch{\"a}tzung in wieweit die somatische Hypermutation der B-Zellen durch T-Zell abh{\"a}ngige Differenzierung erfolgte. Die Plasmazellen vor Therapie zeigten einem verminderten Targeting der RGYW/WRCY Motive. Im Gegensatz hierzu zeigte sich in den rezirkulierenden Plasmazellen w{\"a}hrend der fr{\"u}hen Regenerationsphase ein zunehmendes Targeting der RGYW/WRCY Motive. Dies spricht f{\"u}r einen Repertoire Shift zu mehr T-Zellabh{\"a}ngigen B-Zell Mutation. Ein Zusatand, wie er bei Gesunden beobachtet wird. Um die Hypothese der Rituximab-induzierten Plasmazell Modulation zu st{\"u}tzen wurde die R/S- Ratio (replacement to silent mutations ratio) der hypervariablen Regionen (CDRs) der Plasmazell Ig Sequenzen bestimmt. In unserer Studie war die mittlere R/S Ratio der CDRs der Plasmazellen vor Therapie entsprechend relativ niedrig (1.87). Interessanterweise kam es in der fr{\"u}hen und sp{\"a}ten Regenerationsphase zu einer signifikant erh{\"o}hten R/S Ration in den rezirkulierenden Plasmazellen mit Werten von 2.67 bzw. 3.60. Die verminderte R/S Ratio in den CDRs der Plasmazellen kann als Entwicklung des Ig-Repertoires durch positive Antigenselektion interpretiert werden und weist damit eine Therapie induzierte Ver{\"a}nderung auf, die dem entspricht wie man sie bei Gesunden findet. Zusammenfassend zeigt unsere Studie, dass die passagere B-Zelldepletion mit Rituximab zu einer Modulation des Plasmalzellkompartimentes f{\"u}hrt, welches nicht direkt durch die Therapie targetiert wird. Die Modulation der Plasmazellen bei der RA kann eventuell auch als m{\"o}glicher Biomarker entwickelt werden, um ein Ansprechen auf die Therapie vorherzusagen. Dies muss im Weiteren untersucht werden, um tiefer greifende Einblicke in Prozesse zu erlangen, die durch zuk{\"u}nftige Therapien beeinflussbar werden.},
  subject      = {B-zellen},
  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{BeilhackChopraKrausetal.2013,
  author    = {Beilhack, Andreas and Chopra, Martin and Kraus, Sabrina and Schwinn, Stefanie and Ritz, Miriam and Mattenheimer, Katharina and Mottok, Anja and Rosenwald, Andreas and Einsele, Hermann},
  title     = {Non-Invasive Bioluminescence Imaging to Monitor the Immunological Control of a Plasmablastic Lymphoma-Like B Cell Neoplasia after Hematopoietic Cell Transplantation},
  doi       = {10.1371/journal.pone.0081320},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111341},
  year      = {2013},
  abstract  = {To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.},
  language  = {en}
}
@article{HohnmannMillesSchinkeetal.2014,
  author    = {Hohnmann, Christopher and Milles, Bianca and Schinke, Michael and Schroeter, Michael and Ulzheimer, Jochen and Kraft, Peter and Kleinschnitz, Christoph and Lehmann, Paul V. and Kuerten, Stefanie},
  title     = {Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood},
  series = {Acta Neuropathologica Communications},
  volume    = {2},
  journal   = {Acta Neuropathologica Communications},
  number    = {138},
  doi       = {10.1186/s40478-014-0138-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126124},
  year      = {2014},
  abstract  = {Introduction B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Results Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5\%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40\%) with a pattern II and three of 14 patients (21.4\%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95\% confidence interval 1.87-19.77). Conclusions Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.},
  language  = {en}
}
@article{HohmannMillesSchinkeetal.2014,
  author    = {Hohmann, Christopher and Milles, Bianca and Schinke, Michael and Schroeter, Michael and Ulzheimer, Jochen and Kraft, Peter and Kleinschnitz, Christoph and Lehmann, Paul V. and Kuerten, Stefanie},
  title     = {Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood},
  series = {Acta Neuropathologica Communications},
  volume    = {2},
  journal   = {Acta Neuropathologica Communications},
  number    = {138},
  issn      = {2051-5960},
  doi       = {10.1186/s40478-014-0138-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120580},
  year      = {2014},
  abstract  = {INTRODUCTION: B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). RESULTS: Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5\%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40\%) with a pattern II and three of 14 patients (21.4\%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95\% confidence interval 1.87-19.77). CONCLUSIONS: Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.},
  language  = {en}
}
@article{ArndtHoffackerZellmeretal.2014,
  author    = {Arndt, Andreas and Hoffacker, Peter and Zellmer, Konstantin and Goecer, Oktay and Recks, Mascha S. and Kuerten, Stefanie},
  title     = {Conventional Housing Conditions Attenuate the Development of Experimental Autoimmune Encephalomyelitis},
  series = {PLoS ONE},
  volume    = {9},
  journal   = {PLoS ONE},
  number    = {6},
  doi       = {10.1371/journal.pone.0099794},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119603},
  pages     = {e99794},
  year      = {2014},
  abstract  = {BACKGROUND: The etiology of multiple sclerosis (MS) has remained unclear, but a causative contribution of factors outside the central nervous system (CNS) is conceivable. It was recently suggested that gut bacteria trigger the activation of CNS-reactive T cells and the development of demyelinative disease. METHODS: C57BL/6 (B6) mice were kept either under specific pathogen free or conventional housing conditions, immunized with the myelin basic protein (MBP)-proteolipid protein (PLP) fusion protein MP4 and the development of EAE was clinically monitored. The germinal center size of the Peyer's patches was determined by immunohistochemistry in addition to the level of total IgG secretion which was assessed by ELISPOT. ELISPOT assays were also used to measure MP4-specific T cell and B cell responses in the Peyer's patches and the spleen. Ear swelling assays were performed to determine the extent of delayed-type hypersensitivity reactions in specific pathogen free and conventionally housed mice. RESULTS: In B6 mice that were actively immunized with MP4 and kept under conventional housing conditions clinical disease was significantly attenuated compared to specific pathogen free mice. Conventionally housed mice displayed increased levels of IgG secretion in the Peyer's patches, while the germinal center formation in the gut and the MP4-specific TH17 response in the spleen were diminished after immunization. Accordingly, these mice displayed an attenuated delayed type hypersensitivity (DTH) reaction in ear swelling assays. CONCLUSIONS: The data corroborate the notion that housing conditions play a substantial role in the induction of murine EAE and suggest that the presence of gut bacteria might be associated with a decreased immune response to antigens of lower affinity. This concept could be of importance for MS and calls for caution when considering the therapeutic approach to treat patients with antibiotics."},
  language  = {en}
}
@phdthesis{Alrefai2014,
  author    = {Alrefai, Hani Gouda Alsaid},
  title     = {Molecular Characterization of NFAT Transcription Factors in Experimental Mouse Models},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97905},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {In this work we wanted to investigate the role of NFATc1 in lymphocyte physiology and in pathological conditions (eg. psoriasis). NFATc1 is part of the signal transduction pathways that regulates B cells activation and function. NFATc1 has different isoforms that are due to different promoters (P1 and P2), polyadenylation and alternative splicing. Moreover, we tried to elucidate the points of interactions between the NFAT and the NF-κB pathways in activated B-cell fate. NFAT and NF-κB factors share several properties, such as a similar mode of induction and architecture in their DNA binding domain. We used mice which over-express a constitutive active version of NFATc1/α in their B cells with -or without- an ablated IRF4. IRF4 inhibits cell cycle progression of germinal center B cell-derived Burkitt's lymphoma cells and induces terminal differentiation toward plasma cells. Our experiments showed that a 'double hit' in factors affecting B cell activation (NFATc1 in this case) and late B cell Differentiation (IRF4 in this case) alter the development of the B cells, lead to increase in their numbers and increase in stimulation induced proliferation. Therefore, the overall picture indicates a link between these 2 genes and probable carcinogenic alterations that may occur in B cells. We also show that in splenic B cells, c-Rel (of the NF-κB canonical pathway) Support the induction of NFATc1/αA through BCR signals. We also found evidence that the lack of NFATc1 affects the expression of Rel-B (of the NF-κB non-canonical pathway). These data suggest a tight interplay between NFATc1 and NF-κB in B cells, influencing the competence of B cells and their functions in peripheral tissues. We also used IMQ-induced psoriasis-like inflammation on mice which either lack NFATc1 from B cell. Psoriasis is a systemic chronic immunological disease characterized primarily by abnormal accelerated proliferation of the skin keratinocytes. In psoriasis, the precipitating event leads to immune cell activation. Our experiments showed that NFATc1 is needed for the development of psoriasis. It also showed that IL-10 is the link that enables NFAT from altering the B cell compartment (eg Bregs) in order to affect inflammation. The important role of B cell in psoriasis is supported by the flared up psoriasis-like inflammation in mice that lack B cells. Bregs is a special type of B cells that regulate other B cells and T cells; tuning the immunological response through immunomodulatory cytokines.},
  subject      = {Schuppenflechte},
  language  = {en}
}
@article{BoivinBeyersdorfPalmetal.2015,
  author    = {Boivin, Val{\´e}rie and Beyersdorf, Niklas and Palm, Dieter and Nikolaev, Viacheslav O. and Schlipp, Angela and M{\"u}ller, Justus and Schmidt, Doris and Kocoski, Vladimir and Kerkau, Thomas and H{\"u}nig, Thomas and Ertl, Georg and Lohse, Martin J. and Jahns, Roland},
  title     = {Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by \(Anti-β_1-Adrenoceptor\) Antibodies in a Human-Analogous Rat Model},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {2},
  doi       = {10.1371/journal.pone.0117589},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126028},
  pages     = {e0117589},
  year      = {2015},
  abstract  = {Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the \(β_1\) adrenergic receptor \((β_1EC2)\). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195-225) every 4 weeks; n = 38/114 rats were control-injected with 0.9\% NaCl. Intravenous application of a novel cyclic peptide mimicking \(β_1EC2\) (\(β_1EC2-CP\), 1.0 mg/kg every 4 weeks) or administration of the \(β_1-blocker\) bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received \(β_1EC2-CP/bisoprolol\) co-treatment. We found that \(β_1EC2-CP\) prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, \(β_1EC2-CP\) mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free \(anti-β_1EC2-antibodies\) and by targeting \(β_1EC2\)-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful \(anti-β_1EC2-antibodies\) and also selectively depletes memory B-cells involved in the production of such antibodies. Treatment with immuno-modulating cyclopeptides alone or as an add-on to \(β_1\)-blockade represents a promising new therapeutic option in immune-mediated heart failure.},
  language  = {en}
}
@article{WunschZhangHansonetal.2015,
  author    = {Wunsch, Marie and Zhang, Wenji and Hanson, Jodi and Caspell, Richard and Karulin, Alexey Y. and Recks, Mascha S. and Kuerten, Stefanie and Sundararaman, Srividya and Lehmann, Paul V.},
  title     = {Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity},
  series = {Viruses},
  volume    = {7},
  journal   = {Viruses},
  doi       = {10.3390/v7082828},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151462},
  pages     = {4414 -- 4437},
  year      = {2015},
  abstract  = {Most humans become infected with human cytomegalovirus (HCMV). Typically, the immune system controls the infection, but the virus persists and can reactivate in states of immunodeficiency. While substantial information is available on the contribution of CD8 T cells and antibodies to anti-HCMV immunity, studies of the T\(_{H}\)1, T\(_{H}\)2, and T\(_{H}\)17 subsets have been limited by the low frequency of HCMV-specific CD4 T cells in peripheral blood mononuclear cell (PBMC). Using the enzyme-linked Immunospot\(^{®}\) assay (ELISPOT) that excels in low frequency measurements, we have established these in a sizable cohort of healthy HCMV controllers. Cytokine recall responses were seen in all seropositive donors. Specifically, interferon (IFN)-\({\gamma}\) and/or interleukin (IL)-17 were seen in isolation or with IL-4 in all test subjects. IL-4 recall did not occur in isolation. While the ratios of T\(_{H}\)1, T\(_{H}\)2, and T\(_{H}\)17 cells exhibited substantial variations between different individuals these ratios and the frequencies were relatively stable when tested in samples drawn up to five years apart. IFN-\({\gamma}\) and IL-2 co-expressing polyfunctional cells were seen in most subjects. Around half of the HCMV-specific CD4 cells were in a reversible state of exhaustion. The data provided here established the T\(_{H}\)1, T\(_{H}\)2, and T\(_{H}\)17 characteristic of the CD4 cells that convey immune protection for successful immune surveillance against which reactivity can be compared when the immune surveillance of HCMV fails.},
  language  = {en}
}
@article{BittnerBobakHofmannetal.2015,
  author    = {Bittner, Stefan and Bobak, Nicole and Hofmann, Majella-Sophie and Schuhmann, Michael K. and Ruck, Tobias and G{\"o}bel, Kerstin and Br{\"u}ck, Wolfgang and Wiendl, Heinz and Meuth, Sven G.},
  title     = {Murine K\(_{2P}\)5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K\(_{2P}\)3.1-and K\(_{V}\)1.3-Dependent Mechanisms},
  series = {International Journal of Molecular Sciences},
  volume    = {16},
  journal   = {International Journal of Molecular Sciences},
  doi       = {10.3390/ijms160816880},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151454},
  pages     = {16880 -- 16896},
  year      = {2015},
  abstract  = {Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K\(_{2P}\)5.1(TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K\(_{2P}\)5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K\(_{2P}\)5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K\(_{2P}\)5.1 knockout (K\(_{2P}\)5.1\(^{-/-}\) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K\(_{2P}\)5.1\(^{-/-}\) mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K\(_{2P}\)3.1 and K\(_{V}\)1.3 seems to counterbalance the deletion of K\(_{2P}\)5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K\(_{2P}\)5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K\(_{2P}\)5.1-targeting drugs.},
  language  = {en}
}