@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{WunschHohmannMillesetal.2016, author = {Wunsch, Marie and Hohmann, Christopher and Milles, Bianca and Rostermund, Christina and Lehmann, Paul V. and Schroeter, Michael and Bayas, Antonios and Ulzheimer, Jochen and M{\"a}urer, Mathias and Erg{\"u}n, S{\"u}leyman and Kuerten, Stefanie}, title = {The Correlation between the Virus- and Brain Antigen-Specific B Cell Response in the Blood of Patients with Multiple Sclerosis}, series = {Viruses}, volume = {8}, journal = {Viruses}, number = {4}, doi = {10.3390/v8040105}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146946}, pages = {105}, year = {2016}, abstract = {There is a largely divergent body of literature regarding the relationship between Epstein-Barr virus (EBV) infection and brain inflammation in multiple sclerosis (MS). Here, we tested MS patients during relapse (n = 11) and in remission (n = 19) in addition to n = 22 healthy controls to study the correlation between the EBV- and brain-specific B cell response in the blood by enzyme-linked immunospot (ELISPOT) and enzyme-linked immunosorbent assay (ELISA). Cytomegalovirus (CMV) was used as a control antigen tested in n = 16 MS patients during relapse and in n = 35 patients in remission. Over the course of the study, n = 16 patients were untreated, while n = 33 patients received immunomodulatory therapy. The data show that there was a moderate correlation between the frequencies of EBV- and brain-reactive B cells in MS patients in remission. In addition we could detect a correlation between the B cell response to EBV and disease activity. There was no evidence of an EBV reactivation. Interestingly, there was also a correlation between the frequencies of CMV- and brain-specific B cells in MS patients experiencing an acute relapse and an elevated B cell response to CMV was associated with higher disease activity. The trend remained when excluding seronegative subjects but was non-significant. These data underline that viral infections might impact the immunopathology of MS, but the exact link between the two entities remains subject of controversy.}, language = {en} } @article{RovitusoDuffySchroeteretal.2015, author = {Rovituso, Damiano M. and Duffy, Catharina E. and Schroeter, Michael and Kaiser, Claudia C. and Kleinschnitz, Christoph and Bayas, Antonios and Elsner, Rebecca and Kuerten, Stefanie}, title = {The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients}, series = {Scientific Reports}, volume = {5}, journal = {Scientific Reports}, number = {14265}, doi = {10.1038/srep14265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148172}, year = {2015}, abstract = {B cells have only recently begun to attract attention in the immunopathology of multiple sclerosis (MS). Suitable markers for the prediction of treatment success with immunomodulatory drugs are still missing. Here we evaluated the B cell response to brain antigens in n = 34 relapsing-remitting MS (RRMS) patients treated with glatiramer acetate (GA) using the enzyme-linked immunospot technique (ELISPOT). Our data demonstrate that patients can be subdivided into responders that show brain-specific B cell reactivity in the blood and patients without this reactivity. Only in patients that classified as B cell responders, there was a significant positive correlation between treatment duration and the time since last relapse in our study. This correlation was GA-specific because it was absent in a control group that consisted of interferon-\(\beta\) (IFN-\(\beta\))-treated RRMS patients (n = 23). These data suggest that GA has an effect on brain-reactive B cells in a subset of patients and that only this subset benefits from treatment. The detection of brain-reactive B cells is likely to be a suitable tool to identify drug responders.}, language = {en} } @article{deMunterPavlovGorlovaetal.2021, author = {de Munter, Johannes and Pavlov, Dmitrii and Gorlova, Anna and Sicker, Michael and Proshin, Andrey and Kalueff, Allan V. and Svistunov, Andrey and Kiselev, Daniel and Nedorubov, Andrey and Morozov, Sergey and Umriukhin, Aleksei and Lesch, Klaus-Peter and Strekalova, Tatyana and Schroeter, Careen A.}, title = {Increased Oxidative Stress in the Prefrontal Cortex as a Shared Feature of Depressive- and PTSD-Like Syndromes: Effects of a Standardized Herbal Antioxidant}, series = {Frontiers in Nutrition}, volume = {8}, journal = {Frontiers in Nutrition}, issn = {2296-861X}, doi = {10.3389/fnut.2021.661455}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236326}, year = {2021}, abstract = {Major depression (MD) and posttraumatic stress disorder (PTSD) share common brain mechanisms and treatment strategies. Nowadays, the dramatically developing COVID-19 situation unavoidably results in stress, psychological trauma, and high incidence of MD and PTSD. Hence, the importance of the development of new treatments for these disorders cannot be overstated. Herbal medicine appears to be an effective and safe treatment with fewer side effects than classic pharmaca and that is affordable in low-income countries. Currently, oxidative stress and neuroinflammation attract increasing attention as important mechanisms of MD and PTSD. We investigated the effects of a standardized herbal cocktail (SHC), an extract of clove, bell pepper, basil, pomegranate, nettle, and other plants, that was designed as an antioxidant treatment in mouse models of MD and PTSD. In the MD model of "emotional" ultrasound stress (US), mice were subjected to ultrasound frequencies of 16-20 kHz, mimicking rodent sounds of anxiety/despair and "neutral" frequencies of 25-45 kHz, for three weeks and concomitantly treated with SHC. US-exposed mice showed elevated concentrations of oxidative stress markers malondialdehyde and protein carbonyl, increased gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and other molecular changes in the prefrontal cortex as well as weight loss, helplessness, anxiety-like behavior, and neophobia that were ameliorated by the SHC treatment. In the PTSD model of the modified forced swim test (modFST), in which a 2-day swim is followed by an additional swim on day 5, mice were pretreated with SHC for 16 days. Increases in the floating behavior and oxidative stress markers malondialdehyde and protein carbonyl in the prefrontal cortex of modFST-mice were prevented by the administration of SHC. Chromatography mass spectrometry revealed bioactive constituents of SHC, including D-ribofuranose, beta-D-lactose, malic, glyceric, and citric acids that can modulate oxidative stress, immunity, and gut and microbiome functions and, thus, are likely to be active antistress elements underlying the beneficial effects of SHC. Significant correlations of malondialdehyde concentration in the prefrontal cortex with altered measures of behavioral despair and anxiety-like behavior suggest that the accumulation of oxidative stress markers are a common biological feature of MD and PTSD that can be equally effectively targeted therapeutically with antioxidant therapy, such as the SHC investigated here.}, language = {en} }