14694
2016
eng
105
4
8
article
1
2017-04-07
--
--
The Correlation between the Virus- and Brain Antigen-Specific B Cell Response in the Blood of Patients with Multiple Sclerosis
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.
Viruses
10.3390/v8040105
urn:nbn:de:bvb:20-opus-146946
Viruses 2016, 8, 105; doi:10.3390/v8040105
Marie Wunsch
Christopher Hohmann
Bianca Milles
Christina Rostermund
Paul V. Lehmann
Michael Schroeter
Antonios Bayas
Jochen Ulzheimer
Mathias Mäurer
Süleyman Ergün
Stefanie Kuerten
eng
uncontrolled
B cells
eng
uncontrolled
CMV
eng
uncontrolled
EBV
eng
uncontrolled
ELISPOT
eng
uncontrolled
MS
Krankheiten
open_access
Institut für Anatomie und Zellbiologie
Förderzeitraum 2016
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14694/088_Wunsch_viruses-08-00105.pdf
14769
2016
eng
29847
6
article
1
2017-05-04
--
--
CEACAM1 mediates B cell aggregation in central nervous system autoimmunity
B cell aggregates in the central nervous system (CNS) have been associated with rapid disease progression in patients with multiple sclerosis (MS). Here we demonstrate a key role of carcinoembryogenic antigen-related cell adhesion molecule1 (CEACAM1) in B cell aggregate formation in MS patients and a B cell-dependent mouse model of MS. CEACAM1 expression was increased on peripheral blood B cells and CEACAM1\(^+\) B cells were present in brain infiltrates of MS patients. Administration of the anti-CEACAM1 antibody T84.1 was efficient in blocking aggregation of B cells derived from MS patients. Along these lines, application of the monoclonal anti-CEACAM1 antibody mCC1 was able to inhibit CNS B cell aggregate formation and significantly attenuated established MS-like disease in mice in the absence of any adverse effects. CEACAM1 was co-expressed with the regulator molecule T cell immunoglobulin and mucin domain −3 (TIM-3) on B cells, a novel molecule that has recently been described to induce anergy in T cells. Interestingly, elevated coexpression on B cells coincided with an autoreactive T helper cell phenotype in MS patients. Overall, these data identify CEACAM1 as a clinically highly interesting target in MS pathogenesis and open new therapeutic avenues for the treatment of the disease.
Scientific Reports
10.1038/srep29847
urn:nbn:de:bvb:20-opus-147690
Scientific Reports 6:29847. DOI: 10.1038/srep29847 (2016)
Damiano M. Rovituso
Laura Scheffler
Marie Wunsch
Christoph Kleinschnitz
Sebastian Dörck
Jochen Ulzheimer
Antonios Bayas
Lawrence Steinman
Süleyman Ergün
Stefanie Kuerten
eng
uncontrolled
autoimmunity
eng
uncontrolled
multiple sclerosis
eng
uncontrolled
neuroimmunology
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Förderzeitraum 2016
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14769/116_Kuerten_srep29847.pdf
12612
2014
eng
138
2
article
1
2016-01-28
--
--
Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood
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.
Acta Neuropathologica Communications
10.1186/s40478-014-0138-2
urn:nbn:de:bvb:20-opus-126124
Acta Neuropathologica Communications 2014, 2:138. doi:10.1186/s40478-014-0138-2
Christopher Hohnmann
Bianca Milles
Michael Schinke
Michael Schroeter
Jochen Ulzheimer
Peter Kraft
Christoph Kleinschnitz
Paul V. Lehmann
Stefanie Kuerten
eng
uncontrolled
predictive value
eng
uncontrolled
MS
eng
uncontrolled
ELISPOT
eng
uncontrolled
B cells
eng
uncontrolled
relapse
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Neurologische Klinik und Poliklinik
Förderzeitraum 2015
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12612/Kuerten_s40478-014-0138-2.pdf
12058
2014
eng
138
2
article
1
2015-10-21
--
--
Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood
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.
Acta Neuropathologica Communications
10.1186/s40478-014-0138-2
2051-5960
25597707
urn:nbn:de:bvb:20-opus-120580
Acta Neuropathologica Communications 2014, 2:138. doi:10.1186/s40478-014-0138-2
Christopher Hohmann
Bianca Milles
Michael Schinke
Michael Schroeter
Jochen Ulzheimer
Peter Kraft
Christoph Kleinschnitz
Paul V. Lehmann
Stefanie Kuerten
eng
uncontrolled
ELISPOT
eng
uncontrolled
MS
eng
uncontrolled
predictive value
eng
uncontrolled
relapse
eng
uncontrolled
B cells
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Neurologische Klinik und Poliklinik
Institut für Klinische Epidemiologie und Biometrie
Förderzeitraum 2015
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12058/104_Hohmann_Acta_Neuropatholica_Communications.pdf
11960
2014
eng
e99794
6
9
article
1
2015-10-01
--
--
Conventional Housing Conditions Attenuate the Development of Experimental Autoimmune Encephalomyelitis
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."
PLoS ONE
10.1371/journal.pone.0099794
24919069
urn:nbn:de:bvb:20-opus-119603
PLoS ONE 9(6): e99794. doi:10.1371/journal.pone.0099794
Andreas Arndt
Peter Hoffacker
Konstantin Zellmer
Oktay Goecer
Mascha S. Recks
Stefanie Kuerten
eng
uncontrolled
B cells
eng
uncontrolled
secretion
eng
uncontrolled
multiple sclerosis
eng
uncontrolled
enzyme-linked immunoassays
eng
uncontrolled
Peyer's patches
eng
uncontrolled
gut bacteria
eng
uncontrolled
T cells
eng
uncontrolled
immune response
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11960/045_Arndt_PLOS_ONE.pdf
14817
2015
eng
14265
5
article
1
2017-05-09
--
--
The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients
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.
Scientific Reports
10.1038/srep14265
urn:nbn:de:bvb:20-opus-148172
Scientific Reports 5:14265 (2015). DOI: 10.1038/srep14265
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Damiano M. Rovituso
Catharina E. Duffy
Michael Schroeter
Claudia C. Kaiser
Christoph Kleinschnitz
Antonios Bayas
Rebecca Elsner
Stefanie Kuerten
eng
uncontrolled
cortical pathology
eng
uncontrolled
natural history
eng
uncontrolled
disability
eng
uncontrolled
expression
eng
uncontrolled
antibodies
eng
uncontrolled
disease
eng
uncontrolled
lesions
eng
uncontrolled
trial
eng
uncontrolled
multiple sclerosis
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14817/004_Rovituso_Scientific_Reports.pdf
14841
2015
eng
14850-14865
16
article
1
2017-05-11
--
--
Stepchild or prodigy? Neuroprotection in multiple sclerosis (MS) research
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) and characterized by the infiltration of immune cells, demyelination and axonal loss. Loss of axons and nerve fiber pathology are widely accepted as correlates of neurological disability. Hence, it is surprising that the development of neuroprotective therapies has been neglected for a long time. A reason for this could be the diversity of the underlying mechanisms, complex changes in nerve fiber pathology and the absence of biomarkers and tools to quantify neuroregenerative processes. Present therapeutic strategies are aimed at modulating or suppressing the immune response, but do not primarily attenuate axonal pathology. Yet, target-oriented neuroprotective strategies are essential for the treatment of MS, especially as severe damage of nerve fibers mostly occurs in the course of disease progression and cannot be impeded by immune modulatory drugs. This review shall depict the need for neuroprotective strategies and elucidate difficulties and opportunities.
International Journal of Molecular Sciences
10.3390/ijms160714850
urn:nbn:de:bvb:20-opus-148416
International Journal of Molecular Sciences 2015, 16, 14850-14865. DOI: 10.3390/ijms160714850
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Andrea Rottlaender
Stefanie Kuerten
eng
uncontrolled
experimental autoimmune encephalomyelitis
eng
uncontrolled
white matter
eng
uncontrolled
lesions
eng
uncontrolled
remyelination
eng
uncontrolled
multiple sclerosis
eng
uncontrolled
regeneration
eng
uncontrolled
neuroprotection
eng
uncontrolled
degeneration
eng
uncontrolled
axonal damage
eng
uncontrolled
neurodegeneration
eng
uncontrolled
pathology
eng
uncontrolled
sodium channels
eng
uncontrolled
axonal injury
eng
uncontrolled
central nervous system
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14841/020_Rottlaender_International_Journal_of_Molecular_Sciences.pdf
15021
2015
eng
40-55
1
4
article
1
2017-06-09
--
--
Serial measurements of apoptotic cell numbers provide better acceptance criterion for PBMC quality than a single measurement prior to the T cell assay
As soon as Peripheral Blood Mononuclear Cells (PBMC) are isolated from whole blood, some cells begin dying. The rate of apoptotic cell death is increased when PBMC are shipped, cryopreserved, or stored under suboptimal conditions. Apoptotic cells secrete cytokines that suppress inflammation while promoting phagocytosis. Increased numbers of apoptotic cells in PBMC may modulate T cell functions in antigen-triggered T cell assays. We assessed the effect of apoptotic bystander cells on a T cell ELISPOT assay by selectively inducing B cell apoptosis using α-CD20 mAbs. The presence of large numbers of apoptotic B cells did not affect T cell functionality. In contrast, when PBMC were stored under unfavorable conditions, leading to damage and apoptosis in the T cells as well as bystander cells, T cell functionality was greatly impaired. We observed that measuring the number of apoptotic cells before plating the PBMC into an ELISPOT assay did not reflect the extent of PBMC injury, but measuring apoptotic cell frequencies at the end of the assay did. Our data suggest that measuring the numbers of apoptotic cells prior to and post T cell assays may provide more stringent PBMC quality acceptance criteria than measurements done only prior to the start of the assay.
Cells
10.3390/cells4010040
urn:nbn:de:bvb:20-opus-150213
Cells 2015, 4:1, 40-55. DOI: 10.3390/cells4010040
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Marie Wunsch
Richard Caspell
Stefanie Kuerten
Paul V. Lehmann
Srividya Sundararaman
eng
uncontrolled
T cell assay
eng
uncontrolled
apoptosis
eng
uncontrolled
acceptance
eng
uncontrolled
viability
eng
uncontrolled
ELISPOT
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15021/129_Wunsch_Cells.pdf
16578
2016
eng
1-14
99
14
article
1
2018-07-26
--
--
Autoantigen-specific immunosuppression with tolerogenic peripheral blood cells prevents relapses in a mouse model of relapsing-remitting multiple sclerosis
Background: Dendritic cells (DCs) rendered suppressive by treatment with mitomycin C and loaded with the autoantigen myelin basic protein demonstrated earlier their ability to prevent experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). This provides an approach for prophylactic vaccination against autoimmune diseases. For clinical application such DCs are difficult to generate and autoantigens hold the risk of exacerbating the disease.
Methods: We replaced DCs by peripheral mononuclear cells and myelin autoantigens by glatiramer acetate (Copaxone ®), a drug approved for the treatment of MS. Spleen cells were loaded with Copaxone®, incubated with mitomycin C (MICCop) and injected into mice after the first bout of relapsing-remitting EAE. Immunosuppression mediated by MICCop was investigated in vivo by daily assessment of clinical signs of paralysis and in in vitro restimulation assays of peripheral immune cells. Cytokine profiling was performed by enzyme-linked immunosorbent assay (ELISA). Migration of MICCop cells after injection was examined by biodistribution analysis of 111Indium-labelled MICCop. The number and inhibitory activity of CD4+CD25+FoxP3+ regulatory T cells were analysed by histology, flow cytometry and in vitro mixed lymphocyte cultures. In order to assess the specificity of MICCop-induced suppression, treated EAE mice were challenged with the control protein ovalbumin. Humoral and cellular immune responses were then determined by ELISA and in vitro antigen restimulation assay.
Results: MICCop cells were able to inhibit the harmful autoreactive T-cell response and prevented mice from further relapses without affecting general immune responses. Administered MICCop migrated to various organs leading to an increased infiltration of the spleen and the central nervous system with CD4+CD25+FoxP3+ cells displaying a suppressive cytokine profile and inhibiting T-cell responses.
Conclusion: We describe a clinically applicable cell therapeutic approach for controlling relapses in autoimmune encephalomyelitis by specifically silencing the deleterious autoimmune response.
Journal of Translational Medicine
10.1186/s12967-016-0860-6
urn:nbn:de:bvb:20-opus-165787
J Transl Med (2016) 14:99, p1-14
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Christian Kleist
Elisabeth Mohr
Sadanand Gaikwad
Laura Dittmar
Stefanie Kuerten
Michael Platten
Walter Mier
Michael Schmitt
Gerhard Opelz
Peter Terness
eng
uncontrolled
Autoimmunity
eng
uncontrolled
Cell therapy
eng
uncontrolled
Copaxone®
eng
uncontrolled
Immune tolerance
eng
uncontrolled
Mitomycin C
eng
uncontrolled
Relapsing-remitting MS
eng
uncontrolled
Regulatory T cells
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16578/085_Kleist_JOURNAL_OF_TRANSLATIONAL_MEDICINE.pdf
16550
2016
eng
11626
7
article
1
2018-07-24
--
--
Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells
Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
Nature Communications
10.1038/ncomms11626
urn:nbn:de:bvb:20-opus-165503
Nature Communications, 2015, 7:11626. DOI: 10.1038/ncomms11626
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Kerstin Göbel
Susann Pankratz
Chloi-Magdalini Asaridou
Alexander M. Herrmann
Stefan Bittner
Monika Merker
Tobias Ruck
Sarah Glumm
Friederike Langhauser
Peter Kraft
Thorsten F. Krug
Johanna Breuer
Martin Herold
Catharina C. Gross
Denise Beckmann
Adelheid Korb-Pap
Michael K. Schuhmann
Stefanie Kuerten
Ioannis Mitroulis
Clemens Ruppert
Marc W. Nolte
Con Panousis
Luisa Klotz
Beate Kehrel
Thomas Korn
Harald F. Langer
Thomas Pap
Bernhard Nieswandt
Heinz Wiendl
Triantafyllos Chavakis
Christoph Kleinschnitz
Sven G. Meuth
eng
uncontrolled
blood coagulation
eng
uncontrolled
factor XII
eng
uncontrolled
neuroinflammation
eng
uncontrolled
dendric cells
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Neurologische Klinik und Poliklinik
Rudolf-Virchow-Zentrum
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16550/Goebel_Nature_Communications.pdf
15146
2015
eng
4414
4437
7
article
1
2017-07-13
--
--
Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity
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.
Viruses
10.3390/v7082828
urn:nbn:de:bvb:20-opus-151462
Viruses 2015, 7, 4414-4437. DOI: 10.3390/v7082828
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Marie Wunsch
Wenji Zhang
Jodi Hanson
Richard Caspell
Alexey Y. Karulin
Mascha S. Recks
Stefanie Kuerten
Srividya Sundararaman
Paul V. Lehmann
eng
uncontrolled
memory cells
eng
uncontrolled
hcv infection
eng
uncontrolled
signature
eng
uncontrolled
Enzyme-Linked Immunospot assay (ELISPOT)
eng
uncontrolled
cytokine secretion kinetics
eng
uncontrolled
chronic viral infection
eng
uncontrolled
HCMV infection
eng
uncontrolled
CD4 T cells
eng
uncontrolled
exhaustion
eng
uncontrolled
activation
eng
uncontrolled
human cytomegalovirus (HCMV)
eng
uncontrolled
B cells
eng
uncontrolled
cytomegalovirus
eng
uncontrolled
elispot
Krankheiten
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15146/012_Wunsch_Viruses.pdf
17265
2017
eng
4
6
article
1
2018-11-22
--
--
Danger: high voltage - the role of voltage-gated calcium channels in central nervous system pathology
Voltage-gated calcium channels (VGCCs) are widely distributed within the central nervous system (CNS) and presumed to play an important role in the pathophysiology of a broad spectrum of CNS disorders including Alzheimer’s and Parkinson’s disease as well as multiple sclerosis. Several calcium channel blockers have been in clinical practice for many years so that their toxicity and side effects are well studied. However, these drugs are primarily used for the treatment of cardiovascular diseases and most if not all effects on brain functions are secondary to peripheral effects on blood pressure and circulation. While the use of calcium channel antagonists for the treatment of CNS diseases therefore still heavily depends on the development of novel strategies to specifically target different channels and channel subunits, this review is meant to provide an impulse to further emphasize the importance of future research towards this goal.
Cells
10.3390/cells6040043
urn:nbn:de:bvb:20-opus-172653
Cells (2017) 6(4):43. https://doi.org/10.3390/cells6040043
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Andrea Schampel
Stefanie Kuerten
eng
uncontrolled
cells
eng
uncontrolled
calcium
eng
uncontrolled
calcium channel antagonists
eng
uncontrolled
CNS
eng
uncontrolled
EAE
eng
uncontrolled
neurodegeneration
eng
uncontrolled
MS
eng
uncontrolled
regeneration
eng
uncontrolled
remyelination
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17265/Schampel_cells-06-00043-v2.pdf
28506
2017
eng
10
18
article
1
--
2017-09-29
--
Splitting the "unsplittable": Dissecting resident and infiltrating macrophages in experimental autoimmune encephalomyelitis
Macrophages predominate the inflammatory landscape within multiple sclerosis (MS) lesions, not only regarding cellularity but also with respect to the diverse functions this cell fraction provides during disease progression and remission. Researchers have been well aware of the fact that the macrophage pool during central nervous system (CNS) autoimmunity consists of a mixture of myeloid cells. Yet, separating these populations to define their unique contribution to disease pathology has long been challenging due to their similar marker expression. Sophisticated lineage tracing approaches as well as comprehensive transcriptome analysis have elevated our insight into macrophage biology to a new level enabling scientists to dissect the roles of resident (microglia and non-parenchymal macrophages) and infiltrating macrophages with unprecedented precision. To do so in an accurate way, researchers have to know their toolbox, which has been filled with diverse, discriminating approaches from decades of studying neuroinflammation in animal models. Every method has its own strengths and weaknesses, which will be addressed in this review. The focus will be on tools to manipulate and/or identify different macrophage subgroups within the injured murine CNS.
International Journal of Molecular Sciences
1422-0067
10.3390/ijms18102072
urn:nbn:de:bvb:20-opus-285067
2022-09-05T15:46:10+00:00
sword
swordwue
attachment; filename=deposit.zip
b4bfc2d104c53dafe2a9a272b7cf16d3
International Journal of Molecular Sciences (2017) 18:10, 2072. https://doi.org/10.3390/ijms18102072
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Tobias Koeniger
Stefanie Kuerten
eng
uncontrolled
CNS
eng
uncontrolled
distinction
eng
uncontrolled
experimental autoimmune encephalomyelitis
eng
uncontrolled
inflammation
eng
uncontrolled
macrophages
eng
uncontrolled
markers
eng
uncontrolled
microglia
eng
uncontrolled
monocytes
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/28506/ijms-18-02072.pdf
15786
2017
eng
148
14
article
1
2018-02-22
--
--
Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis.
Background:
MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS).
Methods:
MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P\(_{1}\) receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro.
Results:
FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220\(^{+}\) B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs.
Conclusions:
The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.
Journal of Neuroinflammation
10.1186/s12974-017-0924-4
urn:nbn:de:bvb:20-opus-157869
Journal of Neuroinflammation (2017) 14:148. DOI: 10.1186/s12974-017-0924-4
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Kathrin Bail
Quirin Notz
Damiano M. Rovituso
Andrea Schampel
Marie Wunsch
Tobias Koeniger
Verena Schropp
Richa Bharti
Claus-Juergen Scholz
Konrad U. Foerstner
Christoph Kleinschnitz
Stefanie Kuerten
eng
uncontrolled
B cells
eng
uncontrolled
EAE
eng
uncontrolled
FTY720
eng
uncontrolled
fingolimod
eng
uncontrolled
multiple sclerosis
eng
uncontrolled
TLO
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Neurologische Klinik und Poliklinik
Förderzeitraum 2017
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15786/Bail_Journal_of_Neuroinflammation.pdf
22445
2021
eng
227
239
2
39
article
1
--
--
--
Bone marrow‐derived myeloid progenitors in the leptomeninges of adult mice
Although the bone marrow contains most hematopoietic activity during adulthood, hematopoietic stem and progenitor cells can be recovered from various extramedullary sites. Cells with hematopoietic progenitor properties have even been reported in the adult brain under steady‐state conditions, but their nature and localization remain insufficiently defined. Here, we describe a heterogeneous population of myeloid progenitors in the leptomeninges of adult C57BL/6 mice. This cell pool included common myeloid, granulocyte/macrophage, and megakaryocyte/erythrocyte progenitors. Accordingly, it gave rise to all major myelo‐erythroid lineages in clonogenic culture assays. Brain‐associated progenitors persisted after tissue perfusion and were partially inaccessible to intravenous antibodies, suggesting their localization behind continuous blood vessel endothelium such as the blood‐arachnoid barrier. Flt3\(^{Cre}\) lineage tracing and bone marrow transplantation showed that the precursors were derived from adult hematopoietic stem cells and were most likely continuously replaced via cell trafficking. Importantly, their occurrence was tied to the immunologic state of the central nervous system (CNS) and was diminished in the context of neuroinflammation and ischemic stroke. Our findings confirm the presence of myeloid progenitors at the meningeal border of the brain and lay the foundation to unravel their possible functions in CNS surveillance and local immune cell production.
Stem Cells
10.1002/stem.3311
urn:nbn:de:bvb:20-opus-224452
2021-02-15T11:50:01+00:00
sword
swordwue
attachment; filename=deposit.zip
06cf5ecad7180245464cce27858214d9
Stem Cells 2021, 39(2):227–239. DOI: 10.1002/stem.3311
CC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell 4.0 International
Tobias Koeniger
Luisa Bell
Anika Mifka
Michael Enders
Valentin Hautmann
Subba Rao Mekala
Philipp Kirchner
Arif B. Ekici
Christian Schulz
Philipp Wörsdörfer
Stine Mencl
Christoph Kleinschnitz
Süleyman Ergün
Stefanie Kuerten
eng
uncontrolled
hematopoietic
eng
uncontrolled
meninges
eng
uncontrolled
mouse
eng
uncontrolled
myeloid
eng
uncontrolled
progenitor
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/22445/STEM_STEM3311.pdf
17612
2018
eng
225
15
article
1
2019-02-07
--
--
Anti-CD52 antibody treatment depletes B cell aggregates in the central nervous system in a mouse model of multiple sclerosis
Background:
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) for which several new treatment options were recently introduced. Among them is the monoclonal anti-CD52 antibody alemtuzumab that depletes mainly B cells and T cells in the immune periphery. Considering the ongoing controversy about the involvement of B cells and in particular the formation of B cell aggregates in the brains of progressive MS patients, an in-depth understanding of the effects of anti-CD52 antibody treatment on the B cell compartment in the CNS itself is desirable.
Methods:
We used myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice as B cell-dependent model of MS. Mice were treated intraperitoneally either at the peak of EAE or at 60 days after onset with 200 μg murine anti-CD52 vs. IgG2a isotype control antibody for five consecutive days. Disease was subsequently monitored for 10 days. The antigen-specific B cell/antibody response was measured by ELISPOT and ELISA. Effects on CNS infiltration and B cell aggregation were determined by immunohistochemistry. Neurodegeneration was evaluated by Luxol Fast Blue, SMI-32, and Olig2/APC staining as well as by electron microscopy and phosphorylated heavy neurofilament serum ELISA.
Results:
Treatment with anti-CD52 antibody attenuated EAE only when administered at the peak of disease. While there was no effect on the production of MP4-specific IgG, the treatment almost completely depleted CNS infiltrates and B cell aggregates even when given as late as 60 days after onset. On the ultrastructural level, we observed significantly less axonal damage in the spinal cord and cerebellum in chronic EAE after anti-CD52 treatment.
Conclusion:
Anti-CD52 treatment abrogated B cell infiltration and disrupted existing B cell aggregates in the CNS.
Journal of Neuroinflammation
10.1186/s12974-018-1263-9
urn:nbn:de:bvb:20-opus-176120
Journal of Neuroinflammation (2018) 15:225. DOI: 10.1186/s12974-018-1263-9
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Micha Simon
Rojda Ipek
György A. Homola
Damiano M. Rovituso
Andrea Schampel
Christoph Kleinschnitz
Stefanie Kuerten
eng
uncontrolled
Alemtuzumab
eng
uncontrolled
B cells
eng
uncontrolled
CD52
eng
uncontrolled
CNS
eng
uncontrolled
EAE
eng
uncontrolled
MS
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Neurologische Klinik und Poliklinik
Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie)
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17612/Simon_Journal_of_Neuroinflammation.pdf