@article{MahmoodMuhammadSchmalzingetal.2015,
  author    = {Mahmood, Zafar and Muhammad, Khalid and Schmalzing, Marc and Roll, Petra and D{\"o}rner, Thomas and Tony, Hans-Peter},
  title     = {CD27-IgD- memory B cells are modulated by in vivo interleukin-6 receptor (IL-6R) blockade in rheumatoid arthritis},
  series = {Arthritis Research \& Therapy},
  volume    = {17},
  journal   = {Arthritis Research \& Therapy},
  number    = {61},
  doi       = {10.1186/s13075-015-0580-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126506},
  year      = {2015},
  abstract  = {Introduction Enhanced B cell activity, particularly memory B cells have gained interest in evaluating response during therapies with biologics. CD27-IgD- double-negative (DN) B cells lacking the conventional memory marker CD27 are reported to be part of the memory compartment, however, only scarce data is available for rheumatoid arthritis (RA). We therefore focused on DN B cells in RA, studied their isotypes and modulation during interleukin-6 receptor (IL-6R) inhibition by tocilizumab (TCZ). Methods DN B cells were phenotypically analyzed from 40 RA patients during TCZ at baseline week 12, week 24 and 1 year. A single B cell polymerase chain reaction (PCR) approach was used to study Ig receptors, VH gene rearrangements and specific isotypes. Results Phenotypic analysis showed a significantly expanded population of DN B cells in RA which contain a heterogeneous mixture of IgG-, IgA- and IgM-expressing cells with a clear dominance of IgG+ cells. DN B cells carry rearranged heavy chain gene sequences with a diversified mutational pattern consistent with memory B cells. In contrast to tumor necrosis factor alpha (TNF-α) inhibition, a significant reduction in mutational frequency of BCR gene rearrangements at week 12, 24 and 1 year (P <0.0001) was observed by in vivo IL-6R inhibition. These changes were observed for all BCR isotypes IgG, IgA and IgM at week 12, 24 and 1 year (P <0.0001). IgA-RF, IgA serum level and IgA+ DN B cells decreased significantly (P <0.05) at week 12 and week 24 during TCZ. Patients with a good European League Against Rheumatism (EULAR) response to TCZ had less DN B cells at baseline as compared to moderate responders (P = 0.006). Univariate logistic regression analysis revealed that the frequency of DN B cells at baseline is inversely correlated to a subsequent good EULAR response (P = 0.024) with an odds ratio of 1.48 (95\% confidence interval as 1.05 to 2.06). Conclusions In RA, the heterogeneous DN B cell compartment is expanded and dominated by IgG isotype. TCZ can modulate the mutational status of DN Ig isotype receptors over 1 year. Interestingly, the frequency of DN B cells in RA may serve as a baseline predictor of subsequent EULAR response to TCZ.},
  language  = {en}
}
@phdthesis{Muhammad2009,
  author    = {Muhammad, Khalid},
  title     = {Longterm impact of anti-CD20 mediated transient B cell depletion on memory B cells in patients with rheumatoid arthritis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-36319},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {B-Lymphozyten leisten unterschiedliche Beitr{\"a}ge zur Pathophysiologie der Rheumatoiden Arthritis. Sie produzieren Autoantik{\"o}rper, pr{\"a}sentieren Autoantigene und sch{\"u}tten verschiedene Zytokine, die am proinflammatorischen Prozess beteiligt sind, aus. Aufbauend auf diesen Ergebnissen wurden in den letzten Jahren Therapien entwickelt, die gezielt B-Lymphozyten ansteuern um direkt oder indirekt in den autoimmunen Krankheitsverlauf einzugreifen. Die zeitlich begrenzte B-Zell-Depletion mit Rituximab (anti CD20-Antik{\"o}rper) hat dabei in den letzten Jahren einen hohen Stellenwert erlangt und wird im klinischen Alltag insbesondere bei der Behandlung von Patienten mit rheumatoider Arthritis angewandt. Rituximab induziert im peripheren Blut bemerkenswerte Ver{\"a}nderungen in der Hom{\"o}ostase der B-Zell-Subpopulationen. Nach Therapie mit dem anti-CD20 Antik{\"o}rper Rituximab beginnt die Repletionsphase mit der peripheren Aussaat von transitionalen unreifen B-Zellen. Im weiteren Verlauf kommt es zu einer Normalisierung des naiven B-Zell-Pools. Das B-Zell Ged{\"a}chtnis und in besonderem Maße die IgD+CD27+ Ged{\"a}chtniszellen erholen sich nach Therapie nur langsam. In einer prospektiven klinischen Studie hat unsere Arbeitsgruppe gezeigt, dass die Gesamtzahl der Ged{\"a}chtniszellen gut mit der Dauer der klinischen Antwort auf Rituximab korreliert. Es ist wenig {\"u}ber die speziellen molekularen Ver{\"a}nderungen innerhalb der Ged{\"a}chtnis B-Zellen nach Rituximab Therapie bekannt. Um die Ver{\"a}nderungen im peripheren Blut zu verstehen untersuchten wir die somatische Mutationsfrequenz und das Muster der Ig-VH3 Gen Rearrangements, indem wir pr{\"a}- und posttherapeutisch bei 18 Patienten einzelne B-Zellen isolierten und den individuellen B-Zellrezeptor durch eine Einzelzell RT-PCR amplifizierten und sequenzierten. Wir verglichen das Mutationsmuster nach erfolgreicher B-Zelldepletion in den neu rezirkulierenden Ged{\"a}chtnis B-Zellen mit dem Mutationsmuster von vier Gesunden Blutspendern und sechs nicht-RA Patienten, die eine Hochdosis Chemotherapie mit anschließender autologer oder allogener Stammzelltransplantation erhalten hatten. Zun{\"a}chst haben wir die Zusammensetzung der Ged{\"a}chtniszellen im peripheren Blut analysiert. Der Ph{\"a}notyp der peripheren pr{\"a}-switch (IgD+CD27+) und post-switch (IgD-CD27+) Ged{\"a}chtniszellen zeigte keine quantitativen Unterschiede in RA-Patienten im Vergleich zu Gesunden. Bei der direkten Analyse des B-Zell Immunglobulin Rezeptors fanden sich jedoch zwischen klassengeswitchten und ungeswitchten Ged{\"a}chtnis B-Zellen signifikante Unterschiede in der Anzahl der Mutationen in der variablen Region der Ig Rezeptors. Die Population der IgD+CD27+ Ged{\"a}chtniszellen beinhaltete sowohl nicht mutierte, wenig mutierte und stark mutierte (Median= 9 Mutationen pro Sequenz) rearrangierte Ig- Rezeptoren, wohingegen die IgD-CD27+ Ged{\"a}chtniszellen einen durchgehend hoch mutierten (Median = 18 Mutationen pro Sequenz) Rezeptor aufwiesen. Der Unterschied zwischen beiden Gruppen war signifikant (Mutationsfrequenzen 3.83±0.19\% vs. 7.1±0.53\%; P=0.0001). Grundlegende Ver{\"a}nderungen wurden bei den rezirkulierenden ungeswitchten Ged{\"a}chtniszellen (IgD+CD27+) nach vor{\"u}bergehender B-Zell Depletion mit Rituximab festgestellt. Diese Zellen wurden bis 6 Jahre nach Rituximab beobachtet und zeigten eine stark verz{\"o}gerte Zunahme an Mutationen im Ig-Rezeptor. Ein Jahr nach einmaliger Gabe von Rituximab waren 84\% der einzelnen zirkulierenden IgD+/CD27+ B-Zellen unmutiert. Zu diesem Zeitpunkt fanden sich keine stark mutierten Ig-VH3 Gen Rearrangements (P=0.0001). Mit zunehmendem Abstand zur B-Zell depletierenden Therapie konnten in der Repopulationsphase zunehmende Zahlen an Mutationen in den B-Zell Ig Rezeptoren festgestellt werden. Beispielsweise waren w{\"a}hrend des 2. Jahres der Regeneration (P=0.0001) 7.8\%, sowie nach 4 Jahren nur 14\% der Ig Rezeptoren mutiert. Sogar 6 Jahre nach Behandlung, waren VH Mutationen in IgD+ Ged{\"a}chtniszellen noch deutlich vermindert. Selbst nach dieser Zeit fanden sich in der pr{\"a}-switch Ged{\"a}chtnispopulation nur 27\% hochmutierte Sequenzen w{\"a}hrend vor der passageren B-Zelldepletion 52\% ein hohe Zahl an Mutationen trugen (P=0.0001). Die posttherapeutische Analyse der CDR3 L{\"a}nge der regenerierten IgD+ Ged{\"a}chtniszellen ergab eine erh{\"o}hte CDR3 L{\"a}nge, die signifikant mit der Anzahl der nicht mutierten VH Genrearrangements w{\"a}hrend der Repletionsphase korreliert. Interessanterweise regenerierten Patienten nach Hochdosis Chemotherapie und allogener Stammzelltransplantation ihre IgD+ Ged{\"a}chtniszellen mit einer deutlich h{\"o}heren Anzahl an Mutationen. Ein Jahr nach Transplantation zeigten die Ig Rezeptoren schon 22\% hoch mutierte und 42\% unmutierte VH Rearrangements. Das zeigt, dass eine gegen CD20 gerichtete Behandlung nicht nur eine Verz{\"o}gerung der Produktion der ungeswitchten Ged{\"a}chtniszellen zur Folge hat, sondern dar{\"u}ber hinaus einen signifikanten Effekt auf die Mutationsrate im pr{\"a}switch Ged{\"a}chtnis B-Zellpool besitzt. Im Gegensatz zum Mutationsmuster der IgD+ Ged{\"a}chtniszellen regenerierten die klassengeswitchten Ged{\"a}chtniszellen nach anti-CD20 Depletion im peripheren Blut mit quantitativ normalen Mutationen im Ig Rezeptor. Interessanterweise fand sich allerdings eine {\"A}nderung der exprimierten Isotypen mit deutlicher Dominanz IgA exprimierender B Zellen. Weitere Analysen der klassengeswitchten Ged{\"a}chtnis B-Zellen zeigen außerdem eine Therapie induzierte qualitative Ver{\"a}nderung dieses B-Zellpools. So waren posttherapeutisch die Mutationen in bestimmten T-Zell abh{\"a}ngigen Mutationshotspots, dem RGYW/WRCY Motiv, signifikant vermehrt (Mutationstargeting vor Therapie 27\% vs. 43\% nach Rituximab, P=0.0003). Dies weist darauf hin, dass die Mechanismen der Affinit{\"a}tsreifung im klassengeswitchten B-Zellged{\"a}chtnis vor und nach B-Zelldepletion unterschiedlich funktionieren. Der Mutationsmechanismus selbst ist allerdings in diesen Zellen quantitativ nicht eingeschr{\"a}nkt. Zusammenfassend zeigt unsere Arbeit zum erstem mal, dass es nach einer passageren B-Zelldepletion mit anti-CD20 Antik{\"o}rpern zu einer {\"u}ber Jahre hinweg nachweisbaren ausgepr{\"a}gten Verz{\"o}gerung in der Aquisition von somatischen Mutationen in rearrangierten VH Genen der IgD+ Ged{\"a}chtniszellen kommt. Demgegen{\"u}ber erholt sich das klassengeswitchte B-Zellged{\"a}chtnis mit uneingeschr{\"a}nkter Zahl von Mutationen im Ig Rezeptor. Diese Resultate zeigen, dass anti-CD20 gerichtete Therapien in besonderem Maße IgD+ Ged{\"a}chtniszellen beeinflussen. Der Selektionsdruck durch Antigene und/oder die Selektion der Ig Rezeptoren erscheint unter diesen Bedingungen speziell bei IgD-Ged{\"a}chtnis B-Zellen reduziert. Die Daten unterst{\"u}tzen die Hypothese, dass pr{\"a}-switch Ged{\"a}chtnis B-Zellen im Vergleich zu post-switch Ged{\"a}chtnis B-Zellen andere Bedingungen f{\"u}r die Aktivierung der Mutationsmaschinerie ben{\"o}tigen. Die Resultate er{\"o}ffnen neue Wege f{\"u}r das Verst{\"a}ndnis der Pathophysiologie der B-Zell Ged{\"a}chtnisentwicklung und k{\"o}nnen helfen neue zielgerichtete Therapien zur Behandlung von Autoimmunerkrankungen zu konzipieren.},
  subject      = {Rheumatoider arthritis},
  language  = {en}
}
@article{SerflingRudolfBuschetal.2014,
  author    = {Serfling, Edgar and Rudolf, Ronald and Busch, Rhoda and Patra, Amiya K. and Muhammad, Khalid and Avots, Andris and Andrau, Jean-Christophe and Klein-Hessling, Stefan},
  title     = {Architecture and expression of the Nfatc1 gene in lymphocytes},
  doi       = {10.3389/fimmu.2014.00021},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112718},
  year      = {2014},
  abstract  = {In lymphocytes, the three NFAT factors NFATc1 (also designated as NFAT2), NFATc2 (NFAT1), and NFATc3 (NFAT4 or NFATx) are expressed and are the targets of immune receptor signals, which lead to a rapid rise of intracellular Ca++, the activation of phosphatase calcineurin, and to the activation of cytosolic NFATc proteins. In addition to rapid activation of NFAT factors, immune receptor signals lead to accumulation of the short NFATc1/αA isoform in lymphocytes which controls their proliferation and survival. In this mini-review, we summarize our current knowledge on the structure and transcription of the Nfatc1 gene in lymphocytes, which is controlled by two promoters, two poly A addition sites and a remote downstream enhancer. The Nfatc1 gene resembles numerous primary response genes (PRGs) induced by LPS in macrophages. Similar to the PRG promoters, the Nfatc1 promoter region is organized in CpG islands, forms DNase I hypersensitive sites, and is marked by histone tail modifications before induction. By studying gene induction in lymphocytes in detail, it will be important to elucidate whether the properties of the Nfatc1 induction are not only typical for the Nfatc1 gene but also for other transcription factor genes expressed in lymphocytes.},
  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{KleinHesslingMuhammadKleinetal.2017,
  author    = {Klein-Hessling, Stefan and Muhammad, Khalid and Klein, Matthias and Pusch, Tobias and Rudolf, Ronald and Fl{\"o}ter, Jessica and Qureischi, Musga and Beilhack, Andreas and Vaeth, Martin and Kummerow, Carsten and Backes, Christian and Schoppmeyer, Rouven and Hahn, Ulrike and Hoth, Markus and Bopp, Tobias and Berberich-Siebelt, Friederike and Patra, Amiya and Avots, Andris and M{\"u}ller, Nora and Schulze, Almut and Serfling, Edgar},
  title     = {NFATc1 controls the cytotoxicity of CD8\(^{+}\) T cells},
  series = {Nature Communications},
  volume    = {8},
  journal   = {Nature Communications},
  number    = {511},
  doi       = {10.1038/s41467-017-00612-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170353},
  year      = {2017},
  abstract  = {Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.},
  language  = {en}
}
@article{RauschenbergerSchmittAzeemetal.2019,
  author    = {Rauschenberger, Tabea and Schmitt, Viola and Azeem, Muhammad and Klein-Hessling, Stefan and Murti, Krisna and Gr{\"a}n, Franziska and Goebeler, Matthias and Kerstan, Andreas and Klein, Matthias and Bopp, Tobias and Serfling, Edgar and Muhammad, Khalid},
  title     = {T cells control chemokine secretion by keratinocytes},
  series = {Frontiers in Immunology},
  volume    = {10},
  journal   = {Frontiers in Immunology},
  number    = {1917},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2019.01917},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195695},
  year      = {2019},
  abstract  = {The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8\(^+\)T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8\(^+\)T cells. One key molecule is IFN-γ that is synthesized by CD8\(^+\)T cells under the control of NFATc1 and NFATc2. CD8\(^+\)T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8\(^+\)T cells induced numerous type I IFN-inducible "defense genes" in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level.},
  language  = {en}
}
@article{KleinHesslingRudolfMuhammadetal.2016,
  author    = {Klein-Hessling, Stefan and Rudolf, Ronald and Muhammad, Khalid and Knobeloch, Klaus-Peter and Maqbool, Muhammad Ahmad and Cauchy, Pierre and Andrau, Jean-Christophe and Avots, Andris and Talora, Claudio and Ellenrieder, Volker and Screpanti, Isabella and Serfling, Edgar and Patra, Amiya Kumar},
  title     = {A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  doi       = {10.1038/ncomms11841},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172974},
  year      = {2016},
  abstract  = {NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.},
  language  = {en}
}
@article{AlrefaiMuhammadRudolfetal.2016,
  author    = {Alrefai, Hani and Muhammad, Khalid and Rudolf, Ronald and Pham, Duong Anh Thuy and Klein-Hessling, Stefan and Patra, Amiya K. and Avots, Andris and Bukur, Valesca and Sahin,, Ugur and Tenzer, Stefan and Goebeler, Matthias and Kerstan, Andreas and Serfling, Edgar},
  title     = {NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  doi       = {10.1038/ncomms11724},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173053},
  year      = {2016},
  abstract  = {Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.},
  language  = {en}
}
@article{MuhammadRudolfPhametal.2018,
  author    = {Muhammad, Khalid and Rudolf, Ronald and Pham, Duong Anh Thuy and Klein-Hessling, Stefan and Takata, Katsuyoshi and Matsushita, Nobuko and Ellenrieder, Volker and Kondo, Eisaku and  Serfling, Edgar},
  title     = {Induction of Short NFATc1/αA Isoform Interferes with Peripheral B Cell Differentiation},
  series = {Frontiers in Immunology},
  volume    = {9},
  journal   = {Frontiers in Immunology},
  number    = {32},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2018.00032},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197501},
  year      = {2018},
  abstract  = {In lymphocytes, immune receptor signals induce the rapid nuclear translocation of preformed cytosolic NFAT proteins. Along with co-stimulatory signals, persistent immune receptor signals lead to high levels of NFATc1/αA, a short NFATc1 isoform, in effector lymphocytes. Whereas NFATc1 is not expressed in plasma cells, in germinal centers numerous centrocytic B cells express nuclear NFATc1/αA. When overexpressed in chicken DT40 B cells or murine WEHI 231 B cells, NFATc1/αA suppressed their cell death induced by B cell receptor signals and affected the expression of genes controlling the germinal center reaction and plasma cell formation. Among those is the Prdm1 gene encoding Blimp-1, a key factor of plasma cell formation. By binding to a regulatory DNA element within exon 1 of the Prdm1 gene, NFATc1/αA suppresses Blimp-1 expression. Since expression of a constitutive active version of NFATc1/αA interfered with Prdm1 RNA expression, LPS-mediated differentiation of splenic B cells to plasmablasts in vitro and reduced immunoglobulin production in vivo, one may conclude that NFATc1/αA plays an important role in controlling plasmablast/plasma cell formation.},
  language  = {en}
}
@article{MahmoodSchmalzingDoerneretal.2020,
  author    = {Mahmood, Zafar and Schmalzing, Marc and D{\"o}rner, Thomas and Tony, Hans-Peter and Muhammad, Khalid},
  title     = {Therapeutic Cytokine Inhibition Modulates Activation and Homing Receptors of Peripheral Memory B Cell Subsets in Rheumatoid Arthritis Patients},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.572475},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212380},
  year      = {2020},
  abstract  = {Memory B cells have known to play an important role in the pathogenesis of rheumatoid arthritis (RA). With the emergence of B cell-targeted therapies, the modulation of memory B cells appears to be a key therapeutic target. Human peripheral memory B cells can be distinguished based on the phenotypic expression of CD27 and IgD, characterizing the three major B cell subpopulations: CD27+IgD+ pre-switch, CD27+IgD- post-switch, and CD27-IgD- double-negative memory B cells. We evaluated different memory cell populations for activation markers (CD95 and Ki-67) and chemokine receptors (CXCR3 and 4) expressing B cells in active RA, as well as under IL6-R blockade by tocilizumab (TCZ) and TNF-α blockade by adalimumab (ADA). Memory B cells were phenotypically analyzed from RA patients at baseline, week 12, and week 24 under TCZ or ADA treatment, respectively. Using flow cytometry, surface expression of CD95, intracellular Ki-67, and surface expressions of CXCR3 and CXCR4 were determined. Compared with healthy donors (n = 40), the phenotypic analysis of RA patients (n = 80) demonstrated that all three types of memory B cells were activated in RA patients. Surface and intracellular staining of B cells showed a significantly higher percentage of CD95+ (p < 0.0001) and Ki-67+ (p < 0.0001) cells, with numerically altered CXCR3+ and CXCR4+ cells in RA. CD95 and Ki-67 expressions were highest in post-switch memory B cells, whereas CD19+CXCR3+ and CD19+CXCR4+ expressing cells were substantially higher in the pre-switch compartment. In all subsets of the memory B cells, in vivo IL-6R, and TNF-α blockade significantly reduced the enhanced expressions of CD95 and Ki-67. Based on our findings, we conclude that the three major peripheral memory B cell populations, pre-, post-switch, and double-negative B cells, are activated in RA, demonstrating enhanced CD95 and Ki-67 expressions, and varied expression of CXCR3 and CXCR4 chemokine receptors when compared with healthy individuals. This activation can be efficaciously modulated under cytokine inhibition in vivo.},
  language  = {en}
}