@article{BenkertDietzHartmannetal.2012,
  author    = {Benkert, Thomas F. and Dietz, Lena and Hartmann, Elena M. and Leich, Ellen and Rosenwald, Andreas and Serfling, Edgar and Buttmann, Mathias and Berberich-Siebelt, Friederike},
  title     = {Natalizumab Exerts Direct Signaling Capacity and Supports a Pro-Inflammatory Phenotype in Some Patients with Multiple Sclerosis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-77905},
  year      = {2012},
  abstract  = {Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. While having shown high therapeutic efficacy, treatment by natalizumab has been linked to progressive multifocal leukoencephalopathy (PML) as a serious adverse effect. Furthermore, drug cessation sometimes induces rebound disease activity of unknown etiology. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes could modulate their phenotype by direct induction of intracellular signaling events. Primary CD4+ T lymphocytes either from healthy donors and treated with natalizumab in vitro or from MS patients receiving their very first dose of natalizumab were analyzed. Natalizumab induced a mild upregulation of IL-2, IFN-c and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-c and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action natalizumab possesses mild direct signaling capacities, which can support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity or IRIS is observed in some MS patients after natalizumab cessation.},
  subject      = {Medizin},
  language  = {en}
}
@phdthesis{Buttmann2002,
  author    = {Buttmann, Mathias},
  title     = {Molekularbiologische Untersuchung intrazellul{\"a}rer Signalwege, die in T-Lymphozyten zur Aktivierung des Transkriptionsfaktors NF-ATc f{\"u}hren},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-1181516},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2002},
  abstract  = {Der Transkriptionsfaktor NF-ATc (Nuclear Factor of Activated T cells) kontrolliert die Genexpression in T-Lymphozyten. In dieser Arbeit, in der Jurkat-T-Zellen und embryonale 293-Zellen als Modellsysteme verwendet wurden, konnte gezeigt werden, daß die N-terminale transaktivierende Dom{\"a}ne TAD-A von NF-ATc in vivo induzierbar durch den Phorbolester TPA, in vitro durch die MAP-Kinase Erk2 phosphoryliert wird. In Transfektionsexperimenten mit einer TAD-A-Mutante, in der alle f{\"u}nf Serinreste, die theoretisch durch MAP-Kinasen phosphoryliert werden k{\"o}nnen, durch Alaninreste ersetzt worden waren, konnte gezeigt werden, daß diese Phosphorylierung nicht notwendig f{\"u}r die Aktivierung von TAD-A ist. Vielmehr gelang der Nachweis, daß verschiedene MAP-Kinasen-Signalwege ihre Wirkung auf NF-ATc {\"u}ber die transkriptionellen Koaktivatoren CBP und p300 entfalten, die an die N-terminale transaktivierende Dom{\"a}ne TAD-A von NF-ATc binden und dessen Aktivit{\"a}t kontrollieren. Der Nachweis, daß konstitutiv aktive Mutanten von c-Raf und Rac synergistisch die CBP/p300-vermittelte TAD-A-Aktivierung verst{\"a}rken, unterstreicht die wichtige Rolle, die CBP/p300 bei der Integration von T-Zell-Aktivierungssignalen spielt.},
  language  = {de}
}
@article{HaarmannSchuhmannSilwedeletal.2019,
  author    = {Haarmann, Axel and Schuhmann, Michael K. and Silwedel, Christine and Monoranu, Camelia-Maria and Stoll, Guido and Buttmann, Mathias},
  title     = {Human brain endothelial CXCR2 is inflammation-inducible and mediates CXCL5- and CXCL8-triggered paraendothelial barrier breakdown},
  series = {International Journal of Molecular Science},
  volume    = {20},
  journal   = {International Journal of Molecular Science},
  number    = {3},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20030602},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201297},
  year      = {2019},
  abstract  = {Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood-brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood-brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood-brain barrier stabilization.},
  language  = {en}
}