TY  - JOUR
A1  - Serfling, Edgar
A1  - Avots, Andris
A1  - Klein-Hessling, Stefan
A1  - Rudolf, Ronald
A1  - Vaeth, Martin
A1  - Berberich-Siebelt, Friederike
T1  - NFATc1/alphaA: The other Face of NFAT Factors in Lymphocytes
N2  - In effector T and B cells immune receptor signals induce within minutes a rise of intracellular Ca++, the activation of the phosphatase calcineurin and the translocation of NFAT transcription factors from cytosol to nucleus. In addition to this first wave of NFAT activation, in a second step the occurrence of NFATc1/αA, a short isoform of NFATc1, is strongly induced. Upon primary stimulation of lymphocytes the induction of NFATc1/αA takes place during the G1 phase of cell cycle. Due to an auto-regulatory feedback circuit high levels of NFATc1/αA are kept constant during persistent immune receptor stimulation. Contrary to NFATc2 and further NFATc proteins which dampen lymphocyte proliferation, induce anergy and enhance activation induced cell death (AICD), NFATc1/αA supports antigenmediated proliferation and protects lymphocytes against rapid AICD. Whereas high concentrations of NFATc1/αA can also lead to apoptosis, in collaboration with NF-κB-inducing co-stimulatory signals they support the survival of mature lymphocytes in late phases after their activation. However, if dysregulated, NFATc1/αA appears to contribute to lymphoma genesis and – as we assume – to further disorders of the lymphoid system. While the molecular details of NFATc1/αA action and its contribution to lymphoid disorders have to be investigated, NFATc1/αA differs in its generation and function markedly from all the other NFAT proteins which are expressed in lymphoid cells. Therefore, it represents a prime target for causal therapies of immune disorders in future.
KW  - Medizin
KW  - Activation induced cell death/AICD
KW  - Anergy
KW  - Apoptosis
KW  - Calcineurin
KW  - NFATc
KW  - NFATc1/αA
KW  - NF-κB
KW  - Proliferation
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75748
ER  - 
TY  - JOUR
A1  - Benkert, Thomas F.
A1  - Dietz, Lena
A1  - Hartmann, Elena M.
A1  - Leich, Ellen
A1  - Rosenwald, Andreas
A1  - Serfling, Edgar
A1  - Buttmann, Mathias
A1  - Berberich-Siebelt, Friederike
T1  - Natalizumab Exerts Direct Signaling Capacity and Supports a Pro-Inflammatory Phenotype in Some Patients with Multiple Sclerosis
N2  - 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.
KW  - Medizin
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77905
ER  -