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Sebastian Fuchs, Anne Rensing-Ehl,
Carsten Speckmann,
Bertram Bengsch,
Annette Schmitt-Graeff,
Ilka Bondzio,
Andrea Maul-Pavicic,
Thilo Bass,
Thomas Vraetz,
Brigitte Strahm,
Tobias Ankermann,
Melina Benson,
Almuth Caliebe,
Regina Fölster-Holst,
Petra Kaiser,
Robert Thimme,
Wolfgang W Schamel,
Klaus Schwarz,
Stefan Feske,
Stephan Ehl
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ABSTRACT: Stromal interaction molecule 1 (STIM1) deficiency is a rare genetic disorder of store-operated calcium entry, associated with a complex syndrome including immunodeficiency and immune dysregulation. The link from the molecular defect to these clinical manifestations is incompletely understood. We report two patients with a homozygous R429C point mutation in STIM1 completely abolishing store-operated calcium entry in T cells. Immunological analysis of one patient revealed that despite the expected defect of T cell proliferation and cytokine production in vitro, significant antiviral T cell populations were generated in vivo. These T cells proliferated in response to viral Ags and showed normal antiviral cytotoxicity. However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections with a possible contribution of impaired NK cell function and a lack of NKT cells. Furthermore, autoimmune cytopenia, eczema, and intermittent diarrhea suggested impaired immune regulation. FOXP3-positive regulatory T (Treg) cells were present but showed an abnormal phenotype. The suppressive function of STIM1-deficient Treg cells in vitro, however, was normal. Given these partial defects in cytotoxic and Treg cell function, impairment of other immune cell populations probably contributes more to the pathogenesis of immunodeficiency and autoimmunity in STIM1 deficiency than previously appreciated.
The Journal of Immunology 12/2011; 188(3):1523-33. · 5.79 Impact Factor
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Scandinavian Journal of Immunology 07/2011; 74(5):518-9. · 2.23 Impact Factor
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Andrea Maul-Pavicic,
Samuel C C Chiang, Anne Rensing-Ehl,
Birthe Jessen,
Cyril Fauriat,
Stephanie M Wood,
Sebastian Sjöqvist,
Markus Hufnagel,
Ilka Schulze,
Thilo Bass,
Wolfgang W Schamel,
Sebastian Fuchs,
Hanspeter Pircher,
Christie-Ann McCarl,
Katsuhiko Mikoshiba,
Klaus Schwarz,
Stefan Feske,
Yenan T Bryceson,
Stephan Ehl
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ABSTRACT: Lymphocytes mediate cytotoxicity by polarized release of the contents of cytotoxic granules toward their target cells. Here, we have studied the role of the calcium release-activated calcium channel ORAI1 in human lymphocyte cytotoxicity. Natural killer (NK) cells obtained from an ORAI1-deficient patient displayed defective store-operated Ca(2+) entry (SOCE) and severely defective cytotoxic granule exocytosis leading to impaired target cell lysis. Similar findings were obtained using NK cells from a stromal interaction molecule 1-deficient patient. The defect occurred at a late stage of the signaling process, because activation of leukocyte functional antigen (LFA)-1 and cytotoxic granule polarization were not impaired. Moreover, pharmacological inhibition of SOCE interfered with degranulation and target cell lysis by freshly isolated NK cells and CD8(+) effector T cells from healthy donors. In addition to effects on lymphocyte cytotoxicity, synthesis of the chemokine macrophage inflammatory protein-1β and the cytokines TNF-α and IFN-γ on target cell recognition was impaired in ORAI1-deficient NK cells, as previously described for T cells. By contrast, NK cell cytokine production induced by combinations of IL-12, IL-15, and IL-18 was not impaired by ORAI1 deficiency. Taken together, these results identify a critical role for ORAI1-mediated Ca(2+) influx in granule exocytosis for lymphocyte cytotoxicity as well as for cytokine production induced by target cell recognition.
Proceedings of the National Academy of Sciences 02/2011; 108(8):3324-9. · 9.68 Impact Factor
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Antje Prasse,
Gernot Zissel,
Niklas Lützen,
Jonas Schupp,
Rene Schmiedlin,
Elena Gonzalez-Rey, Anne Rensing-Ehl,
Gerald Bacher,
Vera Cavalli,
Dorian Bevec,
Mario Delgado,
Joachim Müller-Quernheim
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ABSTRACT: Previous studies suggest an important immunoregulatory role of vasoactive intestinal peptide (VIP) in experimental models of chronic noninfectious inflammation. Sarcoidosis is characterized by noncaseating epitheloid cell granulomas, where excessive tumor necrosis factor-alpha production by pulmonary macrophages plays a critical role in granuloma formation and disease progression, which may lead to fatal organ dysfunction.
To test whether inhaled VIP has an immunoregulatory role. Sarcoid alveolitis was used as a prototype of immune-mediated chronic lung inflammation.
In an open clinical phase II study, we treated 20 patients with histologically proved sarcoidosis and active disease with nebulized VIP for 4 weeks.
VIP inhalation was safe, well-tolerated, and significantly reduced the production of tumor necrosis factor-alpha by cells isolated from bronchoalveolar lavage fluids of these patients. VIP treatment significantly increased the numbers of bronchoalveolar lavage CD4(+)CD127(-)CD25(+) T cells, which showed regulatory activities on conventional effector T cells. In vitro experiments demonstrated the capacity of VIP to convert naive CD4(+)CD25(-) T cells into CD4(+)CD25(+)FoxP3(+) regulatory T cells, suggesting the generation of peripheral regulatory T cells by VIP treatment.
This study is the first to show the immunoregulatory effect of VIP in humans, and supports the notion of inhaled VIP as an attractive future therapy to dampen exaggerated immune responses in lung disorders. Thus, the inhalation of neuropeptides may be developed into a new therapeutic principle for chronic inflammatory lung disorders in humans.
American Journal of Respiratory and Critical Care Medicine 05/2010; 182(4):540-8. · 11.08 Impact Factor
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ABSTRACT: Bullous pemphigoid (BP) is an autoimmune blistering skin disease characterized by autoantibodies to hemidesmosomal proteins. The initiation and regulation of the autoimmune response are poorly understood. We analysed cell subsets with immunoregulatory functions in untreated BP patients. While the numbers of circulating NKT and NK cells were normal, gammadelta T cells were reduced in BP patients. gammadelta T cells were rarely detected in lesional skin, arguing against their sequestration in the skin. In most patients, clinical remission and reduction of autoantibody titres after immunosuppressive therapy was not accompanied by an increase of circulating gammadelta T cells. V gammadelta gene usage was not altered in BP patients and the gammadelta T cells of BP patients were functional as they proliferated in response to isopentenyl pyrophosphate. Our data provide a basis for further investigations on the role of gammadelta T cells in the immunopathogenesis of BP.
Experimental Dermatology 04/2009; 18(11):991-3. · 3.54 Impact Factor
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ABSTRACT: Allergic contact dermatitis is induced by chemicals or metal ions. A hallmark of this T cell mediated skin disease is the activation of the innate immune system by contact allergens. This immune response results in inflammation and is a prerequisite for the activation of the adaptive immune system with tissue-specific migration of effector and regulatory T cells. Recent studies have begun to address in detail the innate immune cells as well as the innate receptors on these cells and the associated signaling pathways which lead to skin inflammation. We review here recent findings regarding innate and adaptive immune responses and immune regulation of contact dermatitis and other skin diseases as well as recent developments towards an in vitro assessment of the allergenic potential of chemicals. The elucidation of the innate inflammatory pathways, cellular components and mediators will help to identify new drug targets for more efficient treatment of allergic contact dermatitis and hopefully also for its prevention.
Inflammation & Allergy - Drug Targets (Formerly ?Current Drug Targets - Inflammation & Allergy) 01/2008; 6(4):236-44.
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ABSTRACT: Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with autoantibodies to collagen XVII and tissue-separation along the dermo-epidermal junction. We addressed the question whether the loss of tolerance in BP patients is associated with a reduction and/or functional impairment of CD4+CD25+FOXP3+ regulatory T cells, which are essential for the active maintenance of self tolerance. The relative and absolute frequency of CD4+CD25+ and CD4+CD25(high) regulatory T cells in the peripheral blood of newly diagnosed, untreated patients was similar to that of healthy controls. Interestingly, more than 50% of circulating CD4+CD25(high) regulatory T cells from both patients as well as healthy controls expressed cutaneous lymphocyte-associated antigen. Considerable numbers of FOXP3+ cells were detected in lesional skin of patients. CD4+CD25+ regulatory T cells of patients were functionally intact as assessed by their ability to suppress allogeneic as well as antigen-specific T-cell proliferation. These data argue against a general defect of CD4+CD25+FOXP3+ regulatory T cells in patients with BP.
Experimental Dermatology 02/2007; 16(1):13-21. · 3.54 Impact Factor
