Research Report 2010 - MDC

Ralph KettritzStructure of the GroupGroup LeaderProf. Ralph KettritzGraduate students and clinical fellowsDr. Adrian SchreiberDr. Mira ChoiDr. Julia BontschoDr. Uwe JerkeDr. Astrid BergmannClaudia EulenbergNeutrophil biology in healthand diseaseThis group focuses on the neutrophilic granulocyte. Neutrophils form an essential part of theinnate immune system. Neutrophils circulate in the blood stream and migrate into tissuesduring inflammation and also in some cancers. This process is initiated by signals, such asInterleukin-8 (IL-8), Interferon-gamma (IFN-γ), and complement fraction C5a. The fundamentalfinding that some systemic vasculitidis are caused by autoantibodies directed at neutrophilproteinase 3 and myeloperoxidase, sparked our interest in neutrophils. These antineutrophilcytoplasmic antibodies (PR3 and MPO ANCA) cause a common syndrome featuring upper andlower airway disease as well as rapidly progressive “pauci-immune” glomerulonephritis (ANCAvasculitis). In addition, our group is interested in all aspects of neutrophil function.A mouse model of ANCA vasculitisAdrian Schreiber, a DFG-sponsored research fellow, participatedin the development of a mouse model duringhis fellowship at the University of North Carolina withCharles Jennette. They immunized MPO gene-deficientmice with MPO inducing MPO ANCA. Then, these micewere irradiated and underwent bone-marrow transplantwith MPO+/+ marrow. The animals now had MPOANCA and MPO in their neutrophils and developed aclassic MPO ANCA vasculitis, including glomerulonephritis.Werecently made the novel observation that the C5areceptor mediates neutrophil activation in this model.Supernatants from ANCA-stimulated neutrophils activatedthe complement cascade in normal serum in vitro,producing C5a. This conditioned serum primed neutrophilsfor ANCA-induced activation and C5aR blockadeabrogated this effect. In our mouse model, bone marrowtransplants were done from C5a-/- and C5a+/+ mice.Theresults were convincing and showed that the complementsystem is pivotal to MPO ANCA vasculitis raisingimportant therapeutic possibilities.The CD177 glycoprotein NB1 and PR3 cell-surfacepresentationThe serine protease proteinase 3 (PR3) is a mainautoantigen in ANCA vasculitis. PR3 surface presentationon neutrophilis, the main effector cells, is pathogenicallyimportant. PR3 is presented by the NB1 (CD177)glycoprotein, but how the presentation develops duringneutrophil differentiation is not known. The Kettritzteam is intensively studying the relationship betweenNB1 and PR3. An N-terminally unprocessed PR3 (proPR3)is produced early during neutrophil development andpromotes myeloid cell differentiation. The group recentlytested whether or not it depended on NB1 duringneutrophil differentiation and if PR3 and proPR3 couldboth be presented by NB1. NB1-mediated PR3 presentationdepended on PR3 N-terminal processing implicatingthe PR3-N-terminus as NB1-binding site. Kettritzand associates are currently pursuing this promisingarea of investigation further.The adage is “starve a fever, feed a cold.”Physicians spend much of their time fighting fever;even William Osler thought that the issue was important.We asked whether or not fever regulates neutrophilbehavior in a series of studies. Mira Choi was primarilyresponsible for this work. The group tested thehypothesis that exposure of mice to fever-like temperaturesabrogates neutrophil recruitment and NF-kappaBactivation in a mouse model of skin inflammation. Mice210 The Experimental and Clinical Research Center