Oppermann, Martin

[["dc.bibliographiccitation.firstpage","251"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","HISTOLOGY AND HISTOPATHOLOGY"],["dc.bibliographiccitation.lastpage","258"],["dc.bibliographiccitation.volume","19"],["dc.contributor.author","Jozsi, M."],["dc.contributor.author","Manuelian, T."],["dc.contributor.author","Heinen, S."],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Zipfel, Peter F."],["dc.date.accessioned","2018-11-07T10:52:37Z"],["dc.date.available","2018-11-07T10:52:37Z"],["dc.date.issued","2004"],["dc.description.abstract","Complement is a central element of innate immunity and this vital defense system initiates and coordinates immediate immune reactions which attack and eliminate microbes, foreign particles and altered self cells. Newly generated activation products are extremely toxic and consequently, activation is highly restricted in terms of time and space. The initial activation of the alternative complement pathway occurs continuously and the early phase acts indiscriminatoryl and forms on any surface. However, the system discriminates between self and foreign, and therefore allows activation on foreign surfaces e.g. Microbes, and restricts activation on host cells. Consequently, self cells and tissues are protected from the harmful activation products. This protection is mediated by specific regulators or inhibitors, which exist in the fluid phase and/or in membrane-bound forms. Here we review a novel mechanism, i.e. the attachment of the soluble complement regulator factor H to the surface of self cells. This attachment, which is demonstrated experimentally by means of immunofluorescense microscopy and by flow cytometry, increases the inhibitory potential at the cell surface and mediates protection by reducing the local formation of toxic inflammatory products. This attachment is highly relevant and has pathophysiological consequences in several human diseases, including Factor H-associated hemolytic uremic syndrome (FH-HUS), membrano-proliferative glomerulonephritis type II, recurrent microbial infections and chronic inflammation, e.g. rheumatoid arthritis and immune evasion of tumor cells. Defects of this safeguard activity have been recently understood in patients with FH-HUS. Point mutations in the Factor H gene occurring in the C-terminus of the protein result in impaired cell binding capacity of Factor H and, consequently, during an inflammatory insult endothelial cells are not properly protected and are damaged."],["dc.identifier.isi","000188355400030"],["dc.identifier.pmid","14702193"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/49151"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","F Hernandez"],["dc.relation.issn","0213-3911"],["dc.title","Attachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","342"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Clinical & Experimental Immunology"],["dc.bibliographiccitation.lastpage","352"],["dc.bibliographiccitation.volume","144"],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Manuelian, T."],["dc.contributor.author","Jozsi, M."],["dc.contributor.author","Brandt, E."],["dc.contributor.author","Jokiranta, T. S."],["dc.contributor.author","Heinen, S."],["dc.contributor.author","Meri, S."],["dc.contributor.author","Skerka, C."],["dc.contributor.author","Gotze, O."],["dc.contributor.author","Zipfel, Peter F."],["dc.date.accessioned","2018-11-07T09:51:20Z"],["dc.date.available","2018-11-07T09:51:20Z"],["dc.date.issued","2006"],["dc.description.abstract","The complement inhibitor Factor H has three distinct binding sites for C3b and for heparin, but in solution uses specifically the most C-terminal domain, i.e. short consensus repeats (SCR) 20 for ligand interaction. Two novel monoclonal antibodies (mABs C14 and C18) that bind to the most C-terminal domain SCR 20 completely blocked interaction of Factor H with the ligands C3b, C3d, heparin and binding to endothelial cells. In contrast, several mAbs that bind to the N-terminus and to the middle regions of the molecule showed no or minor inhibitory effects when assayed by enzyme-linked immunosorbent assay (ELISA) and ligand interaction assays. This paradox between a single functional binding site identified for native Factor H versus multiple interaction sites reported for deletion constructs is explained by a compact conformation of the fluid phase protein with one accessible binding site. On zymosan particles mAbs C14 and C18 blocked alternative pathway activation completely. Thus demonstrating that native Factor H makes the first and initial contact with the C terminus, which is followed by N terminally mediated complement regulation. These results are explained by a conformational hypothetical model: the native Factor H protein has a compact structure and only one binding site accessible. Upon the first contact the protein unfolds and exposes the additional binding sites. This model does explain how Factor H mediates recognition functions during complement control and the clustering of disease associated mutations in patients with haemolytic uraemic syndrome that have been reported in the C-terminal recognition domain of Factor H."],["dc.identifier.doi","10.1111/j.1365-2249.2006.03071.x"],["dc.identifier.isi","000236766600021"],["dc.identifier.pmid","16634809"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/35890"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Blackwell Publishing"],["dc.relation.issn","0009-9104"],["dc.title","The C-terminus of complement regulator Factor H mediates target recognition: evidence for a compact conformation of the native protein"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","136"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nephrology Dialysis Transplantation"],["dc.bibliographiccitation.lastpage","144"],["dc.bibliographiccitation.volume","25"],["dc.contributor.author","Strobel, Stefanie"],["dc.contributor.author","Hoyer, Peter F."],["dc.contributor.author","Mache, Christoph J."],["dc.contributor.author","Sulyok, Endre"],["dc.contributor.author","Liu, Wei-shih"],["dc.contributor.author","Richter, Heiko"],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Zipfel, Peter F."],["dc.contributor.author","Jozsi, Mihaly"],["dc.date.accessioned","2018-11-07T08:48:11Z"],["dc.date.available","2018-11-07T08:48:11Z"],["dc.date.issued","2010"],["dc.description.abstract","Methods. CFH autoantibodies were identified and antibody levels were analysed in three aHUS patients during the disease course by the ELISA method. Epitope mapping was performed using recombinant factor H fragments and domain-mapped monoclonal antibodies. The effect of the antibodies on cell-protective activity of CFH was measured by haemolytic assays. CFH:autoantibody complexes were analysed by ELISA. Results. All three autoantibodies bound to the C-terminal domain of CFH, which is essential for CFH binding to cell surfaces. In patient 1, plasma exchanges and immune adsorption temporarily reduced the autoantibody titre and led to temporary clinical improvement. In patient 2, plasma exchanges and long-term immunosuppression strongly reduced the CFH autoantibody level, and induced a stable remission of aHUS. Patient 3 had lower autoantibody levels that decreased during the follow-up and is in good clinical condition. The patients' plasma samples caused enhanced lysis of sheep erythrocytes, and the degree of lysis correlated with the CFH autoantibody titre and the amount of CFH:autoantibody complexes. An addition of purified CFH to aHUS plasma or removal of IgG inhibited the haemolytic activity. Conclusion. These results support a direct role of the autoantibodies in aHUS pathology by inhibiting the regulatory function of CFH at cell surfaces and suggest that reduction of the autoantibody titre is beneficial for the patients."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft; Kidneeds Foundation, Cedar Rapids, US"],["dc.identifier.doi","10.1093/ndt/gfp388"],["dc.identifier.isi","000273113100024"],["dc.identifier.pmid","19666655"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/21150"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0931-0509"],["dc.title","Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1516"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Blood"],["dc.bibliographiccitation.lastpage","1518"],["dc.bibliographiccitation.volume","110"],["dc.contributor.author","Jozsi, Mihaly"],["dc.contributor.author","Strobel, Stefanie"],["dc.contributor.author","Dahse, Hans-Martin"],["dc.contributor.author","Liu, Wei-Shih"],["dc.contributor.author","Hoyer, Peter F."],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Skerka, Christine"],["dc.contributor.author","Zipfel, Peter F."],["dc.date.accessioned","2018-11-07T10:58:46Z"],["dc.date.available","2018-11-07T10:58:46Z"],["dc.date.issued","2007"],["dc.description.abstract","The atypical form of the kidney disease hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. In addition to mutations in complement regulators, factor H (FH)specific autoantibodies have been reported for aHUS patients. The aim of the present study was to understand the role of these autoantibodies in aHUS. First, the binding sites of FH autoantibodies from 5 unrelated aHUS patients were mapped using recombinant FH fragments and competitor antibodies. For all 5 autoantibodies, the binding site was localized to the FH C-terminus. In a functional assay, isolated patient IgG inhibited FH binding to C3b. In addition, autoantibody positive patients' plasma caused enhanced hemolysis of sheep erythrocytes, which was reversed by adding FH in excess. These results suggest that aHUS associated FH autoantibodies mimic the effect of C-terminal FH mutations, as they inhibit the regulatory function of FH at cell surfaces by blocking its C-terminal recognition region."],["dc.identifier.doi","10.1182/blood-2007-02-071472"],["dc.identifier.isi","000249151800026"],["dc.identifier.pmid","17495132"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/50540"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Soc Hematology"],["dc.relation.issn","0006-4971"],["dc.title","Anti-factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","13"],["dc.bibliographiccitation.journal","Molecular Immunology"],["dc.bibliographiccitation.volume","47"],["dc.contributor.author","Lauer, Nadine"],["dc.contributor.author","Fritsche, Lars G."],["dc.contributor.author","Weber, Bernhard H. F."],["dc.contributor.author","Hartmann, Andrea"],["dc.contributor.author","Keilhauer, Claudia N."],["dc.contributor.author","Haelbich, Steffi"],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Pandey, Manoij"],["dc.contributor.author","Koehl, Joerg"],["dc.contributor.author","Zipfel, Peter F."],["dc.contributor.author","Skerka, Christine"],["dc.date.accessioned","2018-11-07T08:41:00Z"],["dc.date.available","2018-11-07T08:41:00Z"],["dc.date.issued","2010"],["dc.format.extent","2211"],["dc.identifier.doi","10.1016/j.molimm.2010.05.049"],["dc.identifier.isi","000280268400043"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19372"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Pergamon-elsevier Science Ltd"],["dc.publisher.place","Oxford"],["dc.relation.eventlocation","New York, NY"],["dc.relation.issn","0161-5890"],["dc.title","Imbalance of complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age related macular degeneration (AMD)"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","16"],["dc.bibliographiccitation.journal","Molecular Immunology"],["dc.bibliographiccitation.volume","44"],["dc.contributor.author","Strobel, Stefanie"],["dc.contributor.author","Dahse, Hans-Martin"],["dc.contributor.author","Liu, Wei-shih"],["dc.contributor.author","Hoyer, Peter F."],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Terenyi, Nora"],["dc.contributor.author","Skerka, Christine"],["dc.contributor.author","Zipfel, Peter F."],["dc.contributor.author","Jozsi, Mihaly"],["dc.date.accessioned","2018-11-07T10:59:12Z"],["dc.date.available","2018-11-07T10:59:12Z"],["dc.date.issued","2007"],["dc.format.extent","3974"],["dc.identifier.doi","10.1016/j.molimm.2007.06.171"],["dc.identifier.isi","000249512100156"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/50647"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Pergamon-elsevier Science Ltd"],["dc.publisher.place","Oxford"],["dc.relation.conference","11th European Meeting on Complement in Human Disease"],["dc.relation.eventlocation","Cardiff, WALES"],["dc.relation.issn","0161-5890"],["dc.title","Factor H-autoantibodies in atypical hemolytic uremic syndrome"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2697"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Molecular Immunology"],["dc.bibliographiccitation.lastpage","2706"],["dc.bibliographiccitation.volume","44"],["dc.contributor.author","Jozsi, Mihaly"],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Lambris, John D."],["dc.contributor.author","Zipfel, Peter F."],["dc.date.accessioned","2018-11-07T11:03:45Z"],["dc.date.available","2018-11-07T11:03:45Z"],["dc.date.issued","2007"],["dc.description.abstract","Complement is a powerful self-amplifying system of innate immune defense with the capacity to eliminate microbes directly. Factor H is a central regulator in plasma which protects host tissue from complement mediated damage. Here we characterize the relevance of surface attached factor H, and study the regulatory activity of factor H on endothelial cells. Although these cells expressed membrane bound regulators, cell bound factor H contributed substantially to complement regulatory activity at the cell surface. Blockade of the C-terminus of factor H with monoclonal antibodies inhibited cell binding of this soluble regulator and resulted in enhanced complement activation on the cells. In the absence of factor H, increased deposition and slower inactivation of C3b resulted in higher amount of membrane attack complexes on the cell surface. When the membrane regulators CD55 and CD59 were removed by enzymatic treatment, complement mediated cell lysis was enhanced in the absence of factor H. Importantly, inhibition of the C-terminus did not compromise the regulatory function of factor H in fluid phase. Altogether these data point to a highly relevant, yet so far underestimated role of factor H for complement control at cellular surfaces, and reveal a decisive role of the factor H C-terminus in host cell recognition and protection. (c) 2006 Elsevier Ltd. All rights reserved."],["dc.description.sponsorship","NIAID NIH HHS [AI 30040, N01AI30040, R01 AI030040, R01 AI030040-12]"],["dc.identifier.doi","10.1016/j.molimm.2006.12.001"],["dc.identifier.isi","000245681200022"],["dc.identifier.pmid","17208302"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/51684"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Pergamon-elsevier Science Ltd"],["dc.publisher.place","Oxford"],["dc.relation.conference","10th Meeting on Complement in Human Disease"],["dc.relation.eventlocation","Heidelberg, GERMANY"],["dc.relation.issn","0161-5890"],["dc.title","The C-terminus of complement factor H is essential for host cell protection"],["dc.type","conference_paper"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4694"],["dc.bibliographiccitation.issue","23"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","4704"],["dc.bibliographiccitation.volume","19"],["dc.contributor.author","Fritsche, Lars G."],["dc.contributor.author","Lauer, Nadine"],["dc.contributor.author","Hartmann, Andrea"],["dc.contributor.author","Stippa, Selina"],["dc.contributor.author","Keilhauer, Claudia N."],["dc.contributor.author","Oppermann, Martin"],["dc.contributor.author","Pandey, Manoj K."],["dc.contributor.author","Koehl, Joerg"],["dc.contributor.author","Zipfel, Peter F."],["dc.contributor.author","Weber, Bernhard H. F."],["dc.contributor.author","Skerka, Christine"],["dc.date.accessioned","2018-11-07T08:36:15Z"],["dc.date.available","2018-11-07T08:36:15Z"],["dc.date.issued","2010"],["dc.description.abstract","A frequent deletion of complement factor H (CFH)-related genes CFHR3 and CFHR1 (Delta CFHR3/CFHR1) is considered to have a protective effect against age-related macular degeneration (AMD), although the underlying mechanism remains elusive. The deletion seems to be linked to one of the two protective CFH haplotypes which are both tagged by the protective allele of single nucleotide polymorphism rs2274700 (CFH:A473A). In a German cohort of 530 AMD patients, we now show that protection against AMD conferred by Delta CFHR3/CFHR1 is independent of the effects of rs2274700 and rs1061170 (CFH:Y402H). This suggests a functional role of CFHR1 and/or CFHR3 in disease pathogenesis. We therefore characterized the CFHR3 function and identified CFHR3 as a novel human complement regulator that inhibits C3 convertase activity. CFHR3 displays anti-inflammatory effects by blocking C5a generation and C5a-mediated chemoattraction of neutrophils. In addition, CFHR3 and CFHR1 compete with factor H for binding to the central complement component C3. Thus, deficiency of CFHR3 and CFHR1 results in a loss of complement control but enhances local regulation by factor H. Our findings allude to a critical balance between the complement regulators CFHR3, CFHR1 and factor H and further emphasize the central role of complement regulation in AMD pathology."],["dc.identifier.doi","10.1093/hmg/ddq399"],["dc.identifier.isi","000283930200013"],["dc.identifier.pmid","20843825"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/18266"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0964-6906"],["dc.title","An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD)"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]