1,721,141 research outputs found
The C-terminus of complement factor H is essential for host cell protection
No full textComplement 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.NIAID NIH HHS [AI 30040, N01AI30040, R01 AI030040, R01 AI030040-12
Anti-factor H autoantibodies and hemolytic uremic syndrome: role of the C-terminus of factor H for activity on endothelial cells
No full textAttachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology
No full textComplement 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
Attachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology
No full textComplement 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
Anti-factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome
No full textThe 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
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
C1q and the glomerulonephritides: therapeutic approaches for the treatment of complement-mediated kidney diseases
No full textVariations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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