期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 18, 期 4, 页码 876-884出版社
WILEY
DOI: 10.1111/jth.14742
关键词
C1 inhibitor deficiency; coagulation; complement; factor H; factor XII
资金
- Innovation Fund Denmark [52-2014-1]
Background The complement and coagulation systems share an evolutionary origin with many components showing structural homology. Certain components, including complement factor H (FH) and coagulation factor XII (FXII), have separately been shown to have auxiliary activities across the two systems. Objectives The interaction between FXII and FH was investigated. Methods Using enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) complex formation between different FXII forms and FH was investigated. The presence of alpha-FXIIa:FH complexes upon contact activation in plasma was evaluated by ELISA and immunoprecipitation. Results We identified and characterized a direct interaction between the components and demonstrated that among different forms of FXII, only the activated alpha-FXIIa formed complexes with FH, with an apparent binding strength K(d )of 34 +/- 9 nmol/L. The complex formation involved the kringle domain of the heavy chain of FXII. C1-inhibitor induced inhibition of alpha-FXIIa did not alter the binding of alpha-FXIIa toward FH. We further demonstrated the presence of alpha-FXIIa:FH complexes in normal human plasma upon contact activation, indicating formation of alpha-FXIIa:FH complexes as a consequence of alpha-FXIIa generation. Complex formation between alpha-FXIIa and FH was also assessed in hereditary angioedema (HAE) patients with C1-inhibitor deficiency as well as rheumatoid arthritis (RA) patients with high levels of anti-cyclic citrullinated peptide (anti-CCP) upon contact activation. We observed elevated levels of alpha-FXIIa:FH complexes in HAE patients, and equal levels of complexes in RA patients and healthy individuals upon contact activation. Conclusion A direct interaction between alpha-FXIIa and FH is demonstrated. Our findings represent a new crosstalk between these systems, potentially important in the onset and pathology of inflammatory vascular diseases.
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