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 α-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 α-FXIIa formed complexes with FH, with an apparent binding strength Kd of 34 ± 9 nmol/L. The complex formation involved the kringle domain of the heavy chain of FXII. C1-inhibitor induced inhibition of α-FXIIa did not alter the binding of α-FXIIa toward FH. We further demonstrated the presence of α-FXIIa:FH complexes in normal human plasma upon contact activation, indicating formation of α-FXIIa:FH complexes as a consequence of α-FXIIa generation. Complex formation between α-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 α-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 α-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.
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 α-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 α-FXIIa formed complexes with FH, with an apparent binding strength Kd of 34 ± 9 nmol/L. The complex formation involved the kringle domain of the heavy chain of FXII. C1-inhibitor induced inhibition of α-FXIIa did not alter the binding of α-FXIIa toward FH. We further demonstrated the presence of α-FXIIa:FH complexes in normal human plasma upon contact activation, indicating formation of α-FXIIa:FH complexes as a consequence of α-FXIIa generation. Complex formation between α-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 α-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 α-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.
Authors: Cristina Puy; Jiaqing Pang; Stéphanie E Reitsma; Christina U Lorentz; Erik I Tucker; David Gailani; András Gruber; Florea Lupu; Owen J T McCarty Journal: J Immunol Date: 2021-04-15 Impact factor: 5.422
Authors: Nathalie Khoury; Michael J Betley; Zurine De Miguel; Benoit Lehallier; Drew Willoughby; Niclas Olsson; Andrew C Yang; Oliver Hahn; Nannan Lu; Ryan T Vest; Liana N Bonanno; Lakshmi Yerra; Lichao Zhang; Nay Lui Saw; J Kaci Fairchild; Davis Lee; Hui Zhang; Patrick L McAlpine; Kévin Contrepois; Mehrdad Shamloo; Joshua E Elias; Thomas A Rando; Tony Wyss-Coray Journal: Nature Date: 2021-12-08 Impact factor: 69.504