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DOI: 10.1055/a-2057-8710
Antibodies against Noncatalytic B Subunit of Factor XIII Inhibit Activation of Factor XIII and Fibrin Crosslinking
Funding This study was supported in part by research aids to A.I. from the Japanese Ministry of Health, Labor, and Welfare (21FC1008), the Japanese Ministry of Education, Culture, Sports, Science, and Technology (16K09820), and the Japan Agency for Medical Research and Development (AMED; JP16ek0109043).
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Abstract
Background Coagulation factor XIII (FXIII) is a proenzyme of plasma transglutaminase. It comprises two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B). We previously reported that alloantibodies against FXIII-B could promote FXIII clearance in a patient with congenital FXIII-B deficiency who had received infusions of plasma-derived human FXIII (A2B2 heterotetramer).
Objectives We aimed to investigate whether anti-FXIII-B antibodies affect the catalytic function of FXIII.
Methods FXIII activation and fibrin crosslinking were examined in the presence of patient plasma, isolated patient IgG, or rat anti-FXIII-B monoclonal antibodies.
Results Alloantibody levels were increased by repeated infusions of plasma-derived A2B2 heterotetramer, which enhanced binding to the functionally important FXIII-B sushi domains. The patient plasma strongly inhibited cleavage of the FXIII-A activation peptide, amine incorporation, and fibrin crosslinking in normal plasma. Furthermore, anti-FXIII-B alloantibodies blocked the formation of the complex of FXIII-B with FXIII-A, and fibrinogen. Rat monoclonal antibodies against the 10th sushi domain of FXIII-B inhibited the incorporation of FXIII-B to fibrin, FXIII activation (i.e., cleavage of FXIII-A activation peptide), and ultimately fibrin crosslinking in normal plasma, independent of their effect on heterotetramer assembly with FXIII-A. Alloantibody binding to the A2B2 heterotetramer blocked the access of thrombin to the FXIII-A cleavage site, as indicated by the reaction of the alloantibodies to the A2B2 heterotetramer and FXIII-B, but not to FXIII-A.
Conclusion Anti-FXIII-B antibodies binding to the A2B2 heterotetramer and FXIII-B inhibited FXIII activation and its crosslinking function despite being directed against its noncatalytic subunit (FXIII-B).
Keywords
autoantibody - activation peptide - fibrin crosslinking - A2B2 heterotetramer - sushi domainAuthors' Contribution
A.I. created the research project and wrote and edited the manuscript. M.S. and T.O. performed experiments, wrote, and proofread the manuscript. C.Y. provided rat monoclonal antibodies against human factor XIII-B and proofread the manuscript.
Publikationsverlauf
Eingereicht: 17. Dezember 2022
Angenommen: 14. März 2023
Accepted Manuscript online:
19. März 2023
Artikel online veröffentlicht:
19. April 2023
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