Objective: Our study aimed to elucidate the presence, antigen specificities, and potential clinical association of anti-neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid antibody (aPL)-positive patients who did not have lupus. Methods: Anti-NET IgG/IgM were measured in sera of 389 aPL-positive patients; 308 met the classification criteria for APS. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n=214), we profiled autoantibodies with an autoantigen microarray platform. Results: We found elevated levels of anti-NET IgG and/or IgM in 45% of aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)-DNA complexes, a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with brain white matter lesions even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO-DNA complexes, and nucleosomes. Anti-NET IgM positivity associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen. Conclusion: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear more likely to target NET-associated protein antigens. This article is protected by copyright. All rights reserved.
Anti-NET antibodies in antiphospholipid antibody-positive patients: Results from the Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository / Zuo, Y.u., Navaz, S., Tsodikov, A., Kmetova, K., Kluge, L., Ambati, A., K Hoy, C., Yalavarthi, S., de Andrade, D., G Tektonidou, M., Sciascia, S., Pengo, V., Ruiz-Irastorza, G., Michael Belmont, H., Gerosa, M., R Fortin, P., Ramires de Jesus, G., Ware Branch, D., Andreoli, L., Rodriguez-Almaraz, E., et al.. - In: ARTHRITIS & RHEUMATOLOGY. - ISSN 2326-5205. - (2023). [10.1002/art.42489]
Anti-NET antibodies in antiphospholipid antibody-positive patients: Results from the Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository
Giuseppe Barilaro
2023
Abstract
Objective: Our study aimed to elucidate the presence, antigen specificities, and potential clinical association of anti-neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid antibody (aPL)-positive patients who did not have lupus. Methods: Anti-NET IgG/IgM were measured in sera of 389 aPL-positive patients; 308 met the classification criteria for APS. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n=214), we profiled autoantibodies with an autoantigen microarray platform. Results: We found elevated levels of anti-NET IgG and/or IgM in 45% of aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)-DNA complexes, a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with brain white matter lesions even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO-DNA complexes, and nucleosomes. Anti-NET IgM positivity associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen. Conclusion: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear more likely to target NET-associated protein antigens. This article is protected by copyright. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
