Anti–Neutrophil Extracellular Trap Antibodies and Impaired Neutrophil Extracellular Trap Degradation in Antiphospholipid Syndrome

Zuo, Yu; Yalavarthi, Srilakshmi; Gockman, Kelsey; Madison, Jacqueline A; Guðjónsson, Jóhann E.; Kahlenberg, J. Michelle; McCune, W. Joseph; Bockenstedt, Paula; Karp, David R.; Knight, Jason S.

doi:10.1002/art.41460

Cited by 73 publications

(83 citation statements)

References 14 publications

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“…Triple aPL positivity is the aPL phenotype that confers the highest risk of thrombosis [ 39 ]. Non-criteria aPL, such as aPS/PT [ 40 ], anti-domain-1 aß 2 GPI [ 41 ], anti-protein C/activated protein C resistance (APCr) [ 42 ], and anti-NET antibodies [ 43 ], also appear to be relevant with regard to thrombotic risk. An association between complement activation and recurrent thrombosis in APS patients has been demonstrated using a functional modified HAM (mHAM) assay, and patient-derived aß 2 GPI also increased C5b-9 deposition on the cell surface [ 44 ].…”

Section: And Beyond: Time To Explore New Horizonsmentioning

confidence: 99%

Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION): 10-Year Update

et al. 2021

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Purpose of Review APS ACTION is an international research network created to design and conduct large-scale, multicenter research in persistently antiphospholipid antibody (aPL)–positive patients. Given the expanding research activities of the network in the last decade since its creation, the purpose of this article is to review the scientific contributions of APS ACTION as well as future directions. Recent Findings APS ACTION has achieved increased international collaboration with internal and external investigators for outcome, interventional, and mechanistic antiphospholipid syndrome (APS) studies. This has been linked to substantial progress in Core laboratory work, which has demonstrated that laboratories can achieve good agreement in performance of aPL assays by use of the same reagents, analyzer type, and protocols. Summary APS ACTION will continue to identify gaps in the existing aPL/APS literature, design mechanistic studies to elucidate underlying mechanisms, and conduct prospective, large-scale clinical studies, all for the ultimate goal of early diagnosis and improved management of aPL-positive patients.

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Section: And Beyond: Time To Explore New Horizonsmentioning

confidence: 99%

Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION): 10-Year Update

et al. 2021

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“…Human neutrophil purification. Human neutrophils were isolated as we have done and described previously (22).…”

Section: Methodsmentioning

confidence: 99%

Autoantibodies stabilize neutrophil extracellular traps in COVID-19

Zuo¹,

Yalavarthi²,

Navaz³

et al. 2021

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The release of neutrophil extracellular traps (NETs) by hyperactive neutrophils is recognized to play an important role in the thromboinflammatory milieu inherent to severe presentations of COVID-19. At the same time, a variety of functional autoantibodies have been observed in individuals with severe COVID-19 where they likely contribute to immunopathology. Here, we aimed to determine the extent to which autoantibodies might target NETs in COVID-19 and, if detected, to elucidate their potential functions and clinical associations. We measured anti-NET antibodies in 328 individuals hospitalized with COVID-19 alongside 48 healthy controls. We found high anti-NET activity in the IgG and IgM fractions of 27% and 60% of patients, respectively. There was a strong correlation between anti-NET IgG and anti-NET IgM (r=0.4, p<0.0001). Both anti-NET IgG and IgM tracked with high levels of circulating NETs, impaired oxygenation efficiency, and high circulating D-dimer. Furthermore, patients who required mechanical ventilation had a greater burden of anti-NET antibodies than did those not requiring oxygen supplementation. Levels of anti-NET IgG (and to a lesser extent anti-NET IgM) demonstrated an inverse correlation with the efficiency of NET degradation by COVID sera. Furthermore, purified IgG from COVID sera with high levels of anti-NET antibodies impaired the ability of healthy control serum to degrade NETs. In summary, many individuals hospitalized with COVID-19 have anti-NET antibodies, which likely impair NET clearance and may potentiate SARS-CoV-2-mediated thromboinflammation.

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“…Thus, APLs might be a contributory factor towards thrombosis in AAV. Increasingly, NETosis is being recognized to play a role in the pathogenesis of antiphospholipid antibody syndrome [ 50 , 51 ], and this might form a common link between APLs and AAV.…”

Section: Antiphospholipid Antibodies Associate With Thrombotic Risk In Aavmentioning

confidence: 99%

Mechanisms of thrombosis in ANCA-associated vasculitis

et al. 2021

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Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have a two- to threefold greater risk of developing venous as well as arterial thrombotic events. Although such thrombotic events are more commonly seen during phases of active AAV, they are also recognized to occur during AAV in remission. Endothelial injury is a key pathogenic event in AAV. Endothelial injury can be caused by neutrophil activation and release of thrombogenic tissue factor into the circulation. Neutrophil activation further results in the formation of neutrophil extracellular traps (NETs). NETs contribute to thrombosis by expressing tissue factor. NETs have also been detected in cutaneous thrombi from patients with AAV induced by hydralazine. Activated neutrophils in AAV patients release thrombogenic microparticles loaded with tissue factor which further enhances clotting of blood. Antiphospholipid antibodies (APLs) have been detected in up to a third of AAV and might also be induced by drugs such as cocaine adulterated with levamisole and propylthiouracil, which are known to trigger AAV. Such APLs further drive the thrombosis in AAV. Once thrombogenesis occurs, the homeostatic mechanisms resulting in clot dissolution are further impaired in AAV due to anti-plasminogen antibodies. The ongoing pandemic of coronavirus disease 2019 (COVID-19) is associated with endothelial injury and NETosis, mechanisms which are in common with AAV. Reports of new-onset AAV following COVID-19 have been described in the literature, and there could be shared mechanisms driving these processes that require further evaluation.

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Anti–Neutrophil Extracellular Trap Antibodies and Impaired Neutrophil Extracellular Trap Degradation in Antiphospholipid Syndrome

Cited by 73 publications

References 14 publications

Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION): 10-Year Update

Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION): 10-Year Update

Autoantibodies stabilize neutrophil extracellular traps in COVID-19

Mechanisms of thrombosis in ANCA-associated vasculitis

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