Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage
Objectives The significance of antibodies directed against activated factor X (FXa) and thrombin (Thr) in patients with SLE and/or antiphospholipid syndrome (APS) is unknown. FXa and Thr are coregulated by antithrombin (AT) and activate complement. Therefore, we studied the ability of anti activated...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-07-01
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| Series: | Lupus Science and Medicine |
| Online Access: | https://lupus.bmj.com/content/9/1/e000738.full |
| _version_ | 1797777494534782976 |
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| author | Anisur Rahman Ian Giles Chris Wincup Bahar Artim-Esen Thomas McDonnell Charis Pericleous Raj Amarnani Ian Mackie Carina Spicer Hajar Jbari Valentina A Spiteri |
| author_facet | Anisur Rahman Ian Giles Chris Wincup Bahar Artim-Esen Thomas McDonnell Charis Pericleous Raj Amarnani Ian Mackie Carina Spicer Hajar Jbari Valentina A Spiteri |
| author_sort | Anisur Rahman |
| collection | DOAJ |
| description | Objectives The significance of antibodies directed against activated factor X (FXa) and thrombin (Thr) in patients with SLE and/or antiphospholipid syndrome (APS) is unknown. FXa and Thr are coregulated by antithrombin (AT) and activate complement. Therefore, we studied the ability of anti activated factor X (aFXa) and/or anti-(a)Thr IgG from patients with SLE±APS to modulate complement activation.Methods Patients with SLE±APS were selected on the basis of known aThr and/or aFXa IgG positivity, and the effects of affinity-purified aFXa/aThr IgG on FXa and Thr-mediated C3 and C5 activation were measured ±AT. Structural analyses of FXa and Thr and AT–FXa and AT–Thr complexes were analysed in conjunction with the in vitro ability of AT to regulate aFXa–FXa and aThr–Thr-mediated C3/C5 activation.Results Using affinity-purified IgG from n=14 patients, we found that aThr IgG increased Thr-mediated activation of C3 and C5, while aFXa IgG did not increase C3 or C5 activation. Structural analysis identified potential epitopes and predicted a higher likelihood of steric hindrance of AT on FXa by aFXa IgG compared with the AT–Thr–aThr IgG complex that was confirmed by in vitro studies. Longitudinal analysis of 58 patients with SLE (±APS) did not find a significant association between positivity for aFXa or aTHr IgG and C3 levels or disease activity, although there was a trend for patients positive for aFXa IgG alone or both aFXa and aThr IgG to have lower levels of C3 compared with aThr IgG alone during clinical visits.Conclusions We propose a novel method of complement regulation in patients with SLE±APS whereby aFXa and aThr IgG may have differential effects on complement activation. |
| first_indexed | 2024-03-12T23:05:43Z |
| format | Article |
| id | doaj.art-785035e9ebeb4c33b2e29ad930994361 |
| institution | Directory Open Access Journal |
| issn | 2053-8790 |
| language | English |
| last_indexed | 2024-03-12T23:05:43Z |
| publishDate | 2022-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Lupus Science and Medicine |
| spelling | doaj.art-785035e9ebeb4c33b2e29ad9309943612023-07-18T23:30:06ZengBMJ Publishing GroupLupus Science and Medicine2053-87902022-07-019110.1136/lupus-2022-000738Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavageAnisur Rahman0Ian Giles1Chris Wincup2Bahar Artim-Esen3Thomas McDonnell4Charis Pericleous5Raj Amarnani6Ian Mackie7Carina Spicer8Hajar Jbari9Valentina A Spiteri10Medicine (Rheumatology), University College London, London, UKDepartment of Rheumatology, University College London, London, UKDepartment of Rheumatology, University College London, London, UKDepartment of Internal Medicine, Istanbul University, Fatih, TurkeyBiochemical Engineering Department, UCL, London, UKNational Heart and Lung Institute, Imperial College London, London, UKDepartment of Rheumatology, University College London, London, UKDepartment of Haematology, University College London, London, UKMerck & Co, Kenilworth, New Jersey, USADepartment of Rheumatology, University College London, London, UKDepartment of Structural and Molecular Biology, University College London, London, UKObjectives The significance of antibodies directed against activated factor X (FXa) and thrombin (Thr) in patients with SLE and/or antiphospholipid syndrome (APS) is unknown. FXa and Thr are coregulated by antithrombin (AT) and activate complement. Therefore, we studied the ability of anti activated factor X (aFXa) and/or anti-(a)Thr IgG from patients with SLE±APS to modulate complement activation.Methods Patients with SLE±APS were selected on the basis of known aThr and/or aFXa IgG positivity, and the effects of affinity-purified aFXa/aThr IgG on FXa and Thr-mediated C3 and C5 activation were measured ±AT. Structural analyses of FXa and Thr and AT–FXa and AT–Thr complexes were analysed in conjunction with the in vitro ability of AT to regulate aFXa–FXa and aThr–Thr-mediated C3/C5 activation.Results Using affinity-purified IgG from n=14 patients, we found that aThr IgG increased Thr-mediated activation of C3 and C5, while aFXa IgG did not increase C3 or C5 activation. Structural analysis identified potential epitopes and predicted a higher likelihood of steric hindrance of AT on FXa by aFXa IgG compared with the AT–Thr–aThr IgG complex that was confirmed by in vitro studies. Longitudinal analysis of 58 patients with SLE (±APS) did not find a significant association between positivity for aFXa or aTHr IgG and C3 levels or disease activity, although there was a trend for patients positive for aFXa IgG alone or both aFXa and aThr IgG to have lower levels of C3 compared with aThr IgG alone during clinical visits.Conclusions We propose a novel method of complement regulation in patients with SLE±APS whereby aFXa and aThr IgG may have differential effects on complement activation.https://lupus.bmj.com/content/9/1/e000738.full |
| spellingShingle | Anisur Rahman Ian Giles Chris Wincup Bahar Artim-Esen Thomas McDonnell Charis Pericleous Raj Amarnani Ian Mackie Carina Spicer Hajar Jbari Valentina A Spiteri Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage Lupus Science and Medicine |
| title | Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage |
| title_full | Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage |
| title_fullStr | Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage |
| title_full_unstemmed | Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage |
| title_short | Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage |
| title_sort | antibodies to fxa and thrombin in patients with sle differentially regulate c3 and c5 cleavage |
| url | https://lupus.bmj.com/content/9/1/e000738.full |
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