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Immune Complexes of Beta-2-Glycoprotein I and IgA Antiphospholipid Antibodies Identify Patients With Elevated Risk of Thrombosis and Early Mortality After Heart Transplantation.

ABSTRACT: Background: The presence of anti-Beta 2 glycoprotein antibodies (aB2GP1) of IgA isotype is common in patients with functional impairment of the organs in which B2GP1 is elaborated. Pretransplant IgA aB2GP1 has been associated with increased risk of thrombosis in kidney and heart transplanted patients and has also been related with early mortality after heart transplantation. Circulating immune complexes between IgA and B2GP1 (B2A-CIC) have been described in the blood of patients positive for IgA aB2GP1 with thrombotic clinical symptoms. In kidney transplanted patients, B2A-CIC is a biomarker that predicts which patients IgA aB2GP1 positive are at risk of thrombosis events following kidney transplantation and may lead to early prophylactic treatment. The prevalence of B2A-CIC and its relation with outcomes after heart transplantation is not known. Methods: Follow-up study based on 151 consecutive patients who received a heart transplant. Autoantibodies and B2A-CIC were quantified in pre-transplant serum samples. Three groups of patients were followed-up for 2 years: Group-1, positive for IgA aB2GP1 and B2A-CIC (N = 19). Group-2, only positive for IgA aB2GP1 (N = 28). Group-0 (control group): IgA aB2GP1 negative (N = 104). Results: Kaplan-Meir survival analysis showed that mortality in B2A-CIC positive was higher than group-0 at 3 months (HR:5.08; 95%CI: 1.36-19.01) and at 2 years (HR:3.82; 95%CI: 1.54-12.66). No significant differences were observed between group-2 and group-0. Multivariate analysis identified B2A-CIC as the most important independent risk factor for early mortality (OR = 6.12; 95% CI: 1.93-19.4). Post-transplant incidence of thrombosis was significantly higher in B2A-CIC positive patients than in the control group (OR: 6.42; 95%CI: 2.1-19.63). Multivariate analysis identified the presence of B2A-CIC (OR: 6.13; 95%CI: 2.1-19.63) and the pre-transplant habit of smoking actively (OR: 4.18; 95%CI: 1.35-12.94) as independent risk factor for thrombosis. The proportion of patients who had thrombotic events or died in the first trimester was significantly higher in group-1 (73.7%) than in group-0 (16.3%; p < 0.001) and in group-2 (39.3%; p = 0.02). Multivariate analysis identified B2A-CIC as the main independent risk factor for early outcomes (mortality or thrombosis) in the first 3 months after heart transplant (OR = 11.42, 95% CI: 1.69-9.68). Conclusion: B2A-CIC are a predictor of early mortality and thrombosis after heart transplant.

SUBMITTER: Serrano M

PROVIDER: S-EPMC6935976 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGraft thrombosis is a devastating complication after renal transplantation. We recently described the association of anti-beta-2-glycoprotein-I (IgA-ab2GP1) antibodies with early graft loss mainly caused by thrombosis in a monocenter study.MethodsMulticenter prospective observational cohort study.Setting and participantsSeven hundred forty patients from five hospitals of the Spanish Forum Renal Group transplanted from 2000 to 2002 were prospectively followed-up for 10?years.OutcomesEarly graft loss and graft loss by thrombosis.MeasurementsThe presence of IgA anti-B2GP1 antibodies in pretransplant serum was examined using the same methodology in all the patients.ResultsAt transplantation, 288 patients were positive for IgA-B2GP1 (39%, Group-1) and the remaining were negative (Group-2). Graft loss at 6?months was higher in Group-1 (12.5 vs. 4.2% p?<?0.001), vessel thrombosis being the most frequent cause of early graft loss, especially in Group-1 (6.9 vs. 0.4% p?<?0.001). IgA-aB2GP1 was the most important independent risk factor for graft thrombosis (hazard ratio: 13.83; 95% CI: 3.17-60.27, p?<?0.001). Furthermore, the, presence of IgA-aB2GP1 was associated with early graft loss and delayed graft function. At 10?years, survival figures were also lower in Group-1: graft survival was lower compared with Group-2 (60.4 vs. 76.8%, p?<?0.001). Mortality was significantly higher in Group-1 (19.8 vs. 12.2%, p?=?0.005).LimitationsPatients were obtained during a 3-year period (1 January 2000-31 December 2002) and kidneys were only transplanted from brain-dead donors. Nowadays, the patients are older and the percentage of sensitized and retransplants is high.ConclusionIn a prospective observational multicenter study, we were able to corroborate that pretransplant presence of IgA-aB2GP1 was the main risk factor for graft thrombosis and early graft loss. Therefore, a prospective study is needed to evaluate the efficacy and safety of prophylactic anticoagulation to avoid this severe complication.

Project description:To examine the prevalence of isolated IgA anti-?2 -glycoprotein I (anti-?2 GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of ?2 GPI, with clinical manifestations of the antiphospholipid syndrome (APS) in 3 patient groups and to evaluate the pathogenicity of IgA anti-?2 GPI in a mouse model of thrombosis.Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n = 558), patients with SLE from the Hopkins Lupus Cohort (n = 215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n = 5,098) were evaluated. IgA anti-?2 GPI titers and binding to domain IV/V of ?2 GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti-?2 GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity.A total of 198 patients were found to be positive for IgA anti-?2 GPI isotype, and 57 patients were positive exclusively for IgA anti-?2 GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-?2 GPI-positive serum samples reacted with domain IV/V of anti-?2 GPI, and 77% of those had clinical features of APS. Isolated IgA anti-?2 GPI positivity was associated with an increased risk of arterial thrombosis (P < 0.001), venous thrombosis (P = 0.015), and all thrombosis (P < 0.001). The association between isolated IgA anti-?2 GPI and arterial thrombosis (P = 0.0003) and all thrombosis (P = 0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-?2 GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls.Isolated IgA anti-?2 GPI-positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid tests are negative and APS is suspected is recommended. IgA anti-?2 GPI antibodies directed to domain IV/V of ?2 GPI represent an important subgroup of clinically relevant antiphospholipids.

Project description:Antiphospholipid antibodies (aPL), the serological hallmark of antiphospholipid syndrome (APS), are a heterogeneous group of autoantibodies raised against circulating blood proteins. Of these proteins, the phospholipid-binding b2-glycoprotein I (β2GPI) is considered to be the main autoantigen in APS. Indeed, IgG antibodies targeting b2GPI (ab2GPI) directly cause both thrombosis and pregnancy morbidity in several mouse models. While antibodies raised against all five domains of b2GPI have been reported, a subgroup of IgG ab2GPI raised against the first domain (DI) of b2GPI (aDI), strongly correlate with thrombotic APS, and drive thrombosis and pregnancy loss in vivo. Few studies have focused on determining the type of IgG subclass(es) for aPL. The subclass of an antibody is important as this dictates the potential activity of an antibody; for example, IgG1 and IgG3 can fix complement better and are able to cross the placenta compared to IgG2 and IgG4. It is unknown what subclass IgG aDI are, and whether they are the same as ab2GPI. To determine IgG subclass distribution for ab2GPI and aDI, we purified total IgG from the serum of 19 APS patients with known ab2GPI and aDI activity. Using subclass-specific conjugated antibodies, we modified our established in-house ab2GPI and aDI ELISAs to individually measure IgG1, IgG2, IgG3, and IgG4. We found that while IgG1, IgG2, and IgG3 ab2GPI levels were similar, a marked difference was seen in IgG subclass aDI levels. Specifically, significantly higher levels of IgG3 aDI were detected compared to IgG1, IgG2, or IgG4 (p < 0.05 for all comparisons). Correlation analysis of subclass-specific ab2GPI vs. aDI demonstrated that IgG3 showed the weakest correlation (r = 0.45, p = 0.0023) compared to IgG1 (r = 0.61, p = 0.0001) and IgG2 (r = 0.81, p = 0.0001). Importantly, total subclass levels in IgG purified from APS and healthy serum (n = 10 HC n = 12 APS) did not differ, suggesting that the increased IgG3 aDI signal seen in APS-derived IgG is antigen-specific. To conclude, our data suggests that aDI show a different IgG subclass distribution to ab2GPI. Our results highlight the importance of aDI testing for patient stratification and may point toward differential underlying aPL-driven pathogenic processes that may be subclass restricted.

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Immune Complexes of Beta-2-Glycoprotein I and IgA Antiphospholipid Antibodies Identify Patients With Elevated Risk of Thrombosis and Early Mortality After Heart Transplantation.

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