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Background and Aims

To analyse the clinical and laboratory data and outcomes on a cohort of patients with primary antiphospholipid syndrome (APS) of late onset after 70 years old as compared with younger primary APS.

Methods

The International Registry of primary APS treated with Hydroxychloroquine, HIBISCUS, became a registry within the framework of the European Forum on Antiphospholipid Antibody projects. 55 centres from 16 countries around the world have collaborated and included patient’s data in this registry. Patients with primary APS which fulfilled the Sydney classification criteria, presenting thrombotic and obstetric manifestations related to antiphospholipid antibodies (aPL) who tested positive for aPL at least twice, were included prospectively and retrospectively. The five-year survey results are reported.

Results

The HIBISCUS register includes 851 patients. Relevant data were analysed on 698 patients. Mean follow-up was 39.4 months (9- 68 mo) and mean age 42.5 years old (18-82). Two groups of patients were analyzed : younger than 70 yo and older than 70 yo. Arterial events end especially stroke represented the main initial and recurrence clinical manifestation in older primary APS patients; as well as a significant male predominance, a familial APS history, a higher prevalence of triple positivity, lower C3 and C4. Traditional cardiovascular risk factors and inflammation were similar in both groups. Lower anticoagulation strategies were well tolerated and efficient in older APS patients.

Conclusions

We suggest that the detection of aPL should be included into the screening panel in elderly with thrombotic events and that lower intensity anticoagulation regimens could be a therapeutic option in older APS.

Background and Aims

Systemic Lupus Erythematous (SLE) is one of the most challenging autoimmune disease for clinicians as it may be presented as a severe relapsing and disabling immune-mediated disorder, still remaining incurable. Protein glycosylation is an essential posttranslational modification that participates in the correct recognition of cells by the immune system. In this study we have investigated whether an incorrect protein glycosylation is associated with loss of tolerance in autoimmunity.

Methods

We have analysed the profile of the cellular glycosylation of a subset of biopsy-proven lupus nephritis from SLE patients and normal kidney tissue (from two Porto Centre Hospitals) and blood, through immunohistochemistry and flow-cytometry. MGAT5 null mice (with defects on glycosylation) were monitored for autoimmune signs by analysing proteinuria, weight loss and colonic and renal histologies were analysed.

Results

SLE patients revealed a significant decreased expression of complex N-glycans in the renal parenchyma, when compared to controls. Furthermore, we have identified in lupus patients a unique subset of circulatory CD3⁺T-cells with an abnormal glycosignature and an increased expression of specific glycan-binding receptors. Interestingly, the MGAT5 knock-out mice develop clinical signs compatible within autoimmune-like syndrome, particularly proteinuria and high levels of serum autoantibodies, together with a tissue infiltration of specific CD3⁺T-cells subsets identified in SLE patients.

Conclusions

These findings point towards the identification of a novel immune player with increased ability to sense abnormal N-glycans expression modulating the surrounding immune response. We propose glycosylation as a regulatory mechanism that tips the balance between homeostasis/self-tolerance and autoimmunity opening a potential novel targeted-specific mechanism in SLE pathogenesis.

Background and Aims

Seronegative Antiphospholipid Syndrome refers to patients with clinical profile suggestive of Antiphospholipid Syndrome (APS) but persistently negative for antiphospolipid antibodies (aPL) included in APS classification criteria: anticardiolipin (ACA), anti-beta2Glycoprotein I (B2GP) (both IgG or IgM), and lupus anticoagulant.

Methods

We recruited 63 patients, from three Spanish hospitals, with small vessel brain lesions (SVBL), MRI and clinical manifestations compatible with APS and negative for aPL included in APS criteria. We also tested a control group of patients with autoimmune diseases. We performed:

1-ELISA assays for B2GP and ACA (IgA); anti-phosphatidylserine/prothrombin (PS/PT), phosphatidylethanolamine, prothrombin (PT) (IgG, IgM), anti-annexin A5 (IgG).

2-Chemiluminiscence assay for antibodies to Domain 1 of B2GP IgG.

Results

We found 13 patients positive for extra-criteria aPL: 2 (3.1%) for B2GP IgA; 4 (6.1%) for PT IgG, 1 of them was low positive; 4 (6.1%) for PT IgM , 2 were low positive for PS/PT IgM (3.1%) and 1 was low positive for PT IgG and PS/PT IgM (1.5%). Only 3 controls were positive: 1 for PS/PT IgM, 1 for PT IgG and 1 for Annexin A5, all of them low positive. Excluding low positive results, we detected 9 patients and 0 controls positive.

Conclusions

The presence of Abs to B2GP (IgA) and to PT (IgG and IgM) allowed us to identify as aPL-positive 13.8% of seronegative SVBL patients presenting MRI and clinical findings compatible with APS. Follow-up of these patients and additional studies will confirm our results.This work was funded by a grant from the Spanish Society of Internal Medicine (ref: SAFSN-SNCpv).

Background and Aims

Antiphospholipid syndrome (APS) is an important cause of deep vein thrombosis (DVT), but can be diagnosed by positive antiphospholipid (aPL) test only 24 weeks after DVT. Anticoagulation is usually stopped 3 months after the first DVT episode, which might increase the risk for recurrence in subjects with undiagnosed APS. We evaluated whether APS could be detected by measuring aPL immediately after DVT occurrence.

Methods

196 patients (85 female, 54±2 years) with acute DVT received anticoagulation for 3 months. aPL (aCL IgG/IgM and anti-β2GPI IgG/IgM/IgA) were determined at DVT occurrence and every 4 weeks until week 24. Medium/high aCL titer and/or presence of anti-β2GPI at 24 weeks confirmed APS.

Results

Ultimately, 20/196 (10.2%) patients fulfilled APS classification criteria. Among these, 15/20 (75%) patients had medium or high titer aPL at the time of acute. Two patients (10%) had low positive aCL IgG and one had low titer aCL IgM. Two patients (10%) were negative for aPL, but had later fulfilled APS criteria due to positive LA. Medium/high aCL and/or presence of anti-β2GPI at inclusion had 83% specificity and 90.5% sensitivity for APS. Absence of aPL at inclusion had a negative predictive value of 98.6%.

Conclusions

Here we show that in acute phase of DVT, positive medium or high titer aCL IgG/IgM or anti-β2GPI is suggestive of APS. In these patients continuation of anticoagulation beyond the initial 3 months should be considered.

Background and Aims

Antiphospholipid antibodies (aPL) represent a heterogenous family of autoantibodies, predominantly represented by conventional aPL such as anticardiolipin antibodies (ACL), anti-β2 glycoprotein I antibodies (aβ2GPI) and lupus anticoagulant (LA). aPL are not specific to antiphospholipid syndrome (APS) and can be detected in various clinical settings and in healthy subjects. The prevalence of aPL in the general population is limited.

Methods

Between september 2009 and january 2016, we included healthy subjects in a prospective study. Healthy individuals were recruited at the Amiens branch of the French Blood Agency-North of France and from the general population. Demographic data were collected for all healthy subjects. IgG ACL, IgM ACL, IgG aβ2GPI and IgM aβ2GPI were detected using an enzyme-linked immunosorbent assay. The PTT-LA was performed to detect LA.

Results

We included prospectively 1218 healthy individuals (F/H : 1.12). The median age of the healthy population was 42 years (18-83) at the time of inclusion. The prevalence of aPL was 10.5% (ACL : 9% ; aβ2GPI : 2.2% ; LA : 0.5%). In healthy subjects positive for ACL, there is a higher prevalence of IgM (74.5%) isotype than IgG (30%). ACL and/or aβ2GPI at medium or high titers (ACL > 40 U/mL ; aβ2GPI > 10 U/mL) were present in 27.4% of aPL positive healthy subjects.

Conclusions

This prospective study showed that the prevalence of LA in a healthy population is very low. IgM ACL are more frequent than IgG ACL. The majority of healthy subjects positive for aPL had low titers of ACL and/or aβ2GPI

Background and Aims

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity in the persistent presence of antiphospholipid antibodies (aPL). Pathogenetic mechanisms of aPLs are not yet completely explained. Thrombosis may be linked to diminished production of nitric oxide (NO) in endothelium. Endothelium-derived NO normally exerts anti-thrombotic and vasodilator effects. We aimed to determine endothelium-dependent and endothelium-independent vasodilation in cutaneous microvasculature of APS patients and healthy controls.

Methods

In our measurement protocol electrocardiogram, arterial blood pressure and laser Doppler flux of cutaneous microvessels were monitored in patients with primary or secondary APS (all positive for at least two different aPL) and healthy controls. To assess endothelium-dependent vasodilation we used iontophoresis of acetylcholine, which stimulates NO production in endothelial cells. Iontophoresis of sodium nitroprusside, a direct NO donor, was used to assess endothelium-independent vasodilation. Data were analysed using independent samples t-test or repeated measures ANOVA followed by Dunnett’s test.

Results

34 APS patients and 34 healthy age and sex-matched controls completed the study (24 female and 10 male in each group, age range 22-74). Participants were divided into three age groups, 22-38 years, 39-49 and ≥50. Endothelium-dependent vasodilator response was blunted in older patients (P<0.050 vs. healthy controls), but remained unaltered in younger participants. Endothelium-independent vasodilation was similar in all groups.

Conclusions

Our study shows that endothelium-dependent vasodilation in cutaneous microvasculature is diminished in older APS patients, indicating altered cutaneous microvasculature. This study supports reduced endothelial NO production in APS patients.

Background and Aims

Self-specific B and T cells play a main role in pathogenesis of Systemic lupus erythematosus (SLE) and are a logical target for selective therapy. The complement receptor type 1 (CR1) on human B-lymphocytes has suppressive activity and engagement of this receptor inhibits B cell activation.

The protein Annexin A1 (Anx A1), is a modulator of the immune system and abnormal expression was found on activated B and T cells during human autoimmunity.

We hypothesize that it may be possible to down-modulate the activity of autoreactive T and B cells from SLE patients in humanized NOD/SCID model by treating them with a neutralizing antibody against Anx A1 or by protein engineered molecules, which co-crosslink the BCR and CR1.

Methods

Protein chimeric molecules construction, Immunodeficient NOD/SCID mice transfer with human PBMC from SLE patients, ELISA for dsDNA antibodies and cytokines, flow cytometry for apoptosis and activation markers, ELISpot and MTT assays, protein array.

Results

Reconstituted NOD/SCID mice showed presence of several auto-antibodies, proteinuria, as well as immunoglobulin deposition in the renal glomeruli. Treatment of the transferred NOD/SCID mice either with DNA-like chimera and anti-Anx A1 antibody prevented appearance of anti-DNA antibodies and proteinuria, while the PBS-injected animals had high levels after the transfer. The treatment reduced the levels of disease-associated cytokines also.

Conclusions

It is possible to down-regulate the activity of pathogenic human T and B cells in humanized NOD/SCID mouse model of SLE by targeting Anx A1 or CR1 with a specific monoclonal antibody or chimeric molecule.