Elsevier

Thrombosis Research

Volume 179, July 2019, Pages 15-19
Thrombosis Research

Full Length Article
Prevalence of anti-S100A10 antibodies in antiphospholipid syndrome patients

https://doi.org/10.1016/j.thromres.2019.04.027Get rights and content

Highlights

  • S100A10 is a binding partner of annexin A2

  • S100A10 plays a pivotal role in regulation of fibrinolysis

  • S10010 has been identified as a new autoantigen in antiphospholipid syndrome

  • The prevalence of anti-S100A10 in APS patients (11.9%) was statistically higher than in control group (1.7%)

  • Further studies in large cohort of APS patients are needed to determine whether these antibodies could be pathogenic

Abstract

Introduction

Annexin A2 (ANXA2), an endothelial cell receptor for plasminogen and tissue plasminogen activator, has been identified as a new autoantigen in antiphospholipid syndrome (APS). ANXA2 can exist as a monomer or a heterotetrameric complex with S100A10 protein. This S100A10 subunit also plays a pivotal role in the regulation of fibrinolysis. The aim of this study was to evaluate the prevalence of autoantibodies directed against S100A10 protein in patients with APS.

Methods

Patients with primary antiphospholipid syndrome (PAPS), patients with systemic lupus erythematosus (SLE) and patients with unexplained thrombosis were retrospectively included in this study. Patients were followed in the department of Internal Medicine of Amiens University Hospital, Amiens, France. IgG and IgM anti-S100A10 antibodies were detected in the serum of patients by enzyme-linked immunosorbent assay. The cut-off value for positivity was defined as 3 standard deviations above the mean optical density (OD) obtained in the sera of 116 healthy blood donors.

Results

The study group consisted of 116 healthy individuals and 106 patients: 42 APS patients (26 patients with PAPS and 16 patients with secondary SLE-related APS), 43 SLE patients without APS and 21 patients with unexplained thrombosis. The median age of APS patients, SLE patients without APS, patients with unexplained thrombosis and healthy individuals was 47, 38, 53 and 42 years, respectively. Anti-S100A10 antibodies were detected in 11.9% of APS patients and this prevalence was statistically higher than that observed in healthy individuals (1.7%) (p = 0.0148). Highest levels of anti-S100A10 were observed in the serum of one PAPS patient with venous thrombosis and one SLE patient with APS with a history of stroke and recurrent miscarriage.

Conclusion

S100A10 protein, the binding partner of ANXA2, was identified as a target of autoantibodies in sera from patients with APS. Further studies involving a large cohort of APS patients are required to determine whether these antibodies could play a role in thrombogenic mechanisms of APS and to determine their diagnostic value in discriminating clinical subgroups of patients with APS, particularly those with seronegative APS.

Introduction

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis and/or pregnancy morbidity associated with persistent antiphospholipid antibodies [1]. Several pathogenic mechanisms are involved in APS, such as activation of endothelial cells, platelets and monocytes, inhibition of the natural anticoagulant protein C/protein S pathway, activation of the complement system and impairment of fibrinolysis [2,3]. Many components of the fibrinolytic system are targets for autoantibodies in APS, such as tissue activator plasminogen (tPA), plasminogen (Plg), plasmin and annexin A2 (ANXA2) [3]. ANXA2, an endothelial cell surface receptor for tPA and Plg [4], was identified as a new autoantigen in APS by several groups several years ago [[5], [6], [7]]. ANXA2 belongs to the family of annexins, which are Ca2+-regulated phospholipid-binding proteins [8]. ANXA2 exists as a monomer in cytoplasm or can form a heterotetrameric complex associated with the cell membrane [9]. This complex, comprising two ANXA2 subunits and a dimer of S100A10, is involved in the assembly of tPA and Plg at the endothelial cell surface. S100A10 promotes the translocation of ANXA2 to the cell surface [10] and ANXA2 protects S100A10 from proteasomal degradation [11]. Conflicting models have been proposed concerning the exact role of these proteins (either ANXA2 or S100A10) individually (or as a complex) in the plasmin activation process [[12], [13], [14]]. S100A10 belongs to the S100 family of small dimeric calcium-binding proteins (10–12 kD), which are involved in several cellular processes, such as cell cycle regulation, cell growth, cell differentiation, motility, contraction, secretion and transcription [15]. S100 proteins contain two EF-hand motifs, which, except for S100A10, are responsible for Ca2+-binding [16,17]. S100A10 has been observed in various cell types, such as endothelial cells, macrophages, fibroblasts, epithelial cells and cancer cell lines [17]. S100A10 binds to tPA and Plg and plays a role in regulation of plasmin generation [17]. S100A10 has also been shown to play an important role in fibrinolysis and angiogenesis in vivo [18]. The aim of this study was to evaluate the prevalence of anti-S100A10 autoantibodies in APS.

Section snippets

Patients

Patients with systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (PAPS) and unexplained thrombosis were retrospectively included in this study. All SLE patients met the revised American College of Rheumatology classification criteria [19]. The majority of APS patients met the revised criteria for APS [1], but some patients presented clinical features of APS with low positive anticardiolipin antibodies (ACL) and the diagnosis of APS in these patients can be equivocal [20].

Patient characteristics

One hundred six patients were retrospectively included as follows: 42 APS patients, 43 SLE patients without APS, 21 patients with unexplained thrombosis and 116 healthy individuals. Five patients had seronegative APS, one of whom had seronegative obstetric APS with positive anti-annexin A5 antibodies. Two patients had equivocal APS. Patient demographic characteristics and biological profile of antiphospholipid antibodies of APS and SLE patients are summarized in Table 1. APS patients presented

Discussion

This present study identified, for the first time, S100A10 as a target antigen for autoantibodies in APS. Anti-S100A10 antibodies were significantly more prevalent in patients with APS than in healthy individuals. S100A10 is a binding partner of ANXA2 [24] and plays an important role in fibrinolysis [18]. At the cell surface, S100A10 is present predominantly in a heterotetrameric complex consisting of two ANXA2 subunits and a S100A10 homodimer [17]. ANXA2 stabilizes intracellular S100A10 and

Conflict of interest

There is no conflict of interest with regard to this work.

Acknowledgments

We thank Dr. Agnès Brulé and Dr. Nathalie Becquet (French Blood Agency) for providing blood samples from healthy individuals, Mrs. Lucie Desjardins of the Division of Clinical Research and Innovation of Amiens University Hospital, Dr. Clément Gourguechon of the department of Internal Medicine of Amiens University Hospital and Dr. Ericka Berthe of the Immunology Laboratory of Amiens University Hospital, for their participation in this study.

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