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«Introduction Antiphospholipid syndrome (APS) is an autoimmune multisystemic disorder characterized clinically by recurrent thrombosis and pregnancy ...»

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Chapter 2

What is the Origin of Antiphospholipid


Rohan Willis, Yehuda Shoenfeld, Silvia S. Pierangeli, and Miri Blank


Antiphospholipid syndrome (APS) is an autoimmune multisystemic disorder characterized clinically by recurrent thrombosis and pregnancy morbidity, and serologically by the presence of antiphospholipid antibodies (aPL) including anticardiolipin

antibodies (aCL), anti-b2glycoprotein-I antibodies (ab2GPI), and lupus anticoagulant (LA) [1–3]. It is now widely accepted that aPLs are a heterogeneous group of antibodies that react with a myriad of phospholipids (PLs), PL–protein complexes, and PL-binding proteins. The main antigenic target of these antibodies is recognized to be b2GPI, which along with prothrombin accounts for more than 90% of the antibody-binding activity in APS patients [4–10].

Thus far, little is known about the origin of pathogenic aPL. Several mechanisms have been postulated including infections that were identified to contribute to the production of aPL through molecular mimicry and epitope spreading [11].

Additionally, there is also evidence that endogenous b2GPI may get exposed to the immune system and recognized as an antigen during apoptotic cells’ clearance.

This chapter reviews the most up-to-date scientific evidence regarding proposed genetic and environmental factors contributing to the development of pathogenic aPL.

R. Willis, MBBS, MSc • S.S. Pierangeli, PhD Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA Y. Shoenfeld, MD • M. Blank, PhD (*) Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Ramat-Gan, 52621, Israel e-mail: mblank@post.tau.ac.il; miri.blank@sheba.health.gov.il D. Erkan and S.S. Pierangeli (eds.), Antiphospholipid Syndrome: Insights and Highlights 23 from the 13th International Congress on Antiphospholipid Antibodies, DOI 10.1007/978-1-4614-3194-7_2, © Springer Science+Business Media New York 2012 24 R. Willis et al.

What Is Known?

Genes and the Environment in Antiphospholipid Syndrome Various animal models and family and population studies have been used to highlight HLA associations with the occurrence of aPL and the development of thrombosis in aPL-positive patients. Thus, Major Histocompatibility Complex (MHC) genes may influence not only autoantibody production but also disease expression itself [12]. In addition, the coexistence of other inherited thrombophilia risk factors, i.e., Factor V Leiden (FVL), prothrombin 20210 mutations, may further increase thrombogenic risk in APS. [13]. These pathogenic aPL are thought to be produced after exposure to certain viral or bacterial products with sequence similarity to host antigens inducing a break in tolerance (molecular mimicry) [14]. Antiphospholipid Antibodies represent a heterogeneous group of antibodies with many different antigenic targets; the clinical experience is that not all aPL are pathogenic, making it likely that only a certain group of aPL induced by certain viral or bacterial products are important in disease development [14, 15].

Animal Genetic Studies in Antiphospholipid Syndrome

There are relatively few animal studies that have assessed the genetic basis for the development of APS. The spontaneous production of IgG aCL, which exhibits cofactor (b2GPI)-dependent binding to cardiolipin, has been detected in NZW × BXSB F1 (W/B F1) male mice [16]. W/B F1 mice are SLE-prone mice, which develop several autoantibodies, circulating immune complexes, and nephritis in addition to a high incidence of degenerative coronary vascular disease with myocardial infarction and thrombocytopenia. Thus, W/B F1 mice represent a model of lupus-associated APS [16–18]. Interestingly, analysis of the genes utilized in the production of pathogenic aCL in these mice showed preferential usage of certain VH and Vk genes, whereas other nonpathogenic aCL utilize random V gene combinations [19]. This possibly indicates that pathogenic aCL production in these mice is antigen driven rather than germline encoded.

In 1998, Ida et al. analyzed APS disease features in BXSB and NZW mice and their progeny [20]. Although male BXSB parental mice showed similar disease features to their male NZW × BXSB F1 progeny, these features were of decreased frequency and intensity, and the disease was not apparent in female parental NZW or female NZW × BXSB F1 progeny. These findings suggest that genes from the BXSB strain determines, while NZW genes serve to upregulate or modify, APS disease characteristics in their progeny and that modifying alleles such as BXSB Y-linked autoimmune accelerator gene (Yaa) also play a role [20–22] in disease manifestations. In the same study, genome-wide analysis using microsatellite markers was used to map BXSB alleles affecting the development of aCL, antiplatelet antibodies, thrombocytopenia, and mycocardial infarction in NZW × (NZW × BXSB) F1 backcross male progeny [20].

This analysis showed that the generation of each disease manifestation was controlled 2 What is the Origin of Antiphospholipid Antibodies? 25 by two independently segregating major dominant alleles producing full expression as a complementary gene action. Although there was complete genetic concordance between antiplatelet antibodies and thrombocytopenia, other disease characteristics were independently controlled by different combinations of two dominant alleles suggesting that no single genetic factor can explain the pathogenesis of APS [20].

The presence of IgG aCL has also been demonstrated in other lupus-prone mice, including the MRL/MP/lpr/lpr (MRL/lpr) and MRLlpr/lpr mice [23]. Similar to aCL produced in W/B F1 mice, those produced in MRL/lpr mice showed nonrandom VH and Vk gene usage and also evidence of somatic mutation indicating a role for antigendriven affinity maturation [24]. Anticardiolipin antibodies are also produced in normal C57BL/6J mice with estrogen treatment increasing the incidence and levels of these antibodies, underscoring the role that environmental factors such as hormones modifying genetic susceptibility in APS patients [25]. However, aCL produced in these estrogen-treated C57BL/6J mice and those in MRL/lpr mice are not b2GPI dependent but rather show decreased binding to cardiolipin in the presence of human b2GPI [26].

Interestingly, NZW × NZB F1 mice, another classic murine model of SLE, fail to produce aCL despite the production of other autoantibodies, such as anti-dsDNA [23].

Family and Population Studies: Human Leukocyte Antigen (HLA) and Non-HLA Associations Multiple HLA-DR and DQ associations with the occurrence of aPL have been described, but small patient sample sizes and difficulties regarding obtaining appropriately as well as ethnically matched control populations make interpretation problematic [12, 13]. A familial clustering of individuals with persistently false-positive tests for syphilis in whom overt autoimmune disease developed years later was perhaps the first indication of familial APS [27]. Since 1980, several studies have described families with high incidences of primary APS associated with LA, aCL, and other autoantibodies [28, 29]. The increased incidence of aCL in first-degree relatives of APS patients with or without SLE has also been demonstrated [30, 31].

A 1998 study which assessed 7 families with a high incidence of primary APS, 30 of 101 family members meeting diagnostic criteria, suggested either a dominant or codominant model for inheritance of the disease by segregation analysis but failed to find linkage to HLA and other candidate genes, including b2GPI and Fas [32].

Other family studies, however, have reported several HLA associations. The paternal haplotype A30; Cw3; B60; DR4; DRw53; DQw3 has been shown to be associated with aCL in an English Canadian family, both in asymptomatic individuals and those with APS associated with SLE and autoimmune thyroid disease [33]. The occurrence of LA in families with haplotypes containing either DR4 or DR7 has also been demonstrated [34, 35]. In a family study in which all members had SLE and presented with various APS manifestations, a mother and her twins shared a haplotype that included DR4, DRw53, and DQw7 [36].

Nonfamilial population studies also highlight several HLA associations of APS.

A 1991 study of 20 patients with SLE and LA demonstrated an association with HLA-DQw7 (HLA-DQB1*0301) linked to HLA-DR4 and/or -DR5 [37]. In 13 26 R. Willis et al.

English patients with primary APS, DR4 and DRw53 were found with increased frequency [38]. Other HLA loci associated with primary APS include DRB1*04, DR7, DQB1*0301/4, DQB1*0604/5/6/7/9, DQA1*0102, and DQA1*0301/2 [39–41]. In a large Italian study of SLE patients, aCL was positively associated with HLA-DRB1*04, -DRB1*07, -DQA1*0201, -DQA1*0301, -DQB1*0302, and -DRB3*0301, and ab2GPI was positively associated with DQB1*0302 [42]. The association of aCL with DRB1*09 has been reported in Japanese patients with APS associated with SLE [43]. Anti-b2glycoprotein-I in Caucasian and Mexican Americans is strongly associated with HLA-DR4 haplotypes, especially those carrying HLA-DQ8 (DQB1*0302), while in African-American and white British patients with primary APS, ab2GPI is strongly associated with the HLA-DRB1*1302 and DQB1*0604/0605 haplotypes [39, 44]. The association of C4A or C4B null alleles with the presence of aCL has been reported in black American populations; however, patients in the Hopkins Lupus Cohort who were homozygous for C4A deficiency had a lower frequency of aCL and LA than patients without this deficiency [45–47].

Other genes outside the MHC region also contribute to both autoantibody production and disease expression in APS. A polymorphism in domain 5 of b2GPI, valine instead of leucine at position 247, is found more frequently in patients with APS than matched controls and is associated with ab2GPI production in these patients [48–50].

One study found an increased frequency of this polymorphism in patients with arterial thrombosis than those without [50]. There are other prothrombotic genetic factors that can modify disease expression in APS patients. Those genetic factors clearly related to thrombophilia that have been seen in APS patients include factor V Leiden (FVL) and prothrombin mutations and antithrombin III, protein C, and protein S deficiencies [51].

The gain-of-function FVL G1691A mutation is highly prevalent in Caucasian populations with population frequencies ranging from 1% to 15% [52, 53].

Several reports have demonstrated an increased incidence of thrombosis in APS patients with FVL mutation when compared to those without FVL mutation.

However, this mutation seems to have a more moderate effect on the development of thrombosis in APS than in the general population [54–56]. The G20210A prothrombin mutation (F2 G20210A) is associated with venous thromboembolism in the general population, but there have been conflicting reports of the increased risk of thrombosis related to this gene mutation in APS patients. Initial reports indicated no increased risk, but some of the subsequent studies have demonstrated the association between the mutation and thrombosis in APS patients: the first case was in a young female with SLE-associated APS homozygous for the G20210A mutation [57–60]. Protein C, S, and antithrombin III deficiencies are uncommon diseases, making it difficult for an accurate assessment of the relative contributions of these mutations to thrombus generation in aPL-positive patients. However, there have been reports of increased thrombosis rates in patients with protein C and protein S deficiency [61, 62]. Other polymorphisms that potentially impact the risk of thrombosis in APS patients include platelet glycoproteins GP Ia/IIa and GP IIb/IIIa, platelet Fcg receptor IIa, tissue factor pathway inhibitor, thermolabile variant of methylenetetrahydrofolate reductase, type-I plasminogen activator inhibitor, tumor necrosis factor a, thrombomodulin, annexin A5, P-selectin, P-selectin glycoprotein ligand-1, tolllike receptor 4, factor XIII, and CD40 [63–73].

2 What is the Origin of Antiphospholipid Antibodies? 27 Fig. 2.1 Amino acid similarities of peptides from viral and bacterial origin with GDKV (a 15 amino acid peptide) from the fifth region of b2GPI. K = lysine residues.

In red: sequence similarities among peptides Environmental Factors and the Origin of Antiphospholipid Antibodies The processes underlying the production of aPL in APS patients remain undetermined. When these antibodies were first described, aPLs were defined as antibodies reacting to cardiolipin; however, it is now well accepted that these antibodies recognize various PL and protein antigenic complexes [4–7]. Indeed, as stated previously, the main antigenic target for these antibodies is b2GPI, an abundant serum protein that is a necessary cofactor for aPL’s binding to phospholipid. In fact, efforts to induce high titer production of pathogenic aPL in animal models succeeded only after immunization with heterologous b2GPI rather than pure phospholipids [4, 74].

This led researchers to believe that perhaps in vivo binding of foreign PL-binding proteins resembling b2GPI to self-phospholipids in APS patients may lead to the formation of immunogenic complexes against which aPL are produced.

The Infectious Origin of Antiphospholipid Antibodies

Many infections may be accompanied by aPL elevations and, in some, these elevations may be accompanied by clinical manifestations of the APS. Several reviews on this important topic have been deeply detailed in [75–77]. Skin infections (18%), human immunodeficiency virus infection (HIV) (17%), pneumonia (14%), hepatitis C virus (HCV) (13%), and urinary tract infections constituted the most common infections found as “triggering” factors. Viral, bacterial, and parasitic infections have been implicated in aPL production.

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