Presence of Immune Complexes of IgG/IgM Bound to B2-glycoprotein I Is Associated With Non-criteria Clinical Manifestations in Patients With Antiphospholipid Syndrome

ABSTRACT The antiphospholipid syndrome (APS) is usually defined by the association of clinical manifestations that comprise venous and/or arterial thrombosis, recurrent fetal losses, and thrombocytopenia, along with the presence of anticardiolipin (aCL) antibodies and/or lupus anticoagulant. Various infectious diseases can induce aCL; however, these antibodies are not usually associated with thrombotic events, as happens with autoimmune diseases, in which these antibodies need the presence of β2-glycoprotein I. Levels of immunoglobulin G (IgG) and IgM aCL antibodies were determined by enzyme-linked immunosorbent assay for 243 patients with chronic hepatitis C virus (HCV) infection and 100 healthy controls. Clinical events of APS, the level of β2-glycoprotein dependence of aCL, the presence of cryoglobulins and other autoantibodies, and cross-reactivity between purified aCL and HCV were evaluated. Positive results for aCL antibodies were found more frequently (3.3%) for the patients with HCV infection than for healthy controls (0%). All positive aCL antibodies were β2-glycoprotein I independent. No significant association was found between aCL antibodies and clinical manifestations of APS, neither was one found between the presence of other autoantibodies or cryoglobulins and that of aCL. Finally, no cross-reactivity between aCL antibodies and HCV antigens was observed. As previously reported, aCL antibodies seem to be an epiphenomenon, and they do not have clinical or laboratory significance in HCV patients.

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Atherosclerosis and the antiphospholipid syndrome: A link unravelled?

Lupus ◽

10.1177/096120339800700231 ◽

1998 ◽

Vol 7 (2_suppl) ◽

pp. 140-143 ◽

Cited By ~ 46

Author(s):

Y Shoenfeld ◽

D Harats ◽

J George

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Dominant Role ◽

Clinical Manifestations ◽

Humoral Response ◽

Arterial System ◽

Glycoprotein I ◽

Shock Proteins ◽

Modified Forms ◽

Progression Of Atherosclerosis

Atherosclerosis is a multifactorial disease that involves the arterial system. Recent data suggest that immune and autoimmune factors play a dominant role in mediating the progression of atherosclerosis. Among these factors, humoral response to modified forms of LDL and heat-shock proteins has been shown to be influential. The antiphospholipid syndrome (APS) entails clinical manifestations that result from a hypercoagulable state. Antibodies to phospholipids and to β2-glycoprotein I have been suggested to confer the tendency to thrombosis. In a set of recent studies, we have been able to show that generation of antiphospholipid antibodies in mice is associated with enhanced atherosclerosis. These findings imply that APS and atherosclerosis may share a common etiologic background, which may have direct implications for the management of both conditions.

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Is There an Additional Value in Detecting Anticardiolipin and Anti-β2 glycoprotein I IgA Antibodies in the Antiphospholipid Syndrome?

Thrombosis and Haemostasis ◽

10.1055/s-0040-1714653 ◽

2020 ◽

Vol 120 (11) ◽

pp. 1557-1568

Author(s):

Walid Chayoua ◽

Dong-mei Yin ◽

Hilde Kelchtermans ◽

Gary W. Moore ◽

Jean-Christophe Gris ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Immunoglobulin A ◽

Clinical Manifestations ◽

Pregnancy Morbidity ◽

Medical Centers ◽

Glycoprotein I ◽

Iga Antibodies ◽

Obstetric Aps ◽

Current Criterion ◽

Additional Value

Abstract Background Anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) immunoglobulin A (IgA) antiphospholipid antibodies (aPL) have shown to associate with thrombosis and pregnancy morbidity. However, inclusion of IgA aPL in the classification criteria of the antiphospholipid syndrome (APS) has been debated. We investigated the value of aCL and aβ2GPI IgA aPL in the detection of thrombosis and pregnancy morbidity in addition to the current aPL panel for APS. Methods We included 1,068 patients from eight European medical centers: 259 thrombotic APS patients, 122 obstetric APS patients, 204 non-APS thrombosis patients, 33 non-APS obstetric patients, 60 APS patients with unspecified clinical manifestations, 196 patients with autoimmune diseases, and 194 controls. aCL and aβ2GPI IgG/M/A were detected with four commercial assays and lupus anticoagulant was determined by the local center. Results Positivity for IgA aPL was found in 17 to 26% of the patients with clinical manifestations of APS and in 6 to 13% of the control population. Both aCL and aβ2GPI IgA were significantly associated with thrombosis and pregnancy morbidity. Isolated IgA positivity was rare in patients with clinical manifestations of APS (0.3–5%) and not associated with thrombosis and/or pregnancy morbidity. Addition of IgA to the current criterion panel did not increase odds ratios for thrombosis nor pregnancy morbidity. Conclusion aCL and aβ2GPI IgA are associated with clinical manifestations of APS. However, isolated IgA positivity was rare and not associated with thrombosis or pregnancy morbidity. These data do not support testing for aCL and aβ2GPI IgA subsequent to conventional aPL assays in identifying patients with thrombosis or pregnancy morbidity.

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Pathophysiological insights into the antiphospholipid syndrome

Hämostaseologie ◽

10.5482/hamo-16-07-0020 ◽

2017 ◽

Vol 37 (03) ◽

pp. 202-207 ◽

Cited By ~ 1

Author(s):

Davit Manukyan ◽

Nadine Müller-Calleja ◽

Karl Lackner

Keyword(s):

Antiphospholipid Syndrome ◽

Clinical Manifestations ◽

Future Research ◽

Scientific Debate ◽

Pregnancy Morbidity ◽

Anionic Phospholipids ◽

The Third ◽

Glycoprotein I ◽

Underlying Mechanisms

SummaryThe antiphospholipid syndrome (APS) is characterized by venous and/or arterial thrombosis and severe pregnancy morbidity in presence of antiphospholipid antibodies (aPL). While there is compelling evidence that aPL cause the clinical manifestations of APS, the underlying mechanisms are still a matter of scientific debate. This is mainly related to the broad heterogeneity of aPL. There are three major types of aPL: The first one binds to (anionic) phospholipids, e.g. cardiolipin, in absence of other factors (cofactor independent aPL). The second type binds to phospholipids only in presence of protein cofactors, e.g. ß2-glycoprotein I (ß2GPI) (cofactor dependent aPL). The third type binds to cofactor proteins directly without need for phospholipids. It is widely believed that cofactor independent aPL (type 1) are associated with infections and, more importantly, non-pathogenic, while pathogenic aPL belong to the second and in particular to the third type. This view, in particular with regard to type 1 aPL, has not been undisputed and novel research data have shown that it is in fact untenable. We summarize the available data on the pathogenetic role of aPL and the implications for diagnosis of APS and future research.

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Isolated IgA Anti-β2 Glycoprotein I Antibodies in Patients with Clinical Criteria for Antiphospholipid Syndrome

Journal of Immunology Research ◽

10.1155/2014/704395 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 34

Author(s):

Raquel Ruiz-García ◽

Manuel Serrano ◽

José Ángel Martínez-Flores ◽

Sergio Mora ◽

Luis Morillas ◽

...

Keyword(s):

Autoimmune Disease ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Clinical Manifestations ◽

Diagnostic Systems ◽

Clinical Criteria ◽

Glycoprotein I ◽

Standardized Diagnostic ◽

Disease Present

Seronegative antiphospholipid syndrome (SNAPS) is an autoimmune disease present in patients with clinical manifestations highly suggestive of Antiphospholipid Syndrome (APS) but with persistently negative consensus antiphospholipid antibodies (a-PL). IgA anti-β2 Glycoprotein I (aB2-GPI) antibodies are associated with APS. However, they are not currently considered to be laboratory criteria due to the heterogeneity of published works and the use of poor standardized diagnostic systems. We have aimed to assess aPL antibodies in a group of patients with clinical manifestations of APS (C-APS) to evaluate the importance of the presence of IgA aB2GPI antibodies in APS and its relation with other aPL antibodies. Only 14% of patients with C-APS were positive for any consensus antibody, whereas the presence of isolated IgA aB2GPI antibodies was found in 22% of C-APS patients. In patients with arterial thrombosis IgA aB2GPI, antibodies were the only aPL antibodies present. Serologic profile in primary APS (PAPS) is different from systemic autoimmune disorders associated APS (SAD-APS). IgA aB2GPI antibodies are more prevalent in PAPS and IgG aB2GPI antibodies are predominant in SAD-APS. The analysis of IgA aB2GPI antibodies in patients with clinical manifestations of PAPS might avoid underdiagnosed patients and provide a better diagnosis in patients with SAD-APS. Laboratory consensus criteria might consider including analysis of IgA aB2GPI for APS diagnosis.

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[Anti-β2 Glycoprotein I—β2 Glycoprotein I] immune complexes in patients with antiphospholipid syndrome and other autoimmune diseases

Lupus ◽

10.1191/096120399678847506 ◽

1999 ◽

Vol 8 (2) ◽

pp. 121-126 ◽

Cited By ~ 17

Author(s):

A Biasiolo ◽

P Rampazzo ◽

T Brocco ◽

F Barbero ◽

A Rosato ◽

...

Keyword(s):

Autoimmune Diseases ◽

Antiphospholipid Syndrome ◽

Immune Complexes ◽

Glycoprotein I

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Non β2-Glycoprotein I Cofactors for Antiphospholipid Antibodies

Lupus ◽

10.1177/096120339600500511 ◽

1996 ◽

Vol 5 (5) ◽

pp. 388-392 ◽

Cited By ~ 32

Author(s):

M Galli

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Protein C ◽

Activated Protein C ◽

Clinical Manifestations ◽

Annexin V ◽

Protein S ◽

Thromboembolic Events ◽

Glycoprotein I ◽

Recurrent Abortions

The Antiphospholipid Syndrome is defined by the association between peculiar clinical manifestations, namely arterial and/or venous thrombosis, recurrent abortions and thrombocytopenia, and the antiphospholipid antibodies. These antibodies are directed to plasma proteins bound to anionic phospholipids or other anionic surfaces: so far, β2-glycoprotein I is the best known and characterized antiphospholipid ‘cofactor’ ( this issue is specifically treated in other parts of this journal). In recent years, such a role has been reported also for prothrombin, activated Protein C, Protein S, Annexin V, Thrombomodulin, high- and low-molecular weight kininogens. Anti-prothrombin antibodies are detected in approximately 50% of the antiphospholipid-positive patients; conversely, limited data are available regarding the prevalence the other antibodies. ‘Cofactors' are necessary for the expression of both the immunological and the functional properties of their respective antiphospholipid antibodies. In particular, the recognition of the calcium-mediated prothrombin/lipid complex by anti-prothrombin antibodies hampers prothrombin activation, thus causing the prolongation of the phospholipid-dependent coagulation reactions. The interaction between antiphospholipid antibodies and natural inhibitors of coagulation such as activated Protein C, its non-enzymatic accessory protein Protein S or Thrombomodulin might increase the risk to develop thromboembolic events. Similarly, the presence of antibodies to surface-bound Annexin V has been hypothesized to play a role in recurrent abortions and fetal deaths. However, to clearly establish whether and which antiphospholipid antibodies represent risk factors for the thromboembolic events of the antiphospholipid syndrome, further studies of their behaviour and properties as well as the identification and characterization of (possibly) other antibodies are required.

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IgG Autoantibodies againstβ2-Glycoprotein I Complexed with a Lipid Ligand Derived from Oxidized Low-Density Lipoprotein are Associated with Arterial Thrombosis in Antiphospholipid Syndrome

Clinical and Developmental Immunology ◽

10.1080/10446670310001642113 ◽

2003 ◽

Vol 10 (2-4) ◽

pp. 203-211 ◽

Cited By ~ 40

Author(s):

Daniel Lopez ◽

Kazuko Kobayashi ◽

Joan T. Merrill ◽

E. Matsuura ◽

Luis R. Lopez

Keyword(s):

Venous Thrombosis ◽

Antiphospholipid Syndrome ◽

Arterial Thrombosis ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Clinical Manifestations ◽

Density Lipoprotein ◽

Healthy Individuals ◽

Pregnancy Morbidity ◽

Glycoprotein I

We recently reported [J. Lipid Res.42(2001), 697;43(2002), 1486;44(2003), 716] thatβ2-glycoprotein I (β2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship ofβ2GPI/oxLDL complexes and IgG autoantibodies againstβ2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. Theβ2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-β2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation withβ2GPI in SLE and APS patients. In contrast, anti-β2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies againstβ2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.

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The Significance of Antibodies against Domain I of Beta-2 Glycoprotein I in Antiphospholipid Syndrome

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0037-1601329 ◽

2017 ◽

Vol 44 (05) ◽

pp. 458-465 ◽

Cited By ~ 4

Author(s):

Walid Chayouâ ◽

Hilde Kelchtermans ◽

Bas Laat

Keyword(s):

Risk Stratification ◽

Antiphospholipid Syndrome ◽

Clinical Manifestations ◽

Detection Methods ◽

Clinical Value ◽

Pregnancy Morbidity ◽

Glycoprotein I ◽

Patients At Risk ◽

Beta 2 ◽

Domain I

AbstractThe antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Progress is being made in understanding the pathogenesis of the syndrome, but difficulties persist in the identification of patients at risk for thrombosis and/or pregnancy morbidity. Beta-2 glycoprotein I (β2GPI), a plasma protein consisting of five sushi domains, is thought to be the main antigenic target of aPLs. Antibodies recognizing domain I of β2GPI are predominantly present in patients with an elevated risk of thrombosis, whereas antidomain IV/V antibodies are found in nonthrombotic autoimmune diseases. Indeed, domain I antibodies proved to be pathogenic in multiple studies. Retrospective studies have provided evidence for an added clinical value of antidomain I antibodies in the risk stratification of patients with APS. Still, wide ranges of odds ratio exist between studies, probably due to differences in the study and control population, and detection methods used. Despite the proven pathogenicity of antidomain I antibodies and their correlations with clinical manifestations of APS, heterogeneity of the current studies has prohibited their acceptance in the official diagnostic criteria. Well-designed large longitudinal prospective studies with available and new, preferentially functional, assays for the risk stratification of patients with APS are required.

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Gastrointestinal symptoms as the first manifestation of antiphospholipid syndrome

BMC Gastroenterology ◽

10.1186/s12876-021-01736-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xiaojuan Zou ◽

Zhongqi Fan ◽

Ling Zhao ◽

Weiling Xu ◽

Jin Zhang ◽

...

Keyword(s):

Abdominal Pain ◽

Antiphospholipid Syndrome ◽

Clinical Manifestation ◽

High Titer ◽

Clinical Manifestations ◽

Gastrointestinal Symptoms ◽

Recurrent Abdominal Pain ◽

Anticardiolipin Antibodies ◽

Glycoprotein I ◽

Gastrointestinal Lesions

Abstract Background Antiphospholipid syndrome (APS) is an acquired pre-thrombotic autoimmune condition, which produces autoantibodies called antiphospholipid antibodies (APL) against phospholipid-binding plasma proteins. The diagnosis of APS requires at least one of Sapporo standard clinical manifestations and one laboratory criteria (persistently medium/high titer anticardiolipin antibodies, and/or medium/high titer anti-β2-glycoprotein I antibodies, and/or a positive lupus anticoagulant test). Gastrointestinal lesions are rarely reported in APS patients. APS cases with recurrent abdominal pain as the first clinical manifestation are even rarer. Case presentation This report describes an APS case with recurrent abdominal pain as the first clinical manifestation of antiphospholipid syndrome. The patient has a history of two miscarriages. Computed tomography of the abdomen confirmed mesenteric thrombosis and intestinal obstruction while laboratory tests for serum antiphospholipid and anti-β2-glycoprotein I antibodies were positive. This led to the diagnosis of APS. Conclusions This paper provides useful information on gastrointestinal manifestations and APS, also including a brief literature review about possible gastrointestinal symptoms of APS.

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