Anti- 2-glycoprotein I IgG antibodies from 1-year-old healthy children born to mothers with systemic autoimmune diseases preferentially target domain 4/5: might it be the reason for their 'innocent' profile?

Andréoli, Laura; Nalli, Cecilia; Motta, Mario; Norman, Gary L.; Shums, Zakera; Encabo, Susan; Binder, Walter L.; Nuzzo, Monica; Frassi, Micol; Lojacono, Andrea; Avčin, Tadej; Meroni, Pier Luigi; Tincani, Anǵela

doi:10.1136/ard.2010.137281

Cited by 87 publications

(79 citation statements)

References 16 publications

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“…These data corroborate previous observations in clinical studies and indicate that the antibodies to DI detected frequently in APS patients are more often correlated with a history of thrombosis than the antibodies to the other domains in the molecule. 22,29,35 Similarly, Ioannou and colleagues reported an inhibitory effect of soluble DI on the antibody-mediated increase in thrombus size in mice. 7 Despite the distinct clinical and histopathological features of thrombosis and fetal demise, the pathological events leading to the onset of these 2 clinical manifestations are initiated by the antibody specific for the DI domain of b2GPI, although the contribution of antibodies with different specificities cannot be ruled out.…”

Section: Discussionmentioning

confidence: 90%

A non–complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome

Agostinis

Durigutto

Sblattero

et al. 2014

Blood

121

104

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Key Points• A recombinant antibody recognizing the D1 domain of b2 glycoprotein I induces fetal loss and clot formation in animal models.• The CH2-deleted antibody fails to activate complement and prevents the procoagulant and proabortive effects of patient antibodies.A single-chain fragment variable (scFv) recognizing b2-glycoprotein 1 (b2GPI) from humans and other species was isolated from a human phage display library and engineered to contain an IgG1 hinge-CH2-CH3 domain. The scFv-Fc directed against b2GPI domain I-induced thrombosis and fetal loss, thus mimicking the effect of antibodies from patients with antiphospholipid syndrome (APS). Complement is involved in the biological effect of anti-b2GPI scFv-Fc, as demonstrated by its ability to promote in vitro and in vivo complement deposition and the failure to induce vascular thrombosis in C6-deficient rats and fetal loss in C5-depleted mice. A critical role for complement was also supported by the inability of the CH2-deleted scFv-Fc to cause vessel occlusion and pregnancy failure. This antibody prevented the pathological effects of anti-b2GPI antibodies from APS patients and displaced b2GPI-bound patient antibodies. The CH2-deleted antibody represents an innovative approach potentially useful to treat APS patients refractory to standard therapy. (Blood. 2014;123(22):3478-3487)

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Section: Discussionmentioning

confidence: 90%

A non–complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome

Agostinis

Durigutto

Sblattero

et al. 2014

Blood

121

104

View full text Add to dashboard Cite

show abstract

“…The fact that anti-β 2 GPI antibodies specifically reacting against DI are more commonly detected among patients with APS compared to conditions associated with transient aPL positivity due to polyclonal B cell activation implies that anti-DI antibodies provide a higher specificity for APS than antibodies targeting the whole molecule. Indeed, anti-β2GPI IgG isolated from sera of aPL positive asymptomatic carriers, subjects with atherosclerosis, individuals with leprosy or children with atopic dermatitis have been shown to preferentially recognize epitopes on DIV or V [20,[23][24][25]. Further, APS patients at highest risk -those with triple aPL positivityhave been demonstrated to have higher titres of anti-β2GPI-DI antibodies [41,47,48]: therefore, anti-DI IgG have been proposed as an additional tool to risk-stratify APS subjects in order to identify patients with a more aggressive clinical presentation.…”

Section: Resultsmentioning

confidence: 99%

“…Similar findings were reported in 2011 by Andreoli et al, who examined by ELISA kits the specificities of anti-β 2 GPI antibodies in one-year old healthy children born to mothers with systemic autoimmune diseases and in children with atopic dermatitis. Those autoantibodies targeted preferentially DIV/V (41%), whereas sera from APS patients reacted mainly against DI (75%) [25].…”

Section: Reactivity Towards Domains Iv/v Of β 2 Glycoprotein Imentioning

confidence: 99%

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Reactivity against the Five Domains of β2 Glycoprotein I: A Focus on Systemic Lupus Erythematosus

Chighizola¹,

Borghi²,

Grossi³

et al. 2014

J Clin Cell Immunol

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Beta-2 glycoprotein I (β 2 GPI) is the main antigenic target for antiphospholipid antibodies (aPL), the serological markers of antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by vascular thrombosis and/or pregnancy morbidity. aPL are detected in 20 to 50% of patients with systemic lupus erythematosus (SLE), representing a poor prognostic factor. Indeed, thrombotic events heralds high morbidity and mortality, being regarded as the strongest predictors of death in the first five years after SLE onset. It would be thus very important to identify a reliable laboratory tool such as anti-domain antibodies to better risk-stratify lupus patients according to the aPL profile, in order to tailor treatment strategies. Domain I (DI) of β 2 GPI has lately been identified as the main epitope targeted by antibodies reacting against β 2 GPI isolated from APS patients, well correlating with thrombotic as well as obstetric manifestations. Interestingly, anti-DI antibodies have been shown to well correlate with lupus anticoagulant and to predict the clinical manifestations of the syndrome, thrombotic events as well as pregnancy complications. Further, anti-DI antibodies allow to identify patients at highest clinical risk, presenting a good specificity for APS. On the other hand, anti-β 2 GPI antibodies from aPL asymptomatic carriers or subjects with infectious diseases preferentially display reactivity towards DIV or DV of the molecule.Few studies have to date evaluated the domain profile of anti-β 2 GPI antibodies in subjects with SLE, even though it would be very relevant from a clinical point of view to understand whether among patients with SLE the domain specificities of anti-β 2 GPI antibodies display a clinical meaning comparable to the one they exert in APS. It is therefore rather appropriate to review the available evidence about anti-domain specificities with a particular focus on SLE.

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“…However, it is now clear that not all anti-β2GPI target DI, and some anti-β2GPI react with other domains of the β2GPI molecule. Antibodies to DIV/V have been reported in asymptomatic patients, leprosy, and in children with atopic dermatitis [44,45]. In this respect, anti-DIV/V antibodies were reported among asymptomatic aPL carriers, those with no evidence of aPL-related clinical manifestations or any underlying autoimmune disease.…”

Section: Antibodies Directed To the Domain I Of 2gpimentioning

confidence: 99%

Can we withdraw anticoagulation in patients with antiphospholipid syndrome after seroconvertion?

Sciascia

Coloma

Radin

et al. 2017

Autoimmunity Reviews

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Anti- 2-glycoprotein I IgG antibodies from 1-year-old healthy children born to mothers with systemic autoimmune diseases preferentially target domain 4/5: might it be the reason for their 'innocent' profile?

Cited by 87 publications

References 16 publications

A non–complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome

A non–complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome

Reactivity against the Five Domains of β2 Glycoprotein I: A Focus on Systemic Lupus Erythematosus

Can we withdraw anticoagulation in patients with antiphospholipid syndrome after seroconvertion?

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