Antiphospholipid syndrome: multiple mechanisms

Mackworth‐Young, Charles

doi:10.1111/j.1365-2249.2004.02497.x

Cited by 102 publications

(74 citation statements)

References 128 publications

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“…Both of these mAb have been reported to be associated with serious side effects 22,23 that are very similar if not identical with the vascular complications reported in patients with aPL and the aPL antibody syndrome. 24 Of interest as shown in Figure 2, both of these therapeutic mAb manifest significant autoantibody activity following hemin-mediated redox reactions.…”

Section: Resultsmentioning

confidence: 99%

Autoantibody potential of cancer therapeutic monoclonal antibodies

McIntyre

Faulk

2010

Intl Journal of Cancer

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We and others have reported that multiple autoantibodies are unmasked in human polyclonal antibody preparations after exposure to physiological oxidizing agents (hemin) or electromotive force. We now have asked if oxidation unmasks autoantibody reactivities in monoclonal antibodies (mAb). To do this, we have studied 9 FDA approved mAb used therapeutically, including 4 chimeric, 4 humanized and 1 chemically modified chimeric Fab that were exposed to the physiological oxidizing agent hemin at 36°C for 20 hr. These mAb were studied for autoantibody activity to phospholipids and DNA before and after oxidation with hemin and found to develop autoantibody activities after oxidation, while retaining their original specificity as measured by mAb anti-glycophorin A binding of erythrocytes, CD 19 binding to B lymphocytes and anti-HLA-A29 binding to A29-positive lymphocytes. The finding that certain mAb have the potential to unmask autoantibody activities as a consequence of exposure to physiological redox reactions in vitro gives pause to our present understanding of the immunological basis of tolerance and concern for potential autoimmune side effects in patients receiving mAb for diagnosis or treatment.Genetic engineering is a growth strategy in the design and development of monoclonal antibodies (mAb) for clinical therapeutics, such as drug targeting in cancer chemotherapy.1,2 However, the clinical use of mAb has been associated with serious side effects, 3 presumably due to collateral damage from reactions with antigens of unintended targets. 4 Inasmuch as a tenant of the scientific basis for the clinical use of mAb is that they react only with one or a small number of closely related epitopes, 5 we asked if their specificities might be altered by exposure to physiological concentrations of physiological oxidants known to participate in physiological redox reactions. We posed this query due to our earlier reports of the unmasking of autoantibody activities in human blood as well as in purified IgG that had been exposed to such physiological redox reactions. 6 One might then ask why such redox-reactive antibodies exist. We have proposed that redox-reactive antibodies represent elements of the body's immune defense and surveillance network. 7 Recently, a similar explanation has been put forward by others. 8 In the following paragraphs, we present data indicating that autoimmune activities can be unmasked in solutions of FDA approved mAb of several different specificities and immunochemistries. Material and MethodsThe experimental design and techniques used in this study are the same as those used in our earlier report of the unmasking of autoantibody activity in human IgG following oxidation with physiological oxidants such as hemin 6 or by using electromotive force (EMF).9 It was shown that hemin was responsible for oxidation of the antibody because (i) none of the antibody changes occurred in the absence of hemin, (ii) none of the antibody changes occurred in the presence of hemopexin, which is a biological inhibitor ...

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Section: Resultsmentioning

confidence: 99%

Autoantibody potential of cancer therapeutic monoclonal antibodies

McIntyre

Faulk

2010

Intl Journal of Cancer

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“…[1][2][3][4] These autoantibodies are not only markers of APS, but also believed to play pathogenic roles in the development of symptoms in patients with APS. [1][2][3][4] APS was first fully described in the context of connective tissue autoimmune diseases, most usually systemic lupus erythematosus (SLE), although it was soon recognized that the condition can exist as an isolated, primary condition ('primary' APS, PAPS). 5,6 Furthermore, patients with PAPS may subsequently develop SLE, implying a strong relationship between both conditions.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] Thus, it is important to uncover the underlying pathways that are relevant to this condition, since they are likely to be a contributing factor for a significant proportion of patients with a variety of vascular conditions. However, the pathogenic mechanism of aPL-induced thrombosis is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Innate immune response gene expression profiles characterize primary antiphospholipid syndrome

et al. 2007

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Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disorder characterized by thromboembolic episodes and pregnant morbidity with an increasing clinical importance. To gain insight into the pathogenesis of PAPS, we have investigated the gene expression profiles that characterize peripheral blood mononuclear cells derived from PAPS patients. We show that the transcriptional activity of genes involved in innate immune responses, such as toll-like receptor 8 and CD14, as well as downstream genes of this pathway, such as STAT1, OAS2, TNFSF13 and PLSCR1 are significantly increased in PAPS patients. In addition, the expression of monocyte-specific cytokines is also elevated in PAPS mononuclear cells stimulated in vitro with lipopolysaccharide. Taken together, these results reveal a 'response to pathogen' signature in PAPS, which could reflect an altered monocyte activity. Finally, microarray analyses also revealed a reduced expression of genes coding for proteins involved in transcriptional control. Interestingly, a significant proportion of them exhibit E2F-binding sites in their promoter, suggesting that a deregulated RB/E2F activity could play a role in the pathogenesis of antiphospholipid syndrome.

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“…In vitro experiments have shown that anti-prothrombin IgG can interfere with the inactivation of activated FV by activated protein C, which might result in a hypercoagulable state [16]. It is also possible that anti-prothrombin antibodies has a prothrombotic effect due to their capacity to bind to thrombin and thereby protect it from down-regulation by its natural regulator antithrombin [22].…”

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confidence: 99%

Lupus anticoagulants in two children—bleeding due to nonphospholipid-dependent antiprothrombin antibodies

Knobe

Tedgård

et al. 2012

Eur J Pediatr

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Lupus anticoagulants in two children-bleeding due to nonphospholipid-dependent antiprothrombin antibodies.Knobe, Karin; Tedgård, Ulf; Ek, Torben; Sandström, Per-Erik; Hillarp, Andreas Link to publication Citation for published version (APA): Knobe, K., Tedgård, U., Ek, T., Sandström, P-E., & Hillarp, A. (2012). Lupus anticoagulants in two childrenbleeding due to nonphospholipid-dependent antiprothrombin antibodies. European Journal of Pediatrics, 171(9), 1383-1387. DOI: 10.1007/s00431-012-1737-1General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal AbstractWe describe two children with significant bleeding; one with multiple ecchymoses and the other with scrotal bleeding. In both patients, the activated partial thromboplastin time (APTT) was prolonged with positivity for lupus anticoagulants (LA). However, the Owren prothrombin time (PT), usually insensitive for LA, was also prolonged. Presence of LA is associated with diverse clinical manifestations, most patients being asymptomatic while others present venous or arterial thrombosis. Bleeding in conjunction with lupus anticoagulants is rare and it is unusual to see prolongation of the Owren PT assay due to LA. An extended laboratory investigation of one of the patient's plasma revealed not only LA but also a specific non-phospholipid dependent anti-prothrombin antibody causing an acquired hypoprothrombinaemia. Conclusion: It is likely that the low prothrombin activity and not the LA caused the bleeding. The bleeding signs and symptoms in both patients subsided when the PT was normalised although the prolonged APTT and the LA remained.

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Antiphospholipid syndrome: multiple mechanisms

Cited by 102 publications

References 128 publications

Autoantibody potential of cancer therapeutic monoclonal antibodies

Autoantibody potential of cancer therapeutic monoclonal antibodies

Innate immune response gene expression profiles characterize primary antiphospholipid syndrome

Lupus anticoagulants in two children—bleeding due to nonphospholipid-dependent antiprothrombin antibodies

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