Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C–related immunologic thrombocytopenia

Zhang, Wei; Nardi, Michael A.; Borkowsky, William; Li, Zongdong; Karpatkin, Simon

doi:10.1182/blood-2008-09-181073

Cited by 132 publications

(98 citation statements)

References 24 publications

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“…30,35,36 This suggests this effect to be a general feature of antibodies targeting GPIIIa-perhaps the GPIIb/IIIa complex-as we now also report CRP also amplify platelet removal by rat-anti-mouse GPIIb. Importantly, this still needs to be investigated in detail using a panel of antiplatelet antibodies against various GPIIb/IIIa epitopes, ITP sera containing various combinations of antibodies, and against other platelet proteins.…”

Section: Discussionsupporting

confidence: 68%

“…34 That anti-HPA-1a antibodies induce platelet oxidation is in agreement with studies showing that anti-GPIIIa antibodies, the glycoprotein expressing the HPA-1a epitope, also induce cellular activation through oxidative damage initiated by the platelet NADPH oxidase. 30,35,36 This suggests this effect to be a general feature of antibodies targeting GPIIIa-perhaps the GPIIb/IIIa complex-as we now also report CRP also amplify platelet removal by rat-anti-mouse GPIIb. Importantly, this still needs to be investigated in detail using a panel of antiplatelet antibodies against various GPIIb/IIIa epitopes, ITP sera containing various combinations of antibodies, and against other platelet proteins.…”

Section: Discussionsupporting

confidence: 68%

“…Previously, one of the possible mechanisms suggested is the molecular mimicry between platelet antigens and various viral and bacterial antigens, giving rise to cross-reactive autoantibodies. 36,[40][41][42] In addition, 14 of 23 (61%) of the patients with Helicobacter pylori-associated ITP demonstrated an increased platelet count after the H pylori had been eradicated. 43 As H pylori is a gram-negative bacterium, these findings are also in line with the effects of lipopolysaccharide (LPS), a gram-negative bacterial endotoxin, which was shown to enhance FcgR-mediated phagocytosis of IgG-opsonized platelets in vitro 44 and to exert a strong synergistic effect in vivo.…”

Section: Discussionmentioning

confidence: 99%

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C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia

Kapur

Heitink‐Pollé

Porcelijn

et al. 2015

Blood

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Key Points• CRP enhances IgG-mediated respiratory burst and phagocytosis of platelets in vitro and their clearance in vivo.• CRP levels are increased in ITP patients and correlate with platelet counts and bleeding severity and predict time to recovery.Immune-mediated platelet destruction is most frequently caused by allo-or autoantibodies via Fcg receptor-dependent phagocytosis. Disease severity can be predicted neither by antibody isotype nor by titer, indicating that other factors play a role. Here we show that the acute phase protein C-reactive protein (CRP), a ligand for Fc receptors on phagocytes, enhances antibody-mediated platelet destruction by human phagocytes in vitro and in vivo in mice. Without antiplatelet antibodies, CRP was found to be inert toward platelets, but it bound to phosphorylcholine exposed after oxidation triggered by antiplatelet antibodies, thereby enhancing platelet phagocytosis. CRP levels were significantly elevated in patients with allo-and autoantibody-mediated thrombocytopenias compared with healthy controls. Within a week, intravenous immunoglobulin treatment in children with newly diagnosed immune thrombocytopenia led to significant decrease of CRP levels, increased platelet numbers, and clinically decreased bleeding severity. Furthermore, the higher the level of CRP at diagnosis, the longer it took before stable platelet counts were reached. These data suggest that CRP amplifies antibody-mediated platelet destruction and may in part explain the aggravation of thrombocytopenia on infections. Hence, targeting CRP could offer new therapeutic opportunities for these patients. (Blood. 2015;125(11): 1793-1802 IntroductionFetal or neonatal alloimmune thrombocytopenia (FNAIT) and immune thrombocytopenia (ITP) are both antibody-mediated disorders in which platelets are destroyed mainly through activating immunoglobulin (IgG) Fc receptors on phagocytes in the spleen and liver, eventually resulting in thrombocytopenia. 1 In childhood, ITP is characterized by a typical history of acute development of purpura and bruising in an otherwise healthy child, caused by development of platelet autoantibodies, with an incidence of ;5 in 100 000 children.2 Most children with newly diagnosed ITP will not suffer from serious bleeding and will recover within 12 months. In ;60% of ITP, there is a history of a prior infection. [1][2][3] FNAIT is a potentially destructive disease in pregnancies, with intracerebral hemorrhage (ICH) of the fetus or neonate as the most feared complication, resulting in perinatal death in 1% to 7% or in severe neurological impairments in 14% to 26% of affected pregnancies. [4][5][6][7] FNAIT is caused by maternal IgG platelet alloantibodies, in whites mainly directed against human platelet antigen (HPA)-1a (85%), that cross the placenta and destroy the platelets of the fetus or newborn. Immunization against HPA-1a occurs in ;1:450 random pregnancies. [8][9][10] Although platelet decrement is related to antibody titer in FNAIT, 8,11,12 this correlation is not strict, as cas...

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia

Kapur

Heitink‐Pollé

Porcelijn

et al. 2015

Blood

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“…Also, autoimmune thrombocytopenia in chronic HCV infection and detection of anti-platelet antibodies, have been reported [4]. Specific glycoprotein antibodies [5], and immune complex bound to the platelet, have been reported [6]. Furthermore, the finding that thrombocytopenia is reversed by a selective thrombin receptor agonist, indicates that HCV-induced thrombocytopenia might be related to platelet activation due to the infection related inflammation [7].…”

Section: Introductionmentioning

confidence: 99%

Platelets as a Possible Reservoir of HCV And Predictor of Response to Treatment

Amer¹,

Madi²,

Shebl³

et al. 2016

J Virol Antivir Res

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In the era of new Hepatitis C Virus (HCV) therapy, and the detection of extrahepatic HCV reservoirs such as peripheral blood mononuclear cells and platelets, it is important to understand the factors underlying resistance to treatment. Detection and quantitation of HCV-RNA in platelets or leucocytes from patients under antiviral therapy is poorly studied and the limited studies generated contradictory results. Aim:To detect and quantify HCV-RNA in platelets, and to evaluate the relation between HCV-RNA in the serum and the kinetics of HCV-RNA in platelets, in response to treatment.Method: Viral kinetic was tested in 20 chronic HCV genotype4, during the course of therapy.Results: HCV-RNA was detected in sera of all infected patients. The baseline platelet viral load was significantly lower in responders compared to non-responders. Platelet viral load was also related to serum viral load (t=3.39, p=0.001), but not related to platelet count (t=-0.56, p=0.58). ROC curve analysis revealed that in general, platelet viral load at different time points was a better predictor of SVR compared to serum viral load.Conclusion: HCV RNA analysis in whole blood may be more sensitive than platelet-poor plasma, which might underestimate circulating viral load. Early eradication of viremia from platelets is associated with higher rates of SVR. Our data, reconfirm higher HCV-RNA levels in serum compared to platelets. Thrombocytopenia occurring during interferon-based therapy might be a manifestation of viral eradication rather than adverse effects. Our findings warrant testing the sensitivity of platelet viral load as a predictor of poor response.

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“…(1,2) The development of this Ab in HIV-1-ITP patients results from the molecular mimicry of epitopes on the polymorphic regions of HIV or HCV protein. (3,4) By screening a human phage display library with the GPIIIa49-66 peptide as bait, we developed several phagederived Abs against GPIIIa49-66 that exhibit comparable antigen-binding capacity. (5) In the present study, we have developed a scFv format (named A11) based on a previously reported phage antibody (clone 11).…”

Section: Introductionmentioning

confidence: 99%

A Humanized Single-Chain Variable Fragment Antibody Against Beta3 Integrin in Escherichia coli

et al. 2011

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Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C–related immunologic thrombocytopenia

Cited by 132 publications

References 24 publications

C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia

C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia

Platelets as a Possible Reservoir of HCV And Predictor of Response to Treatment

A Humanized Single-Chain Variable Fragment Antibody Against Beta3 Integrin in Escherichia coli

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