Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura

Kuwana, Masataka; Kaburaki, Junichi; Kitasato, Hidero; Kato, Miyako; Kawai, Shinichi; Kawakami, Yutaka; Ikeda, Yasuo

doi:10.1182/blood.v98.1.130

Cited by 116 publications

(111 citation statements)

References 41 publications

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“…20 The other enriched processes such as T-cell activation involved in immune response, positive regulation of leukocyte activation, and lymphocyte co-stimulation, further highlight the importance of T cells in this disease. This supports previous findings such as proliferation of T cells and production of cytokines in response to stimulation with whole platelets or fragments of GPIIb/IIIa and GPIIIa in ITP, [21][22][23][24][25] and that cytotoxic T cells can lyse platelets in patients with ITP. 2,[26][27][28] That both B-cell and T-cell mechanisms are important pathophysiologic mechanisms in ITP has also been shown in an elegant animal model of ITP.…”

Section: Resultssupporting

confidence: 80%

MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP)

Jernås

Nookaew

Wadenvik

et al. 2013

Blood

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Section: Resultssupporting

confidence: 80%

MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP)

Jernås

Nookaew

Wadenvik

et al. 2013

Blood

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“…These data appear to support previous observations in humans, showing that T helper cell abnormalities are responsible for the initiation and perpetuation of the immune effector mechanisms responsible for the human disease. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] In addition, it suggests that the CD4 ϩ T cells can be examined with relation to how a relatively platelet-specific antigen (CD61) initiates their activation, which has relevance to understanding and developing platelet-derived peptide-based therapies for reducing immune responses against platelets. These types of therapies have been proposed for patients with chronic ITP and those patients with human platelet antigen-specific alloantibodies.…”

Section: Discussionmentioning

confidence: 99%

“…For example, it is well established from studies in patients with chronic ITP that the disorder is associated with several T-cell abnormalities, including abnormally activated T helper cells with a T helper type 1 cytokine bias, a deficiency of T regulatory cells that lead to autoantibody production, and, in some patients, thrombocytopenia mediated by CD8 ϩ T cells. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] To date, however, there are no known animal models that mimic these T-cell abnormalities or show the severe form of chronic ITP with active bleeding. We report here the development of such a murine model that shows both antibody (CD8 T cell-depleted)-and cell (CD19-depleted)-mediated effector responses that lead to thrombocytopenia and bleeding mortality.…”

Section: Discussionmentioning

confidence: 99%

A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell–mediated responses that are differentially sensitive to therapy

Chow

Aslam

Speck

et al. 2010

Blood

168

165

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Immune thrombocytopenia (ITP) is a bleeding disorder characterized by antibodyopsonized platelets being prematurely destroyed in the spleen, although some patients with ITP may have a cell-mediated form of thrombocytopenia. Although several animal models of ITP have been developed, few mimic primary chronic ITP nor have any shown cell-mediated platelet destruction. To create this type of model, splenocytes from CD61 knockout mice immunized against CD61 ؉ platelets were transferred into severe combined immunodeficient (SCID) (CD61 ؉ ) mouse recipients, and their platelet counts and phenotypes were observed. As few as 5 ؋ 10 4 splenocytes induced a significant thrombocytopenia and bleeding mortality (80%) in recipients within 3 weeks after transfer. Depletion of lymphocyte subsets before transfer showed that the splenocyte's ability to induce thrombocytopenia and bleeding completely depended on CD4 ؉ T helper cells and that both CD19 ؉ B cell (antibody)-and CD8 ؉ T cell (cell)-mediated effector mechanisms were responsible. Treatment of the SCID mouse recipients with intravenous ␥-globulins raised platelet counts and completely prevented bleeding mortality induced by antibodymediated effector mechanisms but did not affect cell-mediated disease. This novel model not only shows both antibody-and cell-mediated ITP and bleeding but also suggests that these 2 effector mechanisms have a differential response to therapy. (Blood. 2010;115:1247-1253) IntroductionImmune thrombocytopenia (ITP), one of the most common hematologic autoimmune bleeding disorders, is characterized by premature platelet clearance by Fc␥ receptor (Fc␥R)-mediated phagocytosis in the reticuloendothelial system. 1-8 ITP was distinguished by 2 forms, termed acute and chronic, but an international group of recognized experts has significantly revised the definitions of and recommendations for the clinical diagnosis of ITP. 8 Primary ITP is now defined as an autoimmune disorder characterized by isolated thrombocytopenia (peripheral blood platelet count Ͻ 100 ϫ 10 9 /L) in the absence of other causes or disorders that may be associated with thrombocytopenia. 8 The various phases of ITP are defined by the time since diagnosis; newly diagnosed ITP occurs within 3 months from diagnosis, whereas persistent ITP is between 3 and 12 months from diagnosis, and chronic ITP is now defined as thrombocytopenia lasting for more than 12 months. 8 The classification of severe ITP is now reserved for those patients in whom there is the presence of bleeding symptoms at presentation or the occurrence of new bleeding symptoms requiring therapeutic intervention. 8 First-line treatments for patients with chronic ITP include steroids and intravenous ␥-globulins (IVIgs), and previous studies have shown that IVIg can also protect against passive ITP in mice. [9][10][11][12] At least 70% of patients with chronic ITP have identifiable serum autoantibodies that are composed primarily of IgG1 and IgG3 isotypes and generally target platelet glycoproteins (GPs) IIb/IIIa and/or GPIbIX. ...

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“…Abnormal antibody production in ITP appears to originate from a limited number of auto-reactive B-cell clones [44]. Furthermore, auto-reactive CD4 + T-helper cells have been shown to promote this B-cell synthesis of anti-IIb/ IIIa antibodies after exposure to the amino-terminal portions of IIba and IIIa but not to native IIb/IIIa proteins [45]. This phenomenon suggests a role for modification of the intact platelet IIb/IIIa glycoprotein by antigen-presenting cells and subsequent T-helper cell interaction.…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori eradication: Novel therapy for immune thrombocytopenic purpura? A review of the literature

et al. 2005

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Eradication of Helicobacter pylori (H. pylori ) from the gastric mucosa has been associated with improvement of several systemic diseases, including immune thrombocytopenic purpura (ITP). Over the last 5 years, several studies have reported improved platelet counts in H. pylori-positive ITP patients following standard triple H. pylori eradication therapy. Review of published studies in which eradication of H. pylori has been performed in the ITP population indicates an overall response rate of 52% in 193 subjects in whom H. pylori was eradicated. Cohorts from Japan and Italy report higher response rates. There is no established mechanism to explain how this organism, which does not invade the gastric mucosa, could be implicated in the pathogenesis of this immune-based platelet disorder. Several theories including molecular mimicry, platelet aggregation, and immunomodulatory effects of macrolides have been proposed to explain the platelet response to anti-H. pylori therapy. Large randomized-controlled studies enrolling patients from various ethnic backgrounds will be necessary to determine the response rate and mechanism of response and to gain a better understanding of the pathogenesis of ITP. Am.

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Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura

Cited by 116 publications

References 41 publications

MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP)

MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP)

A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell–mediated responses that are differentially sensitive to therapy

Helicobacter pylori eradication: Novel therapy for immune thrombocytopenic purpura? A review of the literature

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