Etiology Of Immune Thrombocytopenia Research Articles

Deciphering the genetic basis of immune thrombocytopenia: current evidence for genetic predisposition in adult ITP.

Immune thrombocytopenia (ITP) is the consequence of a complex, still incompletely understood immunological dysregulation. Proposed mechanisms include autoantibody-induced platelet destruction, impaired platelet production as well as abnormalities in T-cell immunity, such as T helper cells (Th1) polarization, a high proportion of Th17 cells, and a reduced number of regulatory T cells. Although the etiology of ITP is incompletely understood and considered multifactorial in most cases, genetic variants are thought to play a key role in susceptibility to ITP, especially in persistent or chronic ITP. Efforts are currently underway to uncover possible predisposing genetic factors for the development of ITP. Single-nucleotide polymorphisms and copy number variations have been identified in several immune-related genes, such as cytokine genes, Fcγ receptor genes or T-cell costimulation genes, and have been associated with patients' susceptibility to ITP. However, because of the clinical heterogeneity and low incidence of ITP it remains challenging to perform genetic analyses with sufficiently large sample size within informative patient populations, highlighting the need for collection of well-annotated biomaterials in clinical trials or registry projects. Another significant challenge is to go beyond performing association studies alone and to establish genotype-phenotype associations, thus proving causality between a genetic alteration and ITP pathogenesis. This review summarizes our current knowledge on genetic alterations identified as potential predisposing factors for the development of ITP in adults, thereby addressing signaling pathways considered critical for ITP pathogenesis.

ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia.

Heightened platelet phagocytosis by macrophages accompanied by an increase in IFN-γ play key roles in the etiology of immune thrombocytopenia (ITP); however, it remains elusive how macrophage-mediated platelet clearance is regulated in ITP. Here, we report that adhesion and degranulation-protein adaptor protein (ADAP) restrains platelet phagocytosis by macrophages in ITP via modulation of signal transducer and activator of transcription 1 (STAT1)-FcγR signaling. We show that ITP was associated with the underexpression of ADAP in splenic macrophages. Furthermore, macrophages from Adap−/− mice exhibited elevated platelet phagocytosis and upregulated proinflammatory signaling, and thrombocytopenia in Adap−/− mice was mitigated by the depletion of macrophages. Mechanistically, ADAP interacted and competed with STAT1 binding to importin α5. ADAP deficiency potentiated STAT1 nuclear entry, leading to a selective enhancement of FcγRI/IV transcription in macrophages. Moreover, pharmacological inhibition of STAT1 or disruption of the STAT1-importin α5 interaction relieved thrombocytopenia in Adap−/− mice. Thus, our findings not only reveal a critical role for ADAP as an intracellular immune checkpoint for shaping macrophage phagocytosis in ITP but also identify the ADAP-STAT1-importin α5 module as a promising therapeutic target in the treatment of ITP.

Possible Role of CD11a in Primary Immune Thrombocytopenia Patients on Immunosuppressive Therapy

Background and ObjectivesImmune thrombocytopenia (ITP) is one of the autoimmune diseases that presented by thrombocytopenia and increased risk of bleeding. Etiology of immune thrombocytopenia (ITP) is very complex. Lymphocyte function associated antigen-1 (LFA-1) plays important role in ITP. The aim of this study was evaluation of expression of CD11a on lymphocytes to explore its possible role in primary ITP patients also, regarding severity and response to immunosuppressive treatment.Patients and MethodsThis is a cross-sectional case-control study. Forty adult patients aged (18:58) years, 29 females and 11 males were enrolled as newly diagnosed primary ITP. Forty age and sex matched control subjects were randomly selected. The expression of CD11a on lymphocyte subpopulations (CD3+ T cells, CD3+CD4+ T cells and CD19+ B cells) was analyzed by flowcytometry at the start of the study and after 6 months of follow-up.ResultsThe mean fluorescence intensity (MFI) of CD11a on CD3+ T and CD19+ B lymphocytes was significantly highly increased in ITP patients compared to healthy controls while MFI of CD11a on CD3+ CD4+Tclls was non-significant. MFI of CD11a on CD3+ and CD19+ B lymphocytes showed non-significant elevation with platelet count or bleeding score. MFI of CD11a on CD3+ showed significant highly increased level in refractory ITP compared with responder cases.ConclusionCD11a had possible role in the pathogenesis of ITP. Immunosuppressive therapy in ITP did not affect the level of CD11a expression on T and B lymphocytes. Levels of CD11a do not reflect the severity of ITP neither platelet count nor bleeding score. Increased MFI of CD11a in CD3+T lymphocytes of ITP patients may cause resistance to immunosuppressive therapy.

Emerging Concepts in Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease defined by low platelet counts which presents with an increased bleeding risk. Several genetic risk factors (e.g., polymorphisms in immunity-related genes) predispose to ITP. Autoantibodies and cytotoxic CD8+ T cells (Tc) mediate the anti-platelet response leading to thrombocytopenia. Both effector arms enhance platelet clearance through phagocytosis by splenic macrophages or dendritic cells and by induction of apoptosis. Meanwhile, platelet production is inhibited by CD8+ Tc targeting megakaryocytes in the bone marrow. CD4+ T helper cells are important for B cell differentiation into autoantibody secreting plasma cells. Regulatory Tc are essential to secure immune tolerance, and reduced levels have been implicated in the development of ITP. Both Fcγ-receptor-dependent and -independent pathways are involved in the etiology of ITP. In this review, we present a simplified model for the pathogenesis of ITP, in which exposure of platelet surface antigens and a loss of tolerance are required for development of chronic anti-platelet responses. We also suggest that infections may comprise an important trigger for the development of auto-immunity against platelets in ITP. Post-translational modification of autoantigens has been firmly implicated in the development of autoimmune disorders like rheumatoid arthritis and type 1 diabetes. Based on these findings, we propose that post-translational modifications of platelet antigens may also contribute to the pathogenesis of ITP.

Mechanisms of loss of immune tolerance in the production of antiplatelet autoantibodies in primary immune thrombocytopenia

Primary immune thrombocytopenia (ITP) is an organ-specific autoimmune hemorrhagic disease. The etiology of ITP is still unclear, but loss of immune tolerance to platelet surface antigens is considered as a fundamental cause of ITP. Therapeutic strategies that prevent the activation and proliferation of autoreactive cells have been suggested, which includes clearance of autoreactive cells (apoptosis), receptor editing, induction of anergy and extrinsic cellular suppression. Failure at any of these steps may lead to the production of autoantibodies against platelet and megakaryocyte glycoproteins. An improved understanding of the mechanisms for autoantibody production will provide theoretical basis for optimal diagnosis and treatment of ITP. Key words: ITP; Autoantibody; Immune tolerance

DNA Methylation and Primary Immune Thrombocytopenia

DNA methylation is a heritable, stable, and also reversible way of DNA modification; it can regulate gene expression without changing the nucleotide sequences. Because it takes part in regulation of immune responses, the loss of methylation homeostasis in immune cells will result in autoimmune disease by inducing aberrant gene expression. Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease with many immune deficiencies. Recently, it was well documented that abnormal DNA methylation is also involved in the etiology of ITP. In this review, we elucidate the role of DNA methylation in autoimmune diseases by summarizing the DNA methylation-sensitive genes and the relationship between DNA methylation and ITP.

A Survey of the Etiology of Immune Thrombocytopenia (ITP).

AbstractAbstract 2239 Introduction:Socioeconomic, environmental, lifestyle and genetic factors play a role in the etiology of ITP but are poorly understood. A self-reported questionnaire was designed to study these relationships and how these factors prior to the diagnosis of ITP relate to treatment response and disease progression in order to gain insight into the etiology of ITP. Methods:To design the questionnaire that would address topics of interest: 1) 60 ITP patient interviews were performed and 2) the questionnaire was reviewed by project coordinators, nurse practitioners, Platelet Disorder Support Association (PDSA) members, and hematologists. The input was incorporated into a further-revised questionnaire, which was then administered to both “pediatric” (patients <18 years of age at the time of diagnosis) and adult ITP patients from the Platelet Disorders Center at Weill Cornell - New York Presbyterian Hospital. Formal statistical analysis to relate responses to one question to responses of another to define sub-groups of patients is ongoing. Results:109 patients were enrolled. Ages ranged from 2–78 years of age; median age was 55 years, with 21 females and 33 “pediatric” patients. The most frequent environmental exposures in adults were automotive exhaust (n=14) and Teflon (n=12). In pediatrics, preservatives and insecticides (n=8) and Teflon (n=7) were most common. The most prevalent hazardous substances in both groups were cleaning supplies (n=16 adults, n=9 “pediatric”) and chlorinated water (n=13 adult, n=9 “pediatric”). 13 adults also had exposure to gasoline or diesel fumes. Refer to figure 1. 51(47%) patients reported at least one infection prior to diagnosis with ITP. The most common were Strep throat (n=12); influenza (n=9), and respiratory tract infections (n=8). Twenty-four (22%) patients reported at least one autoimmune disease, including celiac (n=2) and discoid lupus (n=2).Twenty-one patients reported a family history of Type II diabetes, 12 Type I diabetes, 13 osteoarthritis and 10 rheumatoid arthritis. Eight (7%) patients reported at least one inflammatory disease including: Crohn’s disease (n=3), Inflammatory bowel disease (n=7), Systemic lupus erythematous and Vitiligo(each n=1). Thirty-seven (34%) patients reported surgeries prior to diagnosis of ITP, especially: appendectomy (n=8) and tonsil removal (n=8). Twenty-three patients traveled close to date of diagnosis, 58 patients reported more stress than usual (i.e. death of a relative, loss of employment); 13 patients reported a drastic change in diet (i.e. decreasing calories (n=7) or becoming vegetarian (n=5)). Vitamin supplementation for vitamin C and D (each n=17), E (n=12) and B (n=11) were common. In addition, 11 vitamin deficiencies were reported, vitamin D (n=5), vitamin B12 (n=3) and other (n=3). The most frequent allergic reactions included: 31 (28%) patients with hay fever, 9 patients with allergies to milk, 7 patients with poison ivy or skin irritation, 6 patients with eczema, and 4 with allergic rhinitis. Other medical conditions reported were: hypothyroidism (n=10), hyperthyroidism (n=9), high blood pressure (N=16), high cholesterol (N=14), and anemia (N=13) [9 additional patients included 4 with iron deficiency anemia and 5 with a family history of iron deficiency anemia]. Seven patients reported a lack of prenatal care in their mothers’ pregnancy and 7 were premature. Medications reported include: acetaminophen (n=53), antibiotics (n=36), antihistamines (n=22), and hormone therapy (n=17). Vaccinations received close to date of diagnosis include: flu vaccine (n=10) and T-dap (n=9). Prednisone was reported most frequently as both the best therapy to minimize symptoms (n=18) and the worst (n=16). Conclusion:Our pilot study intended to capture critical information and to further development of the questionnaire. We can see if there are groups of patients in whom onset and other characteristics relate to outcomes including response to treatment. Following formal statistical analysis of the material acquired (in progress and anticipated by early September), the next step will be for a final updated version of the questionnaire to be posted on the PDSA web site in order to accrue responses from a much larger number of patients. The questionnaire will also be given to a non-ITP patient population to serve as controls. [Display omitted] Disclosures:Bussel:Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

Low expression of FCGRIIB in macrophages of immune thrombocytopenia-affected individuals

Immune thrombocytopenia (ITP) is an autoimmune disorder described as autoantibody-mediated platelet deterioration. Platelets with affiliated IgG are targeted for exploitation by Fc receptor-mediated phagocytic cellular material within the reticuloendothelial system. The objective of this research is to investigate the relationship between the appearance of FC gamma receptors (FCGR) IIB and IIIA on macrophages and clinicopathological characteristics in ITP patients. FCGRIIB and FCGRIIIA were recognized by immunohistochemistry staining of 62 samples, including regular (n = 20) and ITP (n = 42) samples. Subsequently, the relationship of FC gamma expression levels to ITP progression and clinicopathological characteristics was statistically reviewed. Furthermore, the relationship between Helicobacter pylori (HP) infection and FC gamma expression was analyzed. IHC staining with the coordinated spleen tissue trial samples showed that expression of FCGRIIB on macrophages of ITP patients was tremendously reduced in comparison to the healthy control group. However, no variance was discovered between the two groups with respect to FCGRIIIA expression. There was no substantial correlation among FCGRIIB and FCGRIIIA expression and patient age and gender. Significant differences were found between HP infection and decreased expression of FCGRIIB, while there was no difference with the expression of FCGRIIIA. Lower expression of FCGRIIB is likely involved in the etiology of ITP. HP infection is correlated with decreased expression of FCGRIIB. A rise in FCGRIIB may serve as a therapeutic target for human ITP treatment or possibly as a biomarker for ITP analysis.

DNA Methyltransferase 3B Gene Promoter and Interleukin-1 Receptor Antagonist Polymorphisms in Childhood Immune Thrombocytopenia

Primary immune thrombocytopenia (ITP) is one of the most common blood diseases as well as the commonest acquired bleeding disorder in childhood. Although the etiology of ITP is unclear, in the pathogenesis of the disease, both environmental and genetic factors including polymorphisms of TNF-a, IL-10, and IL-4 genes have been suggested to be involved. In this study, we investigated the rs2424913 single-nucleotide polymorphism (SNP) (C46359T) in DNA methyltransferase 3B (DNMT3B) gene promoter and the VNTR polymorphism of IL-1 receptor antagonist (IL-1 Ra) intron-2 in 32 children (17 boys) with the diagnosis of ITP and 64 healthy individuals. No significant differences were found in the genotype distribution of DNMT3B polymorphism between the children with ITP and the control group, whereas the frequency of allele T appeared significantly increased in children with ITP (P = 0.03, OR = 2, 95% CI: 1.06–3.94). In case of IL-1 Ra polymorphism, children with ITP had a significantly higher frequency of genotype I/II, compared to control group (P = 0.043, OR = 2.60, 95% CI: 1.02–6.50). Moreover, genotype I/I as well as allele I was overrepresented in the control group, suggesting that allele I may have a decreased risk for development of ITP. Our findings suggest that rs2424913 DNMT3B SNP as well as IL-1 Ra VNTR polymorphism may contribute to the susceptibility to ITP.

IgG-associated immune thrombocytopenia in Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is characterized by serum IgM monoclonal gammopathy, and only occasionally complicated by immune thrombocytopenia. Rarely, coexistence of non-IgM gammopathy in WM has been reported. Herein, we describe an 81-year-old case of WM with rapidly progressive immune thrombocytopenia accompanied by concurrent IgG gammopathy and elevation of platelet-associated IgG (PA-IgG). Immunostaining of the bone marrow specimen displayed not only IgM positive but also IgG positive plasmacytoid cells. Although dexamethasone therapy had no effect on thrombocytopenia, a modified RCD regimen (rituximab 375 mg/m(2) i.v. day 1, cyclophosphamide 375 mg/m(2) i.v. day 2 and dexamethasone 12 mg/body orally days 1-7) successfully normalized PA-IgG as well as IgG and IgM paraproteinemia and significantly increased platelet count. The current case suggests that the IgG gammopathy associated with WM is likely to be an etiology of immune thrombocytopenia and that tumor reduction, rather than immunosuppression, leads to an improvement of concurrent thrombocytopenia.