NF-κB-94ins/del ATTG Genotype Contributes to the Susceptibility and Imbalanced Th17 Cells in Patients with Immune Thrombocytopenia

Abstract

Background The NLRP3 inflammasome plays important roles in the pathogenesis of autoimmune diseases. However, the role of the NLRP3 inflammasome in the pathophysiology of immune thrombocytopenia (ITP) remains unclear. Methods RT-PCR was used to examine the polymorphism and expression of genes involved in the NLRP3 inflammasome in ITP patients. T helper cells and apoptosis of PBMC from ITP patients were analyzed by flow cytometry. The antiplatelet autoantibodies in plasma were determined by modified monoclonal antibody-specific immobilization of platelet antigens (MAIPA). Results We found that the NF-κB-94ins/del ATTG genotype contributed to the susceptibility of ITP. Furthermore, the platelet counts of ITP patients with the WW genotype or WD genotype were lower than those with the DD genotype of NF-κB-94ins/del ATTG. Compared with controls, NF-κB gene expression was significantly decreased and WW or WD genotype ITP patients displayed higher mRNA expression than DD individuals. Similarly, the mRNA expression of NLRP3 was also increased in the WW genotype. There was a significant gene dose effect of the percentage of Th17 cells for the WW, WD, and DD genotypes (WW < WD < DD) in the unstimulated group and no significant difference was found after being stimulated. The activation of the NLRP3 inflammasome could upregulate Th17 in ITP patients. Conclusion The NF-κB-94ins/del ATTG genotype might serve as a novel biomarker and potential target for ITP.

Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects

“…Given the importance of these cytokine dysregulation, some Authors focused on Treg/Th17 imbalance and on cytokine genes polymorphisms. In a recent study, it has been shown that NF-κB-94ins/del ATTG genotype (involved in the NLRP3 inflammasome) contributes to ITP development and to imbalanced Th17 cell response (119). Another study on IL-17F rs763780 polymorphism, that has been associated with IL-17 expression and activity, showed a lower prevalence in ITP cases (N = 165) compared to healthy controls (118).…”

Increased Expressions of OX40 and OX40 Ligand in Patients with Primary Immune Thrombocytopenia

“…Therefore, the antiplatelet autoantibody is a major causative factor for the pathogenetic mechanism of ITP [ 1 – 4 ]. Antiplatelet autoantibodies mediate platelet destruction by binding to platelet membrane glycoproteins (GPs), including GPIIb/IIIa, GPIb/IX, and GPIV, and impair or inhibit platelet production by megakaryocytes by specifically recognizing platelet antigens located on megakaryocytes (such as GPIb and GPIIb/IIIa) [ 3 – 7 ]. In our study, 40% of ITP patients had positive antiplatelet autoantibodies as well as low platelet counts in comparison with patients with negative antiplatelet autoantibodies, indicating that antiplatelet autoantibodies might aggravate platelet destruction and impair platelet production that causes reduced peripheral platelet counts.…”

“…Twenty-four sex- and age-matched healthy controls (HCs) were recruited from the Healthy Management Center of the First Affiliated Hospital, Zhejiang University School of Medicine. All ITP patients were diagnosed according to consensus guidelines, and the patients and HCs who had cardiovascular disease, diabetes, pregnancy, obesity, infections, or connective tissue diseases were excluded from our study [ 3 ]. The median age of patients at the onset of primary ITP and the median age of the HCs were 37 (range, 19-66) and 37 years old (range, 20-68), respectively.…”

“…Immune thrombocytopenia (ITP) is a hemorrhagic autoimmune disease characterized by low platelet counts and an increased risk of bleeding [ 1 – 3 ]. Antiplatelet autoantibodies are the most causative agents for ITP, and antiplatelet autoantibodies can enhance platelet destruction and impair platelet generation by megakaryocytes [ 3 – 5 ]. The diagnosis of ITP relies on clinical features and laboratory examinations and excludes other factors involved in thrombocytopenia [ 4 – 6 ].…”

Long non-coding RNA maternally expressed gene 3, miR-125a-5p, CXCL13, and NF-kB in patients with immune thrombocytopenia

“…There is also abundant evidence that NF-κB is necessary for maintaining immune tolerance due to its actions during thymic selection, both for negative selection of autoreactive T cells and selection and maintenance of Tregs [ 14 ]. Yu et al reported that increased activation of NF-κB may promote the development of ITP by the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [ 15 ].…”