Immune thrombocytopenic purpura (ITP) is an autoimmune disease in which the body increases antibody production against surface antigens on platelets, leading to platelet destruction and thrombocytopenia. The exact pathogenesis of ITP is unknown; potential causes range from inflammatory responses and reactions to single nucleotide polymorphisms that cause defective genomic changes.
The Cytokine Polymorphisms
Some disease states may cause substitution of nucleotides in the human genome, leading to an imbalance of T-helper-1 (Th1) and Th2 cells. Th1/Th2 imbalance may lead to an overproduction of inflammatory cytokines that can cause conditions such as ITP.
Tumor necrosis factor (TNF)-α is an inflammatory cytokine that upregulates the activity of phagocytes and can cause ITP. Polymorphisms such as Rs1800629 can increase the expression of this cytokine. ITP patients can overexpress TNF- α on T-cytotoxic (TCD8+) cells, which leads to secretions of perforin, granzyme, and increased apoptosis, resulting in platelet destruction. The identification and normalization of apoptotic pathways and TNF-α receptors are potential therapeutic approaches for ITP.
Activated natural killer cells, B-lymphocytes and T-lymphocytes are responsible for the production of TNF-β. The +252(G/G) polymorphism in TNF-β gene increases the concentration of TNF- β, and can contribute to the incidence of ITP and response to therapy. The presence of this polymorphism in patients infected with Helicobactor pylori may be a good prognostic factor.
Th1 cells produce another proinflammatory cytokine called interferon (IFN-ɣ), which activates macrophages and switches antibody isotypes to immunoglobulin G (IgG). The polymorphism IFN-ɣ +874A/T can lead to the AT, AA, and TT genotypes that impact levels of IFN- ɣ production. The TT genotype in particular may be more commonly seen in patients leading to a higher risk of ITP incidence. Targeting pathways that suppress the factors that negatively impact platelet production can reduce the duration of thrombocytopenia and improve platelet levels in patients with ITP.
Polymorphisms in Immune System Genes
When an inflammatory reaction occurs leading to the release of cytokines such as interleukin-6 (IL6), B-cell activating factors (BAFF) are generated by neutrophils, macrophages, and other cells. The -871T/C polymorphism in the promoter gene for BAFF increases its expression and antibody production in patients with ITP. This causes platelet production suppression and destruction. Therefore, BAFF may serve as a diagnostic marker to track the progress of ITP.
Immune responses are regulated by protein tyrosine phosphatase non-receptor type 22 (PTPN22; 1p13), which helps to distinguish self vs non-self-antigens by lymphocytes. Polymorphism 1858C>T inhibits PTPN22 from adhering to signaling molecules in the B-cell receptor. Detection of this polymorphism is indicative of increased risk of ITP. Defects in PTPN22 are likely to generate B and T lymphocytes, as well as antibodies against platelet surface glycoproteins, leading to platelet destruction. Polymorphism in the PTPN22 gene may function as a negative prognostic factor.
Some cells of the immune system possess Fc gamma receptors (FCɣR) to which antibodies bind. FCɣRI and FCɣRIIb receptors regulate antibody production by B-cells, and a mutation of these receptors lead to autoimmune disorders. Polymorphisms on FCɣRIIIa increase the affinity of some immunoglobulins to CD16. This enhances phagocytosis of macrophages and leads to subsequent platelet destruction and ITP exacerbation. The detection of this polymorphism may be viewed as a poor prognostic factor.
Gene Polymorphisms Associated with Response to Treatment
Various cells can release stromal cell-derived factor-1 (SDF-1) which affects the differentiation and proliferation of megakaryocytes and platelet production. The AA and GA genotypes of the Rs2297630 polymorphism in SDF-1 increases platelet counts prior to treatment and is not involved in platelet counts after treatment, and therefore may be a good prognostic factor in patients with ITP who have not been treated.
The Janus kinase-signal transducer and activator of transcription 1 (STAT1) gene is responsible for cytokine and inflammatory mediator production. The Rs1467199 polymorphism of STAT1 is commonly observed in patients with ITP, altering its function and preventing inhibition by glucocorticoids, which are responsible for STAT1 inactivation and therefore prevent inflammation. The presence of this polymorphism may be indicative of glucocorticoid resistance in this patient group.
Thrombopoietin (TPO) receptor agonists may increase platelet production by polymorphisms such as myeloproliferative leukemia (MPL) G340A, and is a target for ITP therapy. The exact mechanism by which TPO receptor agonists increase platelet production has not been fully elucidated.
Although the main cause of ITP remains unidentified, this review points to certain polymorphisms in respective genes as potential factors for developing ITP. The researchers conclude by saying, “the diagnosis and identification of polymorphisms occurring in the factors responding to treatment as well as components of the immune system can be helpful in screening, early detection, and control of disease through the application of appropriate strategies.”
1. Rezaeeyan H, Jaseb K, Alghasi A, et al. Association between gene polymorphisms and clinical features in idiopathic thrombocytopenic purpura patients [published online June 24, 2017]. Blood Coagul Fibrinolysis. doi: 10.1097/MBC.0000000000000646