Materiały źródłowe

• #1 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5332920/

  Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts. The pathogenesis of ITP remains unclear although both antibody-mediated and/or T cell-mediated platelet destruction are key processes. […] ITP is mainly due to IgG autoantibodies, which bind to platelets and MKs, targeting very abundant surface antigens such as glycoprotein (GP) IIb3 (GPIIbIIIA) and GPIb-IX-V. Platelets with bound autoantibodies are subsequently recognized by phagocytes bearing Fc-receptors (FcRs), which results in enhanced antibody-mediated platelet phagocytosis and destruction primarily in the spleen. […] Autoreactive T cells are also involved in platelet and MK destruction, and, despite an increased MK number in the bone marrow of some patients, many present signs of morphological abnormalities including apoptotic ultrastructure as well as activation of Caspase-3.

• #1

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  Various mechanisms support the cytotoxicity mediated by antibodies, such as complement-dependent cytotoxicity (CDC), causing the destruction of targeted cells by the formation of the membrane attack complex (MAC), but also facilitating their phagocytosis (antibody-dependent cellular phagocytosis [ADCP]) by macrophages expressing Fc gamma receptor (FcR) and complement receptor 1 that binds to the complement fraction C3b. […] A major mechanism of peripheral platelet destruction is ADCP, mediated by splenic macrophages. […] Overall, desialylation appears to be involved in both platelet destruction and production and is associated with a lower platelet count and a refractoriness to usual therapies. […] The role of CD4 T cells in ITP has been known for years, with clones recognizing GPIIb/IIIa detected in the spleen and the blood of ITP patients in the early 2000s.

• #1 Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia

  https://www.immunologyresearchjournal.com/articles/pathophysiological-mechanisms-leading-to-low-platelet-count-in-immune-thrombocytopenia.html

  The first and most commonly accepted mechanism of platelet clearance in ITP is the binding of anti-platelet autoantibodies to their antigenic glycoprotein targets that leads to platelet elimination by monocytes/macrophages of the reticuloendothelial system through FcRIIA and FcRIIIA-mediated recognition, mainly in the spleen and liver. However, additional pathological mechanisms including platelet apoptosis and loss of sialic acid from platelet membrane glycoproteins were described in recent years, that also contribute to platelet clearance from circulation. […] Several studies have demonstrated the contribution of platelet apoptosis to ITP pathogenesis. […] Cells expressing PS on their membrane are known to be cleared through scavenger receptors in macrophages, thus, apoptotic platelets would also be eliminated from circulation by this mechanism.

• #1 Pathophysiology, Clinical Manifestations and Diagnosis of Immune Thrombocytopenia: Contextualization from a Historical Perspective

  https://www.mdpi.com/2038-8330/16/2/21

  On many occasions (30–40% of cases), the antibodies are not detected, which also suggests the participation of other alternative immunological mechanisms, such as cellular immunity and an imbalance of regulatory mechanisms, with the participation of cytotoxic and regulatory T lymphocytes. […] In ITP, there is a loss of immunological tolerance to specific self-antigens. […] The prognosis of ITP worsens if it is secondary.

• #1 Immune Thrombocytopenia (ITP): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/202158-overview

  Immune thrombocytopenia (ITP) is a syndrome in which platelets become coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. […] Autoantibody-coated platelets induce Fc receptor-mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. […] The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets. […] Malik et al have identified cytotoxic CD8+ T cells as an antibody-independent mechanism of platelet destruction in chronic ITP. These researchers demonstrated that adults with chronic ITP have clonal expansion of terminally differentiated effector memory CD8+ T cells (TEMRA), compared with age-matched controls. TEMRAs form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the T-cell receptormediated release of cytotoxic granules. […] If bone marrow megakaryocytes cannot increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Impaired thrombopoiesis is attributed to failure of a compensatory increase in thrombopoietin and megakaryocyte apoptosis.

• #1

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  Similarly to most of autoimmune diseases, an imbalance between the proinflammatory and the anti-inflammatory responses is present during ITP, with a skewing of T cells to helper T cell (Th) polarizations, associated with a quantitative or functional deficiency of regulatory T cells (Treg). […] Combined to the peripheral destruction of platelets, there is an inappropriate production in ITP resulting from both an immune response against megakaryocytes but also to inadequate level of TPO. […] As megakaryocytes express different GP recognized by antiplatelet antibodies, they are exposed to the humoral immune response that diminishes their number and maturation, and to the CTL cytotoxicity that disrupts physiological apoptotic mechanisms involved in platelet formation. […] During ITP, the inappropriate levels of TPO are linked to its physiological regulation.

• #1

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. […] A loss of immune tolerance mostly represented by a regulatory T-cell defect allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. […] Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets. The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes.

• #1 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5332920/

  In summary, T cells also play a crucial role in ITP. Indeed, abnormal T cell subsets, including lower Tregs and unbalanced Th17, Th0, and Th1 profiles, as well as the presence of cytotoxic CD8+ T cells constitute the cellular mechanisms of ITP pathogenesis. […] APCs, primarily DCs, are also impaired in ITP, which may suggest that abnormal self-antigen presentation takes place, which contributes to stimulating pathogenic antibody production thereby contributing to the progression of the disease. […] MKs and the whole BM niche are thus also damaged in ITP. It is targeted by autoantibodies and T cells, which leads to impaired MK maturation and platelet production despite relatively normal TPO levels.

• #1

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  Overall, 80% of ITP are considered as primary, favored by a rupture of the immune tolerance leading to an autoimmune process involving both innate and adaptive immune responses. […] An integrative view of ITP pathogenesis is summarized in Figure 1 and Table 1. ITP results from a peripheral destruction of platelets that takes place in the blood, the spleen, and the liver, together with an inappropriate bone marrow production due to an autoimmune response against megakaryocytes and insufficient TPO levels. […] The involvement of the humoral response against platelets is known since the 1950s when Harrington et al observed that sera of ITP patients induced thrombocytopenia when infused to healthy volunteers. […] The spleen plays a major role in ITP pathogenesis, being the site of an intense autoimmune response with an expansion of germinal centers and the generation of mutated, high-affinity-antiplatelet antibody-secreting plasma cells.

• #1 Immune Thrombocytopenia: Immune Dysregulation and Genetic Perturbations Deciphering the Fate of Platelets

  https://www.imrpress.com/journal/FBL/29/10/10.31083/j.fbl2910342/htm

  Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. It involves impaired production and excessive destruction of platelets. It is a complex and heterogeneous disorder with unknown pathophysiology. Both genetic and immunologic perturbations have been implicated in the disease pathogenesis. Immune dysregulations involve both the humoral and cellular immunity. Attack of anti-platelet autoantibodies has been found to be the fundamental cause of platelet destruction. Other mechanisms including T cell mediated platelet destruction, complement activation, apoptosis, and desialylation have also been found in the development of ITP. Genetic testing has revealed various predispositions including single nucleotide polymorphisms (SNPs), copy number variations (CNVs), and epigenetic changes in the immunoregulatory genes of ITP subjects. Varying methylation patterns have also been found in the immune-related genes. This review summarizes the dysregulated immune cells, immunologic cascades, altered signaling pathways, genetic mutations and epigenetic changes in ITP pathogenesis. These alterations induce autoimmune responses against the platelets resulting in complex bleeding manifestations and onset of ITP.

• #1 Immune Thrombocytopenia: Immune Dysregulation and Genetic Perturbations Deciphering the Fate of Platelets

  https://www.imrpress.com/journal/FBL/29/10/10.31083/j.fbl2910342/htm

  Mutations have been found in T cells related genes which induce signaling cascades against platelets. T-1993C mutation of T cell specific TBX21 gene has been found in the pathophysiology of ITP. […] The association of cytokine and chemokine encoding genes has been demonstrated in various studies on ITP patients. These genes play important roles such as stimulation of megakaryocytopoiesis, regulation of platelet production, and generation of autoantibodies. Polymorphisms in IL-1B-31, IL-1Ra, IL-4, IL-10, IL-17F, IL-23R, TNF-α, TNF-β, TGF-B1, TNIP1, IFN-G, MBL, and GPIA are found in ITP pathogenesis.

• #1 Investigation of the correlation between immune thrombocytopenia and T cell activity-regulated gene polymorphism using functional study | Scientific Reports

  https://www.nature.com/articles/s41598-022-10631-z

  Thrombocytopenia is a condition where the platelet count is under 100109/L, which is caused by various disorders. However, the mechanism of thrombocytopenia is still unclear. Hence, we tried to investigate the correlation between immune thrombocytopenia (ITP) and single nucleotide polymorphisms (SNPs) of genes related to T cell activation. […] The excessive destruction of platelets is resulted from platelet antibody (PAIgG) production or other immunological dysfunction, including type 1 helper T cells (Th1) polarization, regulatory T cells (Treg) scarcity, and autoreactive T cells activation and then leading to immune tolerance loss, megakaryocyte apoptosis, and platelet lysis. […] Therefore, the differentiation and activation of immune cells play a vital role in the pathogenesis of ITP.

• #1 A novel approach to immune thrombocytopenia intervention: modulating intestinal homeostasis | BMC Immunology | Full Text

  https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00660-w

  Immune thrombocytopenia (ITP) is a prevalent hemorrhage condition that causes notable immune-related abnormalities. Recently discovered data has shown that the intestinal flora plays a crucial role in maintaining a balanced immune system. Furthermore, an imbalance in gut flora has the potential to increase the possibility of developing ITP. Moreover, some studies reported a strong link between inflammatory bowel disease (IBD) and ITP. In this review, we described the significance of gut immunity in ITP. In addition, we explored the associations between gut flora and ITP as well as IBD and ITP. Finally, we examined the effectiveness of existing therapies that regulate gut homeostasis and their impact on the prognosis of patients with ITP. […] In ITP, antibody and cell-mediated processes lead to the increased platelet destruction and insufficient production.

• #1 A novel approach to immune thrombocytopenia intervention: modulating intestinal homeostasis | BMC Immunology | Full Text

  https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00660-w

  Furthermore, the degree of infection is closely correlated with the number of these immune cells. In the intestinal lymph nodes of patients with inflammatory bowel disease (IBD), IL-17(+) Foxp3(+) T cells are frequently abundant. This demonstrates the critical function of Treg and Th17 cells in controlling the immune response in ITP patients intestines. […] B cells secrete mucosal IgA to modulate gut flora. This restricts bacterial proximity to epithelial cells, thereby regulating intestinal mucosal immunity. […] One study collected fecal samples from 25 ITP children and 16 healthy volunteers to examine alterations in gut microbiota diversity and composition under those conditions. They found that the gut flora of ITP children was noticeably out of balance, with a significant elevation of the anaplasmosis phylum (Bacteroidetes) population. Additionally, there was a direct correlation between this rise and IgG levels. They concluded that the gut microbiota probably regulates ITP development through IgG.

• #1 A novel approach to immune thrombocytopenia intervention: modulating intestinal homeostasis | BMC Immunology | Full Text

  https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00660-w

  Patients with immune ITP who are also afflicted with Helicobacter pylori (HP) infection encounter many abnormalities in their immune system. Specifically, there is a decrease in the number of CD4+ cells and CD4+/CD8+ cells while the number of CD8+ cells increases. The synthesis of anti-platelet antibodies has also significantly increased. […] Treg cells are a subpopulation of T lymphocytes. ITP sufferers often have substantially reduced peripheral blood CD4+CD25+ T regulatory cells. Furthermore, compared to uninfected people, HP-infected patients have higher numbers of CD4+CD25+ T cells in their stomach and duodenum mucosa. These Treg cells exacerbate the infection by inhibiting the gastric mucosal immune response to HP. […] Th1 cells release IL-2, IFN-, and TNF-, which accelerate inflammatory mediators production like NO. ITP sufferers often exhibit enhanced Th1 cell population, suggesting a potential link to inflammatory responses.

• #1

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  This insufficient platelet production supports the use of TPO-RA, whose efficacy inversely correlates with endogen TPO concentrations. […] The advances in the deciphering of ITP pathogenesis support the view of ITP as a syndrome rather than a unique pathology. Different pathological pathways lead to a common feature thrombocytopenia and are probably involved at different levels at a patient scale, as supported by the highly variable responses to drugs with different mechanisms of action from a patient to another.

• #1 How we treat primary immune thrombocytopenia in adults | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01401-z

  The hypothesized pathophysiology of ITP is summarized in Fig. 1. Of note, the above-mentioned pathological mechanisms may play varying roles in different patients due to the heterogeneity of the disease. Identifying which mechanism is dominant in each case is critical for the implementation of pathogenesis-oriented individualized treatment.

• #1

  https://link.springer.com/article/10.1007/s44337-024-00040-8

  ITP is a disease caused by the immune system attacking platelets, and treatment options have been one of the hot topics of research. […] In recent years, significant progress has been made in understanding the complex pathogenesis of ITP, and the disease is becoming clearer, facilitating the development of new therapeutic approaches that target these pathways. […] The pathogenesis of ITP is intricate, and recent years have seen substantial advancements in uncovering different facets of ITP pathogenesis, there are ongoing investigations into new therapies that target these pathways. […] Initially, studies on the pathogenesis of ITP focused on humoral immunity, in which IgG-based platelet antibodies produced by B lymphocytes bind to platelets, leading to phagocytosis of platelets by the monocyte-macrophage system, resulting in increased platelet destruction and shortened lifespan, which is considered to be the most classical pathogenesis of ITP.

• #2

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. […] A loss of immune tolerance mostly represented by a regulatory T-cell defect allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. […] Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets. The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes.

• #2 Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia

  https://www.immunologyresearchjournal.com/articles/pathophysiological-mechanisms-leading-to-low-platelet-count-in-immune-thrombocytopenia.html

  Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by the decrease in peripheral blood platelet count below 100 x 10^9/L, and an increased bleeding risk when thrombocytopenia drops below 30 x 10^9/L. The mechanisms leading to ITP in adults, although not completely elucidated, involves an imbalance between effector and regulatory cells that results in a breakdown of the immune tolerance. Autoantibodies are considered the main responsible for thrombocytopenia, although direct T-cell cytotoxic effect and lysis by Complement attachment and activation could also contribute to platelet elimination from circulation. […] The presence of autoantibodies targeting platelet surface glycoprotein(s) (GP) has been demonstrated in patients with ITP with percentages of patients with positive autoantibodies varying according to different case series. Most of these antibodies are IgG, but IgM and IgA can also be detected, usually in association with IgG. Main autoantibody targets are GPIIbIIIa (integrin IIb3), GPIbIX and GPIaIIa complex, but, autoantibodies against other GPs (i.e. the vitronectin receptor, integrin v3) against thrombopoietin and/or its receptor c-Mpl were also detected in some patients. Therefore, humoral immunity has been classically considered the main cause of thrombocytopenia, although other mechanisms such as direct T-cell cytotoxic effect could contribute to platelet elimination as well.

• #2 Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia

  https://www.immunologyresearchjournal.com/articles/pathophysiological-mechanisms-leading-to-low-platelet-count-in-immune-thrombocytopenia.html

  The first and most commonly accepted mechanism of platelet clearance in ITP is the binding of anti-platelet autoantibodies to their antigenic glycoprotein targets that leads to platelet elimination by monocytes/macrophages of the reticuloendothelial system through FcRIIA and FcRIIIA-mediated recognition, mainly in the spleen and liver. However, additional pathological mechanisms including platelet apoptosis and loss of sialic acid from platelet membrane glycoproteins were described in recent years, that also contribute to platelet clearance from circulation. […] Several studies have demonstrated the contribution of platelet apoptosis to ITP pathogenesis. […] Cells expressing PS on their membrane are known to be cleared through scavenger receptors in macrophages, thus, apoptotic platelets would also be eliminated from circulation by this mechanism.

• #2

  https://link.springer.com/article/10.1007/s44337-024-00008-8

  Antibody-coated platelets bind tissue macrophages through Fc receptors, leading to their clearance primarily in the spleen and to a lesser extent in the liver. […] Furthermore, antiplatelet antibodies might not only bind but also activate the classical complement pathway, causing their lysis by assembling the membrane attack complex. […] A study in 2015 showed that platelet clearance has another Fc-independent pathway via hepatocyte Ashwell-Morell receptors (AMR). […] Dendritic cells from ITP patients exhibit a higher ability to induce CD4+CD25-T lymphocyte proliferation while reducing the induction of Tregs. […] Decrease regulatory T cell activity, which normally inhibits autoimmune response, was first demonstrated by Liu in 2007. […] Stimulation of T cells can result in IL-2 secretion, thus resulting in autoreactive B cell differentiation and antibody secretion.

• #2

  https://haematologica.org/article/view/haematol.2021.279751

  Antibody-mediated platelet apoptosis has also been suggested in ITP. […] Another ITP pathway that has also been previously described is Fc-independent platelet clearance. […] The true extent to which platelet desialylation and/or platelet apoptosis are involved in ITP pathology remains unclear. […] We demonstrated that the presence of APA in ITP patients sera is associated with platelet desialylation in our patient population. […] This supports recent studies which reported that the loss of sialic acid is a more frequent finding in ITP than previously thought. […] Furthermore, in a murine model of ITP utilising patients anti-GPIIb/IIIa antibodies and human platelets, we found solid and reproducible evidence to support the use of neuraminidase inhibitors as potential new therapeutics for ITP.

• #2 Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia

  https://www.immunologyresearchjournal.com/articles/pathophysiological-mechanisms-leading-to-low-platelet-count-in-immune-thrombocytopenia.html

  In 2015, Li and col. described for the first time that plasma from ITP patients containing anti-GPIbIX autoantibodies induced loss of sialic acid capping carbohydrates from platelet glycoproteins. This mechanism is triggered by the ability of these autoantibodies to induce platelet activation, which promote neuraminidase externalization, the ultimate responsible for sialic acid cleavage from membrane glycoproteins. […] Overall, these studies demonstrate that ITP autoantibodies mainly affect specific and different intracellular pathways, depending on their target proteins, interfering with normal megakaryocytic functions within the bone marrow and leading to decreased platelet production.

• #2 How we treat primary immune thrombocytopenia in adults | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01401-z

  By contrast, circulating and splenic Tregs in ITP are found to be numerically decreased and functionally impaired, contributing greatly to the perpetuation of ITP. […] Approximately 20–40% of ITP patients do not have detectable anti-GP autoantibodies, suggesting alternative mechanisms of platelet destruction. […] Many studies have demonstrated that CD8+ cytotoxic T lymphocytes (CTLs) from peripheral blood or spleen of ITP patients can directly lyse platelets or induce platelet apoptosis through granzyme B and perforin, although the target platelet MHC class I peptides recognized by CD8+ T cells have not yet been identified. […] Desialylation-mediated platelet phagocytosis through hepatocyte Ashwell–Morell receptors in the liver is another mechanism of FcγR-independent platelet eradication in ITP.

• #2 Immune Thrombocytopenia (ITP): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/779545-overview

  Immune thrombocytopenia (ITP) is a syndrome in which platelets become coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. […] In immune thrombocytopenia (ITP), an abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins, binds to circulating platelet membranes. […] Autoantibody-coated platelets induce Fc receptor-mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. […] The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets. […] Malik et al have identified cytotoxic CD8+ T cells as an antibody-independent mechanism of platelet destruction in chronic ITP. […] If bone marrow megakaryocytes cannot increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Impaired thrombopoiesis is attributed to failure of a compensatory increase in thrombopoietin and megakaryocyte apoptosis.

• #2 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  The pathogenesis of secondary ITP may share similar mechanisms with primary ITP. However, unique mechanisms have been identified in some types of secondary ITP. For example, antigen mimicry, in which antibodies directed against a foreign protein cross-react with specific epitopes on platelet glycoproteins (GPs), has been observed in thrombocytopenia associated with hepatitis C, Helicobacter pylori, and HIV infections. […] Dysregulation of T cells plays a crucial role in the pathogenesis of ITP. […] Due to a breakdown of self-tolerance, the APC process is triggered and presents platelet autoantigens to autoreactive T cells, which initiates a cascade of events including the stimulation of autoantibody production and cytotoxic T-cell (CTL) activation and proliferation, along with an abnormal number and function of regulatory T cells (Tregs), the production of abnormal Th cells, and abnormal T-cell anergy.

• #2 How we treat primary immune thrombocytopenia in adults | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01401-z

  Platelet autoantibody production involves complex interactions between macrophages/dendritic cells (DCs), T cells, and B cells. […] Defects in DCs, such as elevated surface CD86 expression, reduced indoleamine 2,3-dioxygenase (IDO) levels, and lowered numbers of plasmacytoid DCs, result in enhanced stimulation of autoreactive T cells and impaired induction of regulatory T cells (Tregs) in ITP. […] Dysregulated CD4+ T cell responses, including the broadly accepted dogma of excessive polarization toward the proinflammatory Th1, Th17, and Th22 lineages, resistance to activation-induced cell death (AICD), and oligoclonal expansion of GP-specific T cells, are involved in the development of ITP. […] Follicular Th (Tfh) cell numbers are also increased in the periphery, spleen, and bone marrow of ITP patients, suggesting that their B cell help activity is upregulated.

• #2 Immune Thrombocytopenia: Pathogenesis and Treatment Approaches

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Hematology-and-Transfusion/Immune-Thrombocytopenia%3A-Pathogenesis-and-Treatment-Approaches-1547

  Decreased platelet production: In patients with ITP, platelet production may not be sufficient to replace the platelets that are destroyed. Since megakaryocytes and platelets share common surface antigens, most anti-platelet antibodies may also target megakaryocytes. Thus, decreased platelet production may be a secondary result of the factors leading to increased platelet destruction, which were discussed above. Other potential causes of decreased platelet production include impaired function of megakaryocytes, altered megakaryocyte morphology, or abnormal T-cell response in the bone marrow microenvironment. In addition, insufficient TPO levels are considered to be involved in pathogenesis of ITP because increased serum TPO, a typical compensatory response to thrombocytopenia, is not observed in ITP. […] Pathogenesis of ITP involves 2 major mechanisms: increased platelet destruction and decreased platelet production. The varying levels of contribution of these processes to ITP pathology in patients may be responsible for the heterogeneity of responses to different treatment strategies.

• #2

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  Similarly to most of autoimmune diseases, an imbalance between the proinflammatory and the anti-inflammatory responses is present during ITP, with a skewing of T cells to helper T cell (Th) polarizations, associated with a quantitative or functional deficiency of regulatory T cells (Treg). […] Combined to the peripheral destruction of platelets, there is an inappropriate production in ITP resulting from both an immune response against megakaryocytes but also to inadequate level of TPO. […] As megakaryocytes express different GP recognized by antiplatelet antibodies, they are exposed to the humoral immune response that diminishes their number and maturation, and to the CTL cytotoxicity that disrupts physiological apoptotic mechanisms involved in platelet formation. […] During ITP, the inappropriate levels of TPO are linked to its physiological regulation.

• #2 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  The degree of Treg abnormalities is associated with disease severity. […] Impaired thrombopoiesis with an insufficient production of platelets is the result of an abnormal immune response against megakaryocytes (MKs), which is associated with a low TPO concentration. […] In ITP, since MKs express the same GP as platelets, they are clearly targeted by antiplatelet antibodies that bind to GPIb and GPIIb/IIIa, as well as by CTLs, which induces morphological and physiological changes or even apoptosis. […] Platelet production is correlated with the serum levels of TPO, a major megakaryocyte growth factor.

• #2 Immune Thrombocytopenia (ITP): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/202158-overview

  Immune thrombocytopenia (ITP) is a syndrome in which platelets become coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. […] Autoantibody-coated platelets induce Fc receptor-mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. […] The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets. […] Malik et al have identified cytotoxic CD8+ T cells as an antibody-independent mechanism of platelet destruction in chronic ITP. These researchers demonstrated that adults with chronic ITP have clonal expansion of terminally differentiated effector memory CD8+ T cells (TEMRA), compared with age-matched controls. TEMRAs form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the T-cell receptormediated release of cytotoxic granules. […] If bone marrow megakaryocytes cannot increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Impaired thrombopoiesis is attributed to failure of a compensatory increase in thrombopoietin and megakaryocyte apoptosis.

• #2 Immune Thrombocytopenia: Immune Dysregulation and Genetic Perturbations Deciphering the Fate of Platelets

  https://www.imrpress.com/journal/FBL/29/10/10.31083/j.fbl2910342/htm

  Mutations have been found in T cells related genes which induce signaling cascades against platelets. T-1993C mutation of T cell specific TBX21 gene has been found in the pathophysiology of ITP. […] The association of cytokine and chemokine encoding genes has been demonstrated in various studies on ITP patients. These genes play important roles such as stimulation of megakaryocytopoiesis, regulation of platelet production, and generation of autoantibodies. Polymorphisms in IL-1B-31, IL-1Ra, IL-4, IL-10, IL-17F, IL-23R, TNF-α, TNF-β, TGF-B1, TNIP1, IFN-G, MBL, and GPIA are found in ITP pathogenesis.

• #2 Investigation of the correlation between immune thrombocytopenia and T cell activity-regulated gene polymorphism using functional study | Scientific Reports

  https://www.nature.com/articles/s41598-022-10631-z

  According to our results, we surmised that CTLA4 is involved in the pathogenesis of ITP, and the secondary ITP result from the lower CTLA4 expression that leads to T cell over-activation. […] The promotion or inhibition of T cell activation is determined by the balance of CD28 and CTLA4 signals. In addition, the SNPs located in the promoter region might affect the gene expression, and they would influence the level of protein expression and lead to the pathogenesis of disease. […] Our result indicated that only CTLA4 was associated with ITP but not CD28. It may be explained that CTLA4 has a higher affinity to its ligand (B7) than CD28. Additionally, CTLA4 could have the ability to inhibit T-cell activation without binding B7. […] In conclusion, the present study indicated that CTLA4 gene polymorphism was related to the susceptibility of ITP but not CD28. Helper T cells are majorly regulated by CTLA4, which is involved in the mechanism of ITP, while CD28 is involved in cytotoxic T cell regulation.

• #2 A novel approach to immune thrombocytopenia intervention: modulating intestinal homeostasis | BMC Immunology | Full Text

  https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00660-w

  According to high-throughput sequencing research of fecal samples from ITP patients and healthy volunteers, there are notable differences in the makeup and diversity of the gut microbiota in ITP patients. Specifically, when comparing ITP patients to healthy controls, Bacteroides were increased, and Thick Walled Bacteroides were decreased. Moreover, the Thick Walled Bacteroides to Actinobacteria ratio was markedly reduced in ITP patients. Additionally, they observed a direct association between Thick Walled Bacteroides abundance and platelet counts, whereas an inverse relation was seen between Bacteroides abundance and platelet counts. All of these results pointed to a potential link between platelet counts and changed gut flora in ITP patients. […] A study conducted in 1998 discovered that platelet counts in patients with ITP increased following the eradication therapy for HP, leading to the suspicion that HP may have generated secondary ITP. HP triggers the activation of B lymphocyte clones, leading to the production of autoantibodies that target platelets.

• #2 How we treat primary immune thrombocytopenia in adults | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01401-z

  The hypothesized pathophysiology of ITP is summarized in Fig. 1. Of note, the above-mentioned pathological mechanisms may play varying roles in different patients due to the heterogeneity of the disease. Identifying which mechanism is dominant in each case is critical for the implementation of pathogenesis-oriented individualized treatment.

• #3 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  Immune thrombocytopenia is an autoimmune disease with a very complex pathogenesis. Primary ITP arises from several different mechanisms, such as the peripheral destruction of platelets opsonized by antiplatelet antibodies, impaired thrombopoiesis, and the T-cell-mediated destruction of platelets; each pathogenic mechanism plays an independent role in generating thrombocytopenia. […] Peripheral destruction of platelets occurs in the blood, spleen, and liver and, together with impaired bone marrow production, results in an autoimmune response against megakaryocytes and peripheral thrombocytopenia. […] Persistence of this autoimmune response is favored by a loss of tolerance, which is supported by a deficiency of regulatory T cells (Tregs) in the spleen, blood, and bone marrow, with defects in the B and T cells, leading to both pathological autoantibody formation and abnormal T-cell responses.

• #3 Immune thrombocytopenic purpura – Wikipedia

  https://en.wikipedia.org/wiki/Immune_thrombocytopenic_purpura

  Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is an autoimmune primary disorder of hemostasis characterized by a low platelet count in the absence of other causes. […] Nevertheless, the pathogenesis of ITP is similar in both syndromes involving antibodies against various platelet surface antigens such as glycoproteins. […] In approximately 60 percent of cases, antibodies against platelets can be detected. […] The coating of platelets with IgG renders them susceptible to opsonization and phagocytosis by splenic macrophages, as well by Kupffer cells in the liver. […] Recent research now indicates that impaired production of the glycoprotein hormone, thrombopoietin, which is the stimulant for platelet production, may be a contributing factor to the reduction in circulating platelets. […] The stimulus for auto-antibody production in ITP is probably abnormal T cell activity. […] Preliminary findings suggest that these T cells can be influenced by medications that target B cells, such as rituximab.

• #3 Immune Thrombocytopenia (ITP): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/779545-overview

  Immune thrombocytopenia (ITP) is a syndrome in which platelets become coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. […] In immune thrombocytopenia (ITP), an abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins, binds to circulating platelet membranes. […] Autoantibody-coated platelets induce Fc receptor-mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. […] The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets. […] Malik et al have identified cytotoxic CD8+ T cells as an antibody-independent mechanism of platelet destruction in chronic ITP. […] If bone marrow megakaryocytes cannot increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Impaired thrombopoiesis is attributed to failure of a compensatory increase in thrombopoietin and megakaryocyte apoptosis.

• #3

  https://link.springer.com/article/10.1007/s44337-024-00040-8

  This may be related to abnormal cytokine secretion, abnormal expression of chemokines, and cytotoxic effects. […] Apoptosis is the most common form of programmed cell death (PCD) in physiology. […] Both megakaryocytes and platelets contain functional pathways for PCD, and genetic or induced (e.g., by autoantibodies) dysregulation of these PCD pathways may lead to thrombocytopenia or inefficient platelet production in ITP. […] This can lead to prolonged lifespan of T- and B-lymphocytes, increased IFN- secretion, decreased platelet counts, and ultimately accelerated ITP progression.

• #3 Pathophysiology, Clinical Manifestations and Diagnosis of Immune Thrombocytopenia: Contextualization from a Historical Perspective

  https://www.mdpi.com/2038-8330/16/2/21

  The current and prevailing model of platelet clearance in ITP postulates that the platelet target of autoantibodies determines the pathway of clearance. […] The pathogenesis of the disease remains unknown, because it most likely involves both genetic and acquired factors. […] In ITP, immunoglobulin G-type autoantibodies are generally the most frequent (IgA and IgM are less frequent). […] The cytokine, BAFF (B cell activating factor), is increased, which stimulates autoreactive B cells, thus boosting antiplatelet antibody production. […] The process by which the binding of anti-GPIb antibodies induces platelet desialylation seems to be caused by platelet basal activation, followed by degranulation and translocation of neuraminidase to the membrane, which removes the sialic groups from glycoproteins.

• #3 How we treat primary immune thrombocytopenia in adults | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01401-z

  By contrast, circulating and splenic Tregs in ITP are found to be numerically decreased and functionally impaired, contributing greatly to the perpetuation of ITP. […] Approximately 20–40% of ITP patients do not have detectable anti-GP autoantibodies, suggesting alternative mechanisms of platelet destruction. […] Many studies have demonstrated that CD8+ cytotoxic T lymphocytes (CTLs) from peripheral blood or spleen of ITP patients can directly lyse platelets or induce platelet apoptosis through granzyme B and perforin, although the target platelet MHC class I peptides recognized by CD8+ T cells have not yet been identified. […] Desialylation-mediated platelet phagocytosis through hepatocyte Ashwell–Morell receptors in the liver is another mechanism of FcγR-independent platelet eradication in ITP.

• #3 A novel approach to immune thrombocytopenia intervention: modulating intestinal homeostasis | BMC Immunology | Full Text

  https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00660-w

  Patients with immune ITP who are also afflicted with Helicobacter pylori (HP) infection encounter many abnormalities in their immune system. Specifically, there is a decrease in the number of CD4+ cells and CD4+/CD8+ cells while the number of CD8+ cells increases. The synthesis of anti-platelet antibodies has also significantly increased. […] Treg cells are a subpopulation of T lymphocytes. ITP sufferers often have substantially reduced peripheral blood CD4+CD25+ T regulatory cells. Furthermore, compared to uninfected people, HP-infected patients have higher numbers of CD4+CD25+ T cells in their stomach and duodenum mucosa. These Treg cells exacerbate the infection by inhibiting the gastric mucosal immune response to HP. […] Th1 cells release IL-2, IFN-, and TNF-, which accelerate inflammatory mediators production like NO. ITP sufferers often exhibit enhanced Th1 cell population, suggesting a potential link to inflammatory responses.

• #3 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  The degree of Treg abnormalities is associated with disease severity. […] Impaired thrombopoiesis with an insufficient production of platelets is the result of an abnormal immune response against megakaryocytes (MKs), which is associated with a low TPO concentration. […] In ITP, since MKs express the same GP as platelets, they are clearly targeted by antiplatelet antibodies that bind to GPIb and GPIIb/IIIa, as well as by CTLs, which induces morphological and physiological changes or even apoptosis. […] Platelet production is correlated with the serum levels of TPO, a major megakaryocyte growth factor.

• #3 Immune Thrombocytopenia | Disease Education | Amgen Oncology

  https://www.amgenoncology.com/immune-thrombocytopenia.html

  ITP is a complex and heterogeneous disease triggered by immune system dysregulation, resulting in increased platelet destruction and impaired platelet production. […] Loss of regulation (decrease Treg, increase Th1/Th2 ratio) leads to an unchecked immune response and results in production of antiplatelet autoantibodies. […] Autoantibodies bind to healthy platelets, resulting in their sequestration and destruction by macrophages in the spleen. […] Autoantibodies target specific antigens expressed by megakaryocytes and progenitors, resulting in decreased maturation and impaired platelet production. […] Autoreactive cytotoxic T cells damage megakaryocytes and progenitor cells, and directly lyse healthy platelets. […] Due to the loss of platelet-bound TPO, patients with ITP have functional TPO deficiency, with insufficient levels to overcome immune destruction of platelets.

• #3 Investigation of the correlation between immune thrombocytopenia and T cell activity-regulated gene polymorphism using functional study | Scientific Reports

  https://www.nature.com/articles/s41598-022-10631-z

  According to our results, we surmised that CTLA4 is involved in the pathogenesis of ITP, and the secondary ITP result from the lower CTLA4 expression that leads to T cell over-activation. […] The promotion or inhibition of T cell activation is determined by the balance of CD28 and CTLA4 signals. In addition, the SNPs located in the promoter region might affect the gene expression, and they would influence the level of protein expression and lead to the pathogenesis of disease. […] Our result indicated that only CTLA4 was associated with ITP but not CD28. It may be explained that CTLA4 has a higher affinity to its ligand (B7) than CD28. Additionally, CTLA4 could have the ability to inhibit T-cell activation without binding B7. […] In conclusion, the present study indicated that CTLA4 gene polymorphism was related to the susceptibility of ITP but not CD28. Helper T cells are majorly regulated by CTLA4, which is involved in the mechanism of ITP, while CD28 is involved in cytotoxic T cell regulation.

• #3 Pediatric immune thrombocytopenia (ITP) treatment – Kim – Annals of Blood

  https://aob.amegroups.org/article/view/6316/html

  The genetic and molecular understanding of ITP pathogenesis is expanding. Increasingly, patients thought to have primary ITP without a typical response to therapies or an unexpected disease course, are found to carry novel genetic alterations resulting in loss of immune tolerance. […] Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is constitutively expressed on regulatory T cells and inhibits T cell activation. LPS-responsive beige-like receptor anchor protein (LRBA) is thought to be a regulator of CTLA-4 function. Impacting the same molecular signaling pathway, both CTLA-4 haploinsufficiency and LRBA deficiency lead to abnormal activation and proliferation of T cells resulting in loss of immune tolerance. […] Gain-of-function mutations in PI3K lead to activation of the mTOR pathway and, though Akt phosphorylation, may promote effector T cell development. […] Excess STAT1 signaling results in skewed Th17 differentiation and hyperresponsiveness to IFN-. […] Overall, the TPO-RAs are well tolerated by pediatric patients and shown to be safe in clinical trials.

• #3 Immune Thrombocytopenia (ITP) – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/thrombocytopenia-and-platelet-dysfunction/immune-thrombocytopenia-itp

  Immune thrombocytopenia usually results from development of an autoantibody directed against a structural platelet antigen. These antiplatelet antibodies lead to increased platelet destruction, usually in the spleen, and inhibition of platelet production and release from megakaryocytes. […] In childhood ITP, the autoantibody may be triggered by viral antigens. The trigger in adults is unknown, although in some countries (eg, Japan, Italy), ITP has been associated with Helicobacter pylori infection, and treatment of the infection has been followed by remission of the ITP. […] In immune thrombocytopenia (ITP), the immune system destroys platelets in the circulation and at the same time may attack bone marrow megakaryocytes, thereby reducing platelet production.

• #3 How we treat primary immune thrombocytopenia in adults | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01401-z

  The hypothesized pathophysiology of ITP is summarized in Fig. 1. Of note, the above-mentioned pathological mechanisms may play varying roles in different patients due to the heterogeneity of the disease. Identifying which mechanism is dominant in each case is critical for the implementation of pathogenesis-oriented individualized treatment.

• #4 Pathophysiology, Clinical Manifestations and Diagnosis of Immune Thrombocytopenia: Contextualization from a Historical Perspective

  https://www.mdpi.com/2038-8330/16/2/21

  Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated decrease in the platelet count and an increased risk of bleeding. The pathogenesis is complex, affecting multiple components of the immune system and causing both peripheral destruction of platelets and impaired central megakaryopoiesis and platelet production in the bone marrow. […] The immune-mediated destruction of platelets was demonstrated thanks to the experiment carried out by William J. Harrington and colleagues. […] In 1965, Shulman et al. observed that the humoral factor causing thrombocytopenia was Immunoglobulin G (IgG). […] In 1982, Van Leeuwen et al. found that antibodies from patients with ITP bound to normal platelets, but not to platelets from patients with Glanzmann’s thrombasthenia; thus, he speculated that patients with ITP produced autoantibodies against platelet glycoprotein (GP) IIb or GPIIIa since patients with thrombasthenia lack either of these proteins.

• #4

  https://link.springer.com/article/10.1007/s44337-024-00008-8

  Antibody-coated platelets bind tissue macrophages through Fc receptors, leading to their clearance primarily in the spleen and to a lesser extent in the liver. […] Furthermore, antiplatelet antibodies might not only bind but also activate the classical complement pathway, causing their lysis by assembling the membrane attack complex. […] A study in 2015 showed that platelet clearance has another Fc-independent pathway via hepatocyte Ashwell-Morell receptors (AMR). […] Dendritic cells from ITP patients exhibit a higher ability to induce CD4+CD25-T lymphocyte proliferation while reducing the induction of Tregs. […] Decrease regulatory T cell activity, which normally inhibits autoimmune response, was first demonstrated by Liu in 2007. […] Stimulation of T cells can result in IL-2 secretion, thus resulting in autoreactive B cell differentiation and antibody secretion.

• #4 A novel approach to immune thrombocytopenia intervention: modulating intestinal homeostasis | BMC Immunology | Full Text

  https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00660-w

  Th17 cells are responsible for secreting IL-17, IL-21, IL-22, TNF-, and IL-6. These immune cells fight off bacterial infections outside of cells quite effectively. Unfortunately, there is a clear correlation between the development of severe autoimmune diseases and increased Th17 cell activity. […] Th17 and Treg cells have opposing roles in the inflammatory microenvironment. Tregs can transform into Th17 cells, which are detrimental to the immune microenvironment. ITP patients who also suffer from gastrointestinal infections encounter an imbalance in the Th17 to Treg cells ratio. This imbalance results from both a significant drop in the Treg cell number and an elevation of the Th17 cell population. Therefore, deviations from the Th17/Treg cell ratio could play a role in the development of ITP.

• #4

  https://link.springer.com/article/10.1007/s44337-024-00008-8

  Potential mechanisms were provided by later studies in 2003 suggesting that autoantibodies against platelet surface glycoproteins might interfere with the maturation of megakaryocytes and suppress megakaryocyte production. […] TPO was proposed and named by Kelemen in 1958. […] The timeline of treatment development can be seen in Fig. 1. […] The mechanism involves inhibiting Syk activation in splenic macrophages. […] The mechanisms involve blocking FcRn, preventing IgG1 recycling, and causing targeted IgG degradation.

• #4 The treatment of immune thrombocytopenia (ITP)—focus on thrombopoietin receptor agonists – Kuter – Annals of Blood

  https://aob.amegroups.org/article/view/6335/html

  Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction along with reduced platelet production. […] Whether TPO-RA affect the ITP pathophysiology and directly cause remission remains unclear. […] The pathophysiology of ITP has undergone much investigation in recent decades and is a disease of both increased platelet destruction as well as a disease of inappropriately low platelet production. […] Indeed, modern methods detected antiplatelet antibody on the surface of 280 (69%) of 360 ITP patient platelet samples. […] Other studies have shown that platelet production is inhibited to various degrees in patients with ITP. […] T cells may play a role directly in attacking platelets or megakaryocytes and alterations in T regulatory lymphocytes may also open a window for loss of immune tolerance. […] Megakaryocytes in the bone marrow have been shown to undergo apoptosis.

• #4

  https://journals.lww.com/md-journal/fulltext/2024/01190/recent_advances_in_the_management_of_immune.42.aspx

  Regarding the role of B cells in the development of ITP, immunoglobulin (IgG) antibodies that interact with platelets are the main causes of ITP. These antibodies bind to platelets, effectively marking them as phagocytic cells in the liver and spleen that remove them. This mechanism is known as antibody-mediated platelet destruction. […] The spleen is an immune organ that participates in platelet destruction. Autoantibody-coated platelets are sequestered and destroyed in the spleen. Additionally, spleen may be a site of autoantibody production and T cell activation. Complex interactions between platelets, immunological cells, and the spleen are crucial for the emergence of ITP. […] Current research is focused on developing therapies that target the connections between the spleen, platelets, and immune cells in ITP patients.

• #4 Immune Thrombocytopenia: Immune Dysregulation and Genetic Perturbations Deciphering the Fate of Platelets

  https://www.imrpress.com/journal/FBL/29/10/10.31083/j.fbl2910342/htm

  Mutations have been found in T cells related genes which induce signaling cascades against platelets. T-1993C mutation of T cell specific TBX21 gene has been found in the pathophysiology of ITP. […] The association of cytokine and chemokine encoding genes has been demonstrated in various studies on ITP patients. These genes play important roles such as stimulation of megakaryocytopoiesis, regulation of platelet production, and generation of autoantibodies. Polymorphisms in IL-1B-31, IL-1Ra, IL-4, IL-10, IL-17F, IL-23R, TNF-α, TNF-β, TGF-B1, TNIP1, IFN-G, MBL, and GPIA are found in ITP pathogenesis.

• #5

  https://link.springer.com/article/10.1007/s44337-024-00008-8

  Immune thrombocytopenia (ITP) is a hematologic disorder characterized by a low platelet count, leading to an increased risk of bleeding. […] the groundwork for understanding the immune-mediated platelet destruction intrinsic to ITP. […] Ongoing research continues to unravel the genetic and molecular underpinnings of ITP, offering insights into disease mechanisms and potential therapeutic targets. […] By elucidating the complex interplay between immune dysregulation and platelet destruction, this knowledge serves as a foundation for advancing the diagnosis, management, and future therapeutic innovations in ITP. […] There are several different pathophysiologic mechanisms, mainly centre on peripheral clearance. […] Our understanding of the targets of these antibodies began to form in 1982, with a study showing that the antibodies failed to bind platelets from Glanzmann thrombasthenia patients (who lack GPIIb/IIIa).

• #5 How we treat primary immune thrombocytopenia in adults | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01401-z

  By contrast, circulating and splenic Tregs in ITP are found to be numerically decreased and functionally impaired, contributing greatly to the perpetuation of ITP. […] Approximately 20–40% of ITP patients do not have detectable anti-GP autoantibodies, suggesting alternative mechanisms of platelet destruction. […] Many studies have demonstrated that CD8+ cytotoxic T lymphocytes (CTLs) from peripheral blood or spleen of ITP patients can directly lyse platelets or induce platelet apoptosis through granzyme B and perforin, although the target platelet MHC class I peptides recognized by CD8+ T cells have not yet been identified. […] Desialylation-mediated platelet phagocytosis through hepatocyte Ashwell–Morell receptors in the liver is another mechanism of FcγR-independent platelet eradication in ITP.

• #5 How we treat primary immune thrombocytopenia in adults | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01401-z

  Platelet autoantibody production involves complex interactions between macrophages/dendritic cells (DCs), T cells, and B cells. […] Defects in DCs, such as elevated surface CD86 expression, reduced indoleamine 2,3-dioxygenase (IDO) levels, and lowered numbers of plasmacytoid DCs, result in enhanced stimulation of autoreactive T cells and impaired induction of regulatory T cells (Tregs) in ITP. […] Dysregulated CD4+ T cell responses, including the broadly accepted dogma of excessive polarization toward the proinflammatory Th1, Th17, and Th22 lineages, resistance to activation-induced cell death (AICD), and oligoclonal expansion of GP-specific T cells, are involved in the development of ITP. […] Follicular Th (Tfh) cell numbers are also increased in the periphery, spleen, and bone marrow of ITP patients, suggesting that their B cell help activity is upregulated.

• #6

  https://omim.org/entry/188030

  Immune thrombocytopenic purpura is characterized by a low platelet count, normal bone marrow, and the absence of other causes of thrombocytopenia. It is principally a disorder of increased platelet destruction mediated by autoantibodies to platelet-membrane antigens (George et al., 1994). […] Harrington et al. (1951) observed a child with purpura born to a mother with chronic idiopathic thrombocytopenic purpura. The child’s purpura resolved spontaneously within 3 weeks while the mother remained thrombocytopenic. Harrington argued that transfer of a humoral antiplatelet factor from the mother to her baby occurred. He then administered plasma from patients with chronic AITP to himself and to 9 volunteers with a normal platelet count. Eight of the recipients immediately developed transient thrombocytopenia and some of them purpura as well. One of the volunteers, in spite of an earlier splenectomy, also responded with thrombocytopenia, indicating a secondary role of the spleen. Imbach et al. (2002) stated that Harrington’s experiment clearly suggested an antiplatelet factor in the plasma as the cause of AITP. They also noted that evidence for the role of autoantibodies in chronic AITP was first reported by van Leeuwen et al. (1982).

• #6

  https://link.springer.com/article/10.1007/s44337-024-00040-8

  However, as the understanding of the pathogenesis of ITP has gradually increased, it has been found that humoral immunity can no longer fully explain the pathogenesis of ITP. […] More and more studies have shown that not only humoral immunity abnormalities but also cellular immunity abnormalities exist in the pathogenesis of ITP. […] In addition, with the rapid development in the field of pathophysiology, it is gradually revealed that apoptosis and epigenetics are also important parts of the pathogenesis of ITP. […] These studies suggest the presence of pathogenic B cells and abnormal levels of cytokines in ITP patients, leading to the production of platelet antibodies. […] All this evidence has confirmed that T-cell immunity is crucial for ITP. […] The cellular mechanism behind the pathophysiology of ITP consists of aberrant T-cell subsets, such as lower Tregs and an imbalance of Th17, Th2, and Th1 and cytotoxic CD8+T cells.

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