Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response

Panitsas, Fotios; Θεοδωροπούλου, Μαρία; Kouraklis, Alexandra; Καρακάντζα, Μαρίνα; Θεοδώρου, Γεώργιος; Zoumbos, Nicholas; Maniatis, Alice; Mouzaki, Αthanasia

doi:10.1182/blood-2003-07-2268

Cited by 224 publications

(180 citation statements)

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“…Other studies have also shown the presence of cytotoxic T cells against autologous thrombocytes. In addition, an imbalanced Th1/Th2 ratio, increase of oliclonal T cells, Th17 cells and IL17 levels are the other evidence for T-cell mediated mechanisms (20)(21)(22)(23). A reduction in the numbers and impairment of the functions of regulatory T cells were also demonstrated (24,25).…”

Section: Discussionmentioning

confidence: 91%

Seasonal Association of Immune Thrombocytopenia in Adults

Tombak¹,

Boztepe²,

Tiftik³

et al. 2015

Balkan Med J

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Background:Immune thrombocytopenia (ITP) is an autoimmune disorder. It is characterized by thrombocytopenia due to thrombocyte destruction mediated by autoantibodies; however, cytotoxic and defective regulatory T-lymphocytes play an important role in its pathogenesis. While childhood ITP is usually acute, self-limiting and generally seasonal in nature, ITP in adults is usually chronic; its relation with seasons has not been studied. Aims: We investigated whether months and/or seasons have triggering roles in adults with ITP. Study Design: Descriptive study. Methods: A retrospective case review of adult patients with primary ITP diagnosed at various University Hospitals in cities where Mediterranean climate is seen was performed. Demographic data, date of referral and treatments were recorded. Corticosteroid-resistant, chronic and refractory cases were determined. Relation between sex, corticosteroid-resistant, chronic and refractory ITP with the seasons was also investigated. Results: The study included 165 patients (124 female, mean age=42.8±16.6). Most cases of primary ITP were diagnosed in the spring (p=0.015). Rates of patients diagnosed according to the seasons were as follows: 35.8% in spring, 23% in summer, 20.6% in fall, and 20.6% in winter. With respect to months, the majority of cases occurred in May (18.2%). Time of diagnosis according to the seasons did not differ between genders (p=0.699). First-line treatment was corticosteroids in 97.3%, but 35% of the cases were corticosteroid-resistant. Steroid-resistant patients were mostly diagnosed in the spring (52.1%) (p=0.001). ITP was chronic in 52.7% of the patients and they were also diagnosed mostly in the spring (62.7%) (p=0.149). Conclusion: This is the first study showing seasonal association of ITP in adults and we have observed that ITP in adults is mostly diagnosed in the spring. The reason why more patients are diagnosed in the spring may be due to the existence of atmospheric pollens reaching maximum levels in the spring in places where a Mediterranean climate is seen.

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Section: Discussionmentioning

confidence: 91%

Seasonal Association of Immune Thrombocytopenia in Adults

Tombak¹,

Boztepe²,

Tiftik³

et al. 2015

Balkan Med J

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“…Although at 48 h a trend was observed in response to AngII treatment toward higher IFN-␥ and lower IL-4 production, the difference between AngII treatment and PHA stimulation alone did not reach statistical significance, which could be due to considerable donor variability. We therefore calculated the IFN-␥:IL-4 ( Figure 2C) for each donor for these two groups as has been done previously (18,19), which demonstrates a significant although modest shift toward greater IFN-␥ production and lesser IL-4 production in response to AngII treatment at 48 h as compared with PHA alone. Of note, the ratio of IFN-␥:IL-4 is thought to be more important in bringing about changes in cytokine signaling, as Th1 and Th2 cytokines are mutually inhibitory (18,19).…”

Section: Angii Treatment Increases the Ratio Of Ifn-␥:il-4 But Not Thmentioning

confidence: 99%

“…We therefore calculated the IFN-␥:IL-4 ( Figure 2C) for each donor for these two groups as has been done previously (18,19), which demonstrates a significant although modest shift toward greater IFN-␥ production and lesser IL-4 production in response to AngII treatment at 48 h as compared with PHA alone. Of note, the ratio of IFN-␥:IL-4 is thought to be more important in bringing about changes in cytokine signaling, as Th1 and Th2 cytokines are mutually inhibitory (18,19). The induction of the inflammatory chemokines CCL2/monocyte chemoattractant protein-1 (MCP-1) and CCL5/RANTES by AngII was also assessed.…”

Section: Angii Treatment Increases the Ratio Of Ifn-␥:il-4 But Not Thmentioning

confidence: 99%

Human T and Natural Killer Cells Possess a Functional Renin-Angiotensin System

Jurewicz¹,

McDermott²,

Sechler³

et al. 2007

Journal of the American Society of Nephrology

199

184

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The renin-angiotensin system (RAS) plays an important role in the regulation of inflammation and in the progression of chronic kidney disease. Accumulation of inflammatory cells into the renal parenchyma has been a hallmark of chronic kidney disease; however, little is known concerning the presence and the function of RAS elements in T and natural killer (NK) cells. Here is reported a co-stimulatory effect of angiotensin II (AngII) by showing an augmentation of mitogen and anti-CD3-stimulated T and NK cell proliferation with AngII treatment. Angiotensinogen and AngI also generated the same effect, suggesting that NK and T cells have functional renin and angiotensin-converting enzyme activity. Indeed, they express renin, the renin receptor, angiotensinogen, and angiotensin-converting enzyme by mRNA analysis. Flow cytometric analysis and Western blot revealed angiotensin receptor 2 (AT 2 ) expression in T and NK cells, whereas AT 1 expression was found in T and NK cells and monocytes by Western blot. These receptors were shown to be functional in calcium signaling, chemotaxis, and proliferation. However, AT 1 and AT 2 antagonists alone or in combination were unable to abrogate completely the effects of AngII, suggesting that another AngII receptor may also be functional in leukocytes. This is the first study to show that T and NK cells are fully equipped with RAS elements and are potentially capable of producing and delivering AngII to sites of inflammation. Because their chemotaxis is enhanced by AngII, this creates a potential inflammatory amplification system. B ecause of its hemodynamic effects, angiotensin II (AngII) plays a central role in the progression of chronic kidney diseases (CKD) and ischemic heart disease (1,2). AngII has been shown to be a potent proinflammatory molecule, and the beneficial effects of renin-angiotensin system (RAS) blockade are due not only to lowering BP but also to a reduction in inflammation (3). One of the main features of CKD is the accumulation of inflammatory cells, which plays a crucial role in disease progression (4), and recruitment of macrophages to the kidney through AngII infusion has been reported in various rodent models (5,6). In both diabetic nephropathy and atherosclerosis, monocytes/macrophages have been reported to play a key role (7-9). Monocytes have also been the primary focus of studies that have examined the interaction of AngII and inflammatory cells (10). However, the importance of T, natural killer (NK), and dendritic cells (DC) in inflammation and vascular disease has only recently begun to be appreciated. DC have been shown to present oxidized LDL to T cells, generating autoreactive T cells and promoting arterial injury (11). NK cells participate through the production of proatherogenic cytokines such as IFN-␥ (12). Previous studies on AngII-induced inflammation and its role in kidney disease primarily focused on the induction of inflammatory molecules and the paracrine effects of AngII in vascular remodeling and tissue fibrosis (13,14). Despite these ...

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“…3 Several studies have previously provided evidence supporting a type-1 cytokine polarization and a high Th1/Th2 ratio in the immune response in ITP. 4,5 However, the paradigm of Th1/Th2 in the pathogenesis of ITP has been challenged by the identification of Th17 cells and T regulatory (Treg) cells, two novel CD4 þ T subsets that are distinct from Th1 and Th2 cells.…”

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confidence: 99%

Inactivation of Notch signaling reverses the Th17/Treg imbalance in cells from patients with immune thrombocytopenia

Liu

et al. 2015

Laboratory Investigation

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T helper 17 (Th17) cells and regulatory T (Treg) cells, along with Th1 and Th2 cells, may contribute to the development of immune thrombocytopenia (ITP). The imbalance of Th17/Treg toward Th17 cells has been shown to play a pivotal role in the peripheral immune response. Notch signaling has been implicated in peripheral T-cell activation and effector cell differentiation. However, the role of Th17/Treg in the pathogenesis of ITP and the effect of Notch signaling on Th17/Treg imbalances remain largely elusive in ITP. In vitro, we treated peripheral blood mononuclear cells (PBMCs) from ITP and healthy controls with g-secretase inhibitor (DAPT). Th17 cells and Treg cells were measured by flow cytometry and IL-17, IL-21, and IL-10 secretion by enzyme immunoassay technique. The mRNA expression of Ntoch1, Hes1, Hey1, RORgt, and Foxp3 was investigated by RT-PCR. Cell proliferation and apoptosis were determined by the Cell Counting Kit-8 and apoptosis detection kit. We demonstrated that DAPT was effective in inhibiting mRNA expression of Notch signaling molecules. In untreated cultured PBMCs from ITP patients, we observed elevated Th17 cell and IL-21 levels and RORgt mRNA expression, decreased Treg cells and Foxp3 mRNA expression, and an increased ratio of Th17/Treg and RORgt/Foxp3. After inactivating Notch signal by DAPT, Th17 cells and Th17/Treg ratio were dose dependently decreased and accompanied by the reduction of IL-17 in culture supernatants and RORgt mRNA expression in ITP patients. However, no significant difference was found for Treg cells and Foxp3 mRNA expression, RORgt/Foxp3 ratio, and IL-21 and IL-10 levels after DAPT treatment in ITP patients. We also present evidence that the effect of DAPT inhibition on the Th17 cell response was associated with downregulation of RORgt and IL-17 transcription using human in vitro polarization. In conclusion, our findings highlight the importance of Notch signaling in Th17/Treg imbalances in ITP. Inactivation of Notch signaling might be a potential immunoregulatory strategy in ITP patients.

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Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response

Cited by 224 publications

References 28 publications

Seasonal Association of Immune Thrombocytopenia in Adults

Seasonal Association of Immune Thrombocytopenia in Adults

Human T and Natural Killer Cells Possess a Functional Renin-Angiotensin System

Inactivation of Notch signaling reverses the Th17/Treg imbalance in cells from patients with immune thrombocytopenia

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