Objective:To explore the effect of low-dose rituximab in primary immune thrombocytopenia.Methods:From January 2022 to January 2023,60 patients with primary immune thrombocytopenia were randomly divided into two groups...Objective:To explore the effect of low-dose rituximab in primary immune thrombocytopenia.Methods:From January 2022 to January 2023,60 patients with primary immune thrombocytopenia were randomly divided into two groups.The control group was treated with standard doses of rituximab,and the observation group was treated with low doses of rituximab.Rituximab was used for treatment,and the clinical curative effect of the two groups was observed.Results:Before treatment,there was no statistically significant difference in platelet count(PLT),anti-GPⅡb/Ⅲa antibody,and anti-GPⅠb/Ⅸantibody between the two groups(P>0.05).After treatment,the PLT of the two groups increased significantly.Antibodies were all decreased,and there was no significant difference between the two groups(P>0.05).The incidence of adverse reactions in the observation group was 13.33%,and that in the control group was 40.00%.The adverse reactions in the observation group were significantly lower than the control group(P<0.05).Conclusion:In the clinical treatment of primary immune thrombocytopenia,low-dose rituximab can control the progression of the disease,improve blood routine indicators,and have fewer adverse reactions.展开更多
Immune thrombocytopenia is an autoimmune disease resulting in the destruction of platelets.It is classified as acute,thrombocytopenia occurring for < 6 mo and usually resolving spontaneously,and chronic,lasting >...Immune thrombocytopenia is an autoimmune disease resulting in the destruction of platelets.It is classified as acute,thrombocytopenia occurring for < 6 mo and usually resolving spontaneously,and chronic,lasting >6 mo and requiring therapy to improve the thrombocytopenia.The underlying defects leading to autoantibody production are unknown.Molecular mimicry appears to play a role in the development of self-reactive platelet antibodies after vaccination and certain viral infections.Platelet life span is reduced as a consequence of antibody-mediated clearance by tissue macrophages in essentially all patients.Diagnosis is based on the exclusion of the other causes of thrombocytopenia.Steroid is the first choice of the treatment,often followed by splenectomy in unresponsive cases.Intravenous immunoglobulin,anti-Rho(D) immune globulin,azathioprine,cyclosporine A,cyclophosphamide,danazol,dapsone,mycophenolate mofetil,rituximab,thrombopoietin receptor agonists and vinca alkaloids are other choices of treatment.展开更多
Immune thrombocytopenia (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies. There is growing evidence that the eradication of Helicobacter pylori (H. pylori) effectively increases platelet count i...Immune thrombocytopenia (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies. There is growing evidence that the eradication of Helicobacter pylori (H. pylori) effectively increases platelet count in a considerable proportion of ITP patients infected with this bacterium. In the majority of ITP patients responding to H. pylori eradication therapy, the anti-platelet autoantibody response is completely resolved with no relapse for more than 7 years, indicating that the disease is cured. Therefore, adult patients with suspected ITP should be examined for H. pylori infection, and eradication therapy is recommended if the infection is present. Notably, however, the efficacy of H. pylori eradication therapy in ITP patients varies widely among countries, with a higher response rate in Japan compared with the United States and European countries other than Italy. The pathogenesis of H. pylori-associated ITP is still uncertain, although the mechanisms are known to involve multiple factors. H. pylori may modulate the Fcγ-receptor balance of monocytes/macrophages in favor of activating Fcγ receptors, and H. pylori components may mimic the molecular makeup of platelet antigens. Further studies of the pathogenic process of H. pylori-associated ITP may be useful for the development of new therapeutic strategies for ITP.展开更多
Objective Through bibliometrics and visual analysis of the related studies on traditional Chinese medicine(TCM)treatment of immune thrombocytopenia(ITP),this study aims to sort out the overall research progress,hotspo...Objective Through bibliometrics and visual analysis of the related studies on traditional Chinese medicine(TCM)treatment of immune thrombocytopenia(ITP),this study aims to sort out the overall research progress,hotspots,and trends in this field,and provide reference for further research in ITP.Methods The articles on ITP treated by TCM were retrieved from China National Knowledge Infrastructure(CNKI),Wanfang Database,China Science and Technology Journal Database(VIP),Web of Science Core Collection(WOSCC),and PubMed.The retrieval time was from the establishment of the databases to July 31,2022.VOSviewer,CiteSpace,Carrot2,and Note-Express were used for data analysis of the articles in terms of their quantities,types,and journals,and for visualization of research hotspots,authors,institutions,and keywords.Results 1493 Chinese articles and 40 English articles were included.The articles in Chinese mainly focus on clinical trial research and clinical experience summary,while the English articles mainly focus on clinical trial research and animal research.The Chinese articles were published in 317 Chinese journals,while English articles were published in 29 English journals.Research hotspots include the clinical syndrome differentiation of ITP,the therapeutic effect of TCM compounds on ITP,and the mechanism of ITP treatment.Keyword analysis shows that there are many research achievements in integrated traditional Chinese and western medicine treatment,clinical research,famous doctors’experience,TCM treatment,cellular immunity,and humoral immunity.The authors with the most articles in Chinese and English are Professor CHEN Xinyi and Professor MA Rou,respectively,and the research institutions with the most articles are Dongzhimen Hospital of Beijing University of Chinese Medicine and Xiyuan Hospital of China Academy of Chinese Medical Sciences.Chinese herbs often used to treat ITP clinically include Xianhecao(Agrimoniae Herba),Nvzhenzi(Ligustri Lucidi Fructus),Mohanlian(Ecliptae Herba),Zhongjiefeng(Sarcandrae Herba),etc.,and the prescription usually used to treat ITP include Guipi Decoction(归脾汤),Xijiao Dihuang Decoction(犀角地黄汤),Bazhen Decoction(八珍汤),Erzhi Pill(二至丸),and Xiaochaihu De-coction(小柴胡汤).The main development trends toward retrospective study,TCM treatment mechanism,and data mining.展开更多
Objective: To investigate the biological basis of qi, blood and vessel in immune thrombocytopenia(ITP) patients with syndrome of qi failing to govern blood(SQFGB) based on traditional Chinese medicine.Methods: A total...Objective: To investigate the biological basis of qi, blood and vessel in immune thrombocytopenia(ITP) patients with syndrome of qi failing to govern blood(SQFGB) based on traditional Chinese medicine.Methods: A total of 52 ITP patients with SQFCB were enrolled and divided into bleeding group(38 cases) and non-bleeding group(14 cases).Bleeding group was further divided into mild qi deficiency group(25 cases) and moderate/severe qi deficiency group(13 cases) based on Chinese Medicine syndrome score.20 healthy volunteer were recruited as control group.The count of platelet(PLT) was taken as the blood related indicator.The expressions of cytokines including IL-1β, IL-17 A, TNF-α, CD40 L, and TGF-β, detected by Aim Plex Multiple Immunoassays for Flow, were taken as the qi related indicators.The expressions of VEGF-A, detected by Aim Plex Multiple Immunoassays for Flow and NO, NOS, and ET-1 detected by ELISA, were taken as the vessel related indicators.Results: As compared to the control group, the count of PLT, taken as the blood related indicator, was significantly lower in ITP group patients with SQFCB(P<0.05).The expression levels of IL-17 A and TNF-α, taken as the qi related indicators, were significantly higher, while those of CD40 L, IL-1β, and TGF-β, also taken as the qi related indicators, were significantly lower in ITP patients with SQFCB, respectively(P<0.05).The expression levels of NO and ET-1, taken as the vessel related indicators, were significantly higher, while the expression levels of NOS and VEGF-A also taken as the vessel related indicators, were significantly lower in ITP patients with SQFCB, respectively(P<0.05).The count of PLT, taken as the blood related indicator, was significantly lower in moderate/severe group than those in mild group(P<0.05).The expression levels of CD40 L and TGF-β, taken as the qi related indicators, were also significantly lower in moderate/severe group than those in mild group, respectively(P<0.05).Conclusion: The count of PLT might be the biological basis of blood.The expressions of NO, NOS, ET-1 and VEGF-A might be the biological basis of vessel.The expressions of IL-1β, IL-17 A, TNF-α, TGF-β, and CD40 L may be the biological basis of qi.The expressions of CD40 L and TGF-β could reflect the degree of qi deficiency in ITP patients based on the theory of qi and blood.展开更多
Immune thrombocytopenia (ITP) is a chronic disease resulting from increased platelet destruction and impaired platelet production. Secondary ITP can be a manifestation of chronic graft-versus-host disease (GVHD) and r...Immune thrombocytopenia (ITP) is a chronic disease resulting from increased platelet destruction and impaired platelet production. Secondary ITP can be a manifestation of chronic graft-versus-host disease (GVHD) and represent a lymphoproliferative disorder. A boy with chronic graft-versus-host disease after cord blood stem cell transplantation who had severe refractory immune-mediated thrombocytopenia received infusion of rituximab weekly, 375 mg/m2, for 4 weeks. Platelets count of the patient was recovered, and rituximab was well tolerated with no severe toxicity observed during treatment.展开更多
Immune Thrombocytopenic purpura(ITP)is a haematologicimmune-mediated disorder in which the amount of platelet in the blood decreases abnormally.Single-agent therapies for ITP have not proven successful in achieving lo...Immune Thrombocytopenic purpura(ITP)is a haematologicimmune-mediated disorder in which the amount of platelet in the blood decreases abnormally.Single-agent therapies for ITP have not proven successful in achieving long-term remission,with relapse occurring in about half of the patients(p/t).Treatment options which include Rituximab with Dexamethasone as frontline therapy,have durable response rates ranging from 58%to 76%.In this study,we have used‘Total therapy’as treatment which includes low-dose Rituximab in combination with Thrombopoietin receptor agonist(TPO-RA)(Romiplostim)and high-dose Dexamethasone.In this case series study,each patient received romiplostim(250 mcg weekly s/c,4 doses)in combination with low-dose rituximab(100 mg weekly IV,4 doses)and high-dose dexamethasone(40 mgIV on days 1-4and days 15-18).This treatment combination demonstrated rapid response rates and a low rate of side effects,making it a good alternative for individuals with ITP.展开更多
Objective: To detect the expression and significance of regulatory B cells in patients with immune thrombocytopenia. Methods: 73 ITP patients were divided into glucocorticoids treatment group (n = 42) and recombinant ...Objective: To detect the expression and significance of regulatory B cells in patients with immune thrombocytopenia. Methods: 73 ITP patients were divided into glucocorticoids treatment group (n = 42) and recombinant human thrombopoietin (rhTPO) treatment group (n = 31). According to the therapeutic effect, it was divided into effective group and ineffective group. The expression of CD19+ CD24hiCD38hi Breg in peripheral blood was detected by flow cytometry before and after treatment. The expression levels of transforming growth factor (TGF)-β1, interleukin (IL-10) and interferon (IFN)-γ were detected by ELISA before and after treatment. 30 volunteers were selected as the control group. Results: The expression of CD19+ CD24hiCD38hi Breg and cytokines IL-10 and TGF-β1 in 73 ITP patients before treatment was lower than that in the control group, while the expression of IFN-γ was higher than that in the control group (p < 0. 05). The expression levels of CD19+ CD24hiCD38hi Breg, IL-10 and TGF-β1 in the effective group were significantly higher than before treatment, while the expression of IFN-γ was significantly lower than before treatment (p < 0. 05). The expression of CD19+ CD24hiCD38hi Breg, IFN-γ, IL-10 and TGF-β1 in the invalid group had no significant change compared with before treatment. Conclusion: Abnormal expression of CD19+ CD24hiCD38hi Breg and related cytokines is involved in the pathogenesis of ITP.展开更多
To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia(ITP),this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell le...To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia(ITP),this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight(CyTOF).Thirtysix patients with ITP and nine healthy volunteers were enrolled in the study.As soluble immunomodulatory molecules,more sCD25 and sGalectin-9 were detected in ITP patients.On the cell surface,co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells.In contrast,co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets.Taking a platelet count of 30×10^(9)L^(−1)as the cutoff value,ITP patients with high and low platelet counts showed different T cell immune profiles.Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions,respectively,and participate in the pathogenesis of ITP.In conclusion,the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP.They may offer novel targets to develop personalized immunotherapies.展开更多
Importance:Eltrombopag has been recommended for pediatric immune thrombocytopenia(ITP).Response and adverse drug reactions(ADRs)varied widely between individuals,even at the same dose of eltrombopag.The appropriate el...Importance:Eltrombopag has been recommended for pediatric immune thrombocytopenia(ITP).Response and adverse drug reactions(ADRs)varied widely between individuals,even at the same dose of eltrombopag.The appropriate eltrombopag concentration in ITP has not been reported.Objective:This study aims to explore the appropriate eltrombopag concentration in pediatric ITP.Methods:This was a single-center,prospective cohort study.Children diagnosed with refractory persistent/chronic ITP and platelet count<30×10^(9)/L were treated with eltrombopag and followed up for at least 2 months.Concentration was detected by high-performance liquid chromatography-mass spectrometry at least 2 weeks after eltrombopag.The clinical characteristics-concentration,concentration-response,and concentration-ADRs were analyzed.Results:A total of 30 patients were enrolled,comprising 13 males and 17 females,with a median age of 72(45-94)months.The median dose and concentration were 1.39(1.09-1.56)mg/kg and 2.70(2.25-4.13)mg/L,respectively.Of the enrolled patients,14 responded to treatment,whereas 16 did not.Additionally,five experienced adverse drug reactions.No linear correlation was observed between eltrombopag concentration and clinical characteristics.The concentration was lower in the response group than in the nonresponse group,but there was no significant difference(t=0.755,P=0.457).Patients who experienced ADRs had a higher concentration than those without ADRs(t=2.538,P=0.017).The area under the receiver operating characteristic curve of ADRs was 0.78(95%confidence interval:0.56-1.00).Youden’s index identified the cutoff point as 4.33 mg/L,with a sensitivity of 88%and a specificity of 60%.Logistic regression analysis demonstrated that a higher platelet count before eltrombopag predicted a favorable response.Interpretation:Eltrombopag proves efficacious and well-tolerated for treating pediatric ITP.However,prolonged and high-dose administration may increase the likelihood of ADRs.Thus,examining the appropriate eltrombopag concentration assists in directing individualized management of pediatric ITP.展开更多
Primary immune thrombocytopenia(ITP)is an autoimmune hemorrhagic disorder in which macrophages play a critical role.Mammalian sterile-20-like kinase 4(MST4),a member of the germinal-center kinase STE20 family,has been...Primary immune thrombocytopenia(ITP)is an autoimmune hemorrhagic disorder in which macrophages play a critical role.Mammalian sterile-20-like kinase 4(MST4),a member of the germinal-center kinase STE20 family,has been demonstrated to be a regulator of inflammation.Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive.The expression and function of MST4 in macrophages of ITP patients and THP-1 cells,and of a macrophage-specific Mst4−/−(Mst4ΔM/ΔM)ITP mouse model were determined.Macrophage phagocytic assays,RNA sequencing(RNA-seq)analysis,immunofluorescence analysis,coimmunoprecipitation(co-IP),mass spectrometry(MS),bioinformatics analysis,and phosphoproteomics analysis were performed to reveal the underlying mechanisms.The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients,and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment.The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages.Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines,and impaired phagocytosis,which could be increased by overexpression of MST4.In a passive ITP mouse model,macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid,attenuated the expression of M1 cytokines,and promoted the predominance of FcγRIIb in splenic macrophages,which resulted in amelioration of thrombocytopenia.Downregulation of MST4 directly inhibited STAT1 phosphorylation,which is essential for M1 polarization of macrophages.Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.展开更多
Immune thrombocytopenia(ITP)is common in the elderly.Because of the coexistence of multiple diseases,there are many reservations regarding corticosteroid use in the elderly.Thrombopoietin(TPO)and its analogs can promo...Immune thrombocytopenia(ITP)is common in the elderly.Because of the coexistence of multiple diseases,there are many reservations regarding corticosteroid use in the elderly.Thrombopoietin(TPO)and its analogs can promote platelet production,but it is often difficult to correct TP in a short period.Recombinant human TPO(rh-TPO)acting on the cell membrane and the small-molecule TPO-receptor(MPL)agonist acting on the transmembrane receptor may have synergistic effects and accelerate platelet production because of different sites of action in the signaling pathway.In this study,two elderly patients with refractory ITP were successfully treated with two TPO-MPL signaling pathway agonists:recombinant human thrombopoietin(rh-TPO)and eltrombopag.This combination is safe with rapid and lasting effects.However,in elderly patients with refractory,recurrent,and glucocorticoid contraindications,the combination of different TPO agonists'clinical efficacy and adverse reactions needs to be further evaluated.展开更多
Objective： To measure the proportions of blood T cel subsets, Th1, Th2, Th17, Th22, and Treg cel s, and other parameters in patients with chronic immune thrombocytopenia（CITP） before and after treatment with Yiqi T...Objective： To measure the proportions of blood T cel subsets, Th1, Th2, Th17, Th22, and Treg cel s, and other parameters in patients with chronic immune thrombocytopenia（CITP） before and after treatment with Yiqi Tongyang Decoction（益气通阳方, YTD） to explore T cel status of patients with CITP, and to define the mechanism of action of YTD. Methods： The changes in peripheral blood T lymphocyte subsets, and those of Th1, Th2, Th17, Th22, and Treg cel s in 30 patients with CITP（22 females and 8 males） were analyzed using multiparametric flow cytometry before and after treatment with YTD for 6 months, and 26 healthy volunteers（14 males and 12 females） acted as a control. T-box expressed in T-cel s（T-bet） and GATA binding protein 3（GATA-3） m RNA levels in patients and controls were analyzed using real-time reverse transcription-polymerase chain reaction. Results： The proportions of Th1, Th17, Th22, Th1/Th2, and Th17/Treg cells increased in the peripheral blood of patients with CITP compared to those in controls before YTD therapy（P〈0.05）. Th1 cel numbers and the Th1/Th2 ratio fel in the treated patients with CITP to approximate the values of the control group（P〉0.05）. Th17 cel numbers and the Th17/Treg ratio also decreased in the treatment group（P〈0.05）, but not to the levels of the controls. The number of Treg cel s in the peripheral blood of patients with CITP before treatment was lower than that in the control group（P〈0.05）, but increased after YTD treatment（P〈0.05）, but not to the level of controls. T-bet and GATA-3 m RNA levels in peripheral blood were initially higher in patients before treatment than controls（P〈0.05）, but decreased after YTD therapy（P〈0.05）. Conclusions： Imbalances in T lymphocyte levels, particularly those of Th1/Th2 and Th17/Treg cel s, play important roles in the pathogenesis of CITP. YTD efficiently regulated the dynamics of Th1/Th2 and Th17/Treg equilibria.展开更多
Background The management of patients with refractory immune thrombocytopenia （ITP） is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant huma...Background The management of patients with refractory immune thrombocytopenia （ITP） is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin （rhTPO） in combination with cyclosporin A （CsA） for the management of patients with corticosteroid-resistant primary ITP.展开更多
Quantitative metagenomic studies have linked the gut microbiota to autoimmune disorders.Here,we performed deep shotgun metagenomic sequencing of fecal samples from 99 immune thrombocytopenia(ITP)patients and 52 health...Quantitative metagenomic studies have linked the gut microbiota to autoimmune disorders.Here,we performed deep shotgun metagenomic sequencing of fecal samples from 99 immune thrombocytopenia(ITP)patients and 52 healthy controls.Dysbiosis in the gut microbiome of ITP was detected phylogenetically and functionally,and classifier based on species markers distinguished individuals with ITP from healthy controls.In particular,the abundance of Ruminococcus gnavus,Bifidobacterium longum and Akkermansia muciniphila was markedly increased in treatment-na?ve ITP patients,and the alterations of microbial species were correlated with clinical indices.Functionally,the secondary bile acid biosynthesis and flagellar assembly were depleted in the gut microbiota of ITP,which may contribute to the onset of ITP by affecting the immune system.Furthermore,we found that corticosteroid treatment affected the gut microbiome of ITP.Compared with corticosteroid-sensitive ITP patients,we identified that the corticosteroid-resistant ITP patients displayed a distinct gut microbiome,which was different from that of the treatment-na?ve ITP patients.Together,we provided support for the critical role of gut microbiota in the development of ITP and established a foundation for further research characterizing gut microbiota in relation to corticosteroid resistance of ITP.展开更多
Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity.Intracellular metabolic changes in MDSCs exert a direct immunological influence on th...Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity.Intracellular metabolic changes in MDSCs exert a direct immunological influence on their suppressive activity.Our previous study demonstrated that high-dose dexamethasone(HD-DXM)corrected the functional impairment of MDSCs in immune thrombocytopenia(ITP);however,the MDSC population was not restored in nonresponders,and the mechanism remained unclear.In this study,altered mitochondrial physiology and reduced mitochondrial gene transcription were detected in MDSCs from HD-DXM nonresponders,accompanied by decreased levels of carnitine palmitoyltransferase-1(CPT-1),a rate-limiting enzyme in fatty acid oxidation(FAO).Blockade of FAO with a CPT-1 inhibitor abolished the immunosuppressive function of MDSCs in HD-DXM responders.We also report that MDSCs from ITP patients had lower expression of the glucocorticoid receptor(GR),which can translocate into mitochondria to regulate the transcription of mitochondrial DNA(mtDNA)as well as the level of oxidative phosphorylation.It was confirmed that the expression of CPT-1 and mtDNA-encoded genes was downregulated in GR-siRNA-treated murine MDSCs.Finally,by establishing murine models of active and passive ITP via adoptive transfer of DXM-modulated MDSCs,we confirmed that GR-silenced MDSCs failed to alleviate thrombocytopenia in mice with ITP.In conclusion,our study indicated that impaired aerobic metabolism in MDSCs participates in the pathogenesis of glucocorticoid resistance in ITP and that intact control of MDSC metabolism by GR contributes to the homeostatic regulation of immunosuppressive cell function.展开更多
Heightened platelet phagocytosis by macrophages accompanied by an increase in IFN-γplay key roles in the etiology of immune thrombocytopenia(ITP);however,it remains elusive how macrophage-mediated platelet clearance ...Heightened platelet phagocytosis by macrophages accompanied by an increase in IFN-γplay 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 importinα5.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-importinα5 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-importinα5 module as a promising therapeutic target in the treatment of ITP.展开更多
Primary immune thrombocytopenia(ITP)is an autoimmune disorder characterized by immune-mediated accelerated platelet destruction and/or suppressed platelet production.Although the development of autoantibodies against ...Primary immune thrombocytopenia(ITP)is an autoimmune disorder characterized by immune-mediated accelerated platelet destruction and/or suppressed platelet production.Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP,several abnormalities involving the cellular mechanisms of immune modulation have been identified,and the pathways behind the immune-mediated destruction of platelets have opened new avenues for the design of specific immunotherapies in an attempt to reduce the platelet destruction.This review is primarily focused on the recent literature with respect to immunopathological mechanisms in patients with ITP.展开更多
Background:Recombinant human thrombopoietin(rh-TPO)and eltrombopag are two distinct TPO receptor agonists(TPO-RAs)with different mechanisms.During the pandemic,when immunosuppressive medications are controversial,swit...Background:Recombinant human thrombopoietin(rh-TPO)and eltrombopag are two distinct TPO receptor agonists(TPO-RAs)with different mechanisms.During the pandemic,when immunosuppressive medications are controversial,switching to another TPO-RA may be worth exploring in patients who do not benefit from their first TPO-RA.We investigated the outcomes of switching from rh-TPO to eltrombopag or vice versa in immune thrombocytopenia(ITP)patients.Methods:This prospective,open-label,observational investigation included 96 adult ITP patients who needed to switch between rh-TPO and eltrombopag between January 2020 and January 2021 at Peking University People’s Hospital in China.The study evaluated response rates and platelet counts at different time points after the switch,bleeding events,time to response,duration of response,and adverse events.Results:At 6 weeks after switching,response was observed in 21/49 patients(43%)who switched for inefficacy and 34/47 patients(72%)who switched for non-efficacy-related issues.In the inefficacy group,9/27 patients(33%)responded to eltrombopag,and 12/22 patients(55%)responded to rh-TPO.In the non-efficacy-related group,21/26(81%)and 13/21(62%)patients in the eltrombopag and rh-TPO groups maintained their response rates at 6 weeks after switching,respectively.Response at 6 months was achieved in 24/49 patients(49%)switching for inefficacy and 37/47 patients(79%)switching for non-efficacy issues.In the inefficacy group,13/27 patients(48%)responded to eltrombopag,and 11/22 patients(50%)responded to rh-TPO.In the non-efficacy-related group,22/26 patients(85%)and 15/21 patients(71%)in the eltrombopag and rh-TPO groups maintained their response rates at 6 months after switching,respectively.Both eltrombopag and rh-TPO were well tolerated.Conclusions:Our study confirmed the safety and effectiveness of switching between rh-TPO and eltrombopag for ITP patients who had no response to or experienced adverse events with their first TPO-RA.When the switch was motivated by other reasons,including patient preference and platelet count fluctuations,the probability of response was high.Registration:ClinicalTrials.gov,NCT04214951.展开更多
Primary immune thrombocytopenia （ITP） is the most common hemorrhagic disorder characterized byisolated thrombocytopenia in the absence of conditions known to cause thrombocytopenia. The incidence rate of ITP is simi...Primary immune thrombocytopenia （ITP） is the most common hemorrhagic disorder characterized byisolated thrombocytopenia in the absence of conditions known to cause thrombocytopenia. The incidence rate of ITP is similar in males and females; the incidence was significantly higher among patients older than 60 years） The clinical manifestation of bleeding varies with patient. The severity of bleeding ranges from mild mucocutanous bleeding （petechiae and ecchymoses） to life-threatening hemorrhages （intracranial or gastrointestinal bleeding）; some patients have no bleeding manifestations. Fatal and major nonfatal hemorrhages were extremely higher in patients older than 60 years old.2 The thrombocytopenia in ITP has been traditionally thought to be caused by the production of autoantibodyies targeting platelet antigens. Autoantibodies attach to the platelets and are destructed by macrophages in the reticuloendothelial system. Understanding of the mechanisms of thrombocytopenia in ITP has greatly expanded in recent years. The pathogenesis of ITP is heterogeneous and complex. The thrombocytopenia in ITP is caused not only by increased platelet destruction but also by impaired platelet production. The advances in the understanding of ITP have led to the development of a novel nonimmunologic therapeutic approach by stimulating platelet production and even revised guidelines in the diagnosis and treatment of ITE3 In the process of exploring the pathogenesis of ITP, the researchers from all over the world have done a lot of studies. This review will provide an insight into the pathogenesis-oriented treatment of ITP, mainly focusing on the studies of Chinese researchers.展开更多
文摘Objective:To explore the effect of low-dose rituximab in primary immune thrombocytopenia.Methods:From January 2022 to January 2023,60 patients with primary immune thrombocytopenia were randomly divided into two groups.The control group was treated with standard doses of rituximab,and the observation group was treated with low doses of rituximab.Rituximab was used for treatment,and the clinical curative effect of the two groups was observed.Results:Before treatment,there was no statistically significant difference in platelet count(PLT),anti-GPⅡb/Ⅲa antibody,and anti-GPⅠb/Ⅸantibody between the two groups(P>0.05).After treatment,the PLT of the two groups increased significantly.Antibodies were all decreased,and there was no significant difference between the two groups(P>0.05).The incidence of adverse reactions in the observation group was 13.33%,and that in the control group was 40.00%.The adverse reactions in the observation group were significantly lower than the control group(P<0.05).Conclusion:In the clinical treatment of primary immune thrombocytopenia,low-dose rituximab can control the progression of the disease,improve blood routine indicators,and have fewer adverse reactions.
文摘Immune thrombocytopenia is an autoimmune disease resulting in the destruction of platelets.It is classified as acute,thrombocytopenia occurring for < 6 mo and usually resolving spontaneously,and chronic,lasting >6 mo and requiring therapy to improve the thrombocytopenia.The underlying defects leading to autoantibody production are unknown.Molecular mimicry appears to play a role in the development of self-reactive platelet antibodies after vaccination and certain viral infections.Platelet life span is reduced as a consequence of antibody-mediated clearance by tissue macrophages in essentially all patients.Diagnosis is based on the exclusion of the other causes of thrombocytopenia.Steroid is the first choice of the treatment,often followed by splenectomy in unresponsive cases.Intravenous immunoglobulin,anti-Rho(D) immune globulin,azathioprine,cyclosporine A,cyclophosphamide,danazol,dapsone,mycophenolate mofetil,rituximab,thrombopoietin receptor agonists and vinca alkaloids are other choices of treatment.
基金Supported by A research grant for Research on Intractable Diseases from the Japanese Ministry of Health,Labor,and Welfare,No.H23-Nanchi-Ippan-002
文摘Immune thrombocytopenia (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies. There is growing evidence that the eradication of Helicobacter pylori (H. pylori) effectively increases platelet count in a considerable proportion of ITP patients infected with this bacterium. In the majority of ITP patients responding to H. pylori eradication therapy, the anti-platelet autoantibody response is completely resolved with no relapse for more than 7 years, indicating that the disease is cured. Therefore, adult patients with suspected ITP should be examined for H. pylori infection, and eradication therapy is recommended if the infection is present. Notably, however, the efficacy of H. pylori eradication therapy in ITP patients varies widely among countries, with a higher response rate in Japan compared with the United States and European countries other than Italy. The pathogenesis of H. pylori-associated ITP is still uncertain, although the mechanisms are known to involve multiple factors. H. pylori may modulate the Fcγ-receptor balance of monocytes/macrophages in favor of activating Fcγ receptors, and H. pylori components may mimic the molecular makeup of platelet antigens. Further studies of the pathogenic process of H. pylori-associated ITP may be useful for the development of new therapeutic strategies for ITP.
基金Jiangxi Traditional Chinese Medicine Administration Clinical Research Base Construction Project(Jiangxi TCM Science and Education Letter[2021]No.3)Jiangxi Traditional Chinese Medicine Young and Middle-aged Backbone Talents(First Batch)Training Program Project(Jiangxi TCM Science and Education Letter[2020]No.2)Jiangxi Traditional Chinese Medicine Administration Science and Technology Program Project(2021B050).
文摘Objective Through bibliometrics and visual analysis of the related studies on traditional Chinese medicine(TCM)treatment of immune thrombocytopenia(ITP),this study aims to sort out the overall research progress,hotspots,and trends in this field,and provide reference for further research in ITP.Methods The articles on ITP treated by TCM were retrieved from China National Knowledge Infrastructure(CNKI),Wanfang Database,China Science and Technology Journal Database(VIP),Web of Science Core Collection(WOSCC),and PubMed.The retrieval time was from the establishment of the databases to July 31,2022.VOSviewer,CiteSpace,Carrot2,and Note-Express were used for data analysis of the articles in terms of their quantities,types,and journals,and for visualization of research hotspots,authors,institutions,and keywords.Results 1493 Chinese articles and 40 English articles were included.The articles in Chinese mainly focus on clinical trial research and clinical experience summary,while the English articles mainly focus on clinical trial research and animal research.The Chinese articles were published in 317 Chinese journals,while English articles were published in 29 English journals.Research hotspots include the clinical syndrome differentiation of ITP,the therapeutic effect of TCM compounds on ITP,and the mechanism of ITP treatment.Keyword analysis shows that there are many research achievements in integrated traditional Chinese and western medicine treatment,clinical research,famous doctors’experience,TCM treatment,cellular immunity,and humoral immunity.The authors with the most articles in Chinese and English are Professor CHEN Xinyi and Professor MA Rou,respectively,and the research institutions with the most articles are Dongzhimen Hospital of Beijing University of Chinese Medicine and Xiyuan Hospital of China Academy of Chinese Medical Sciences.Chinese herbs often used to treat ITP clinically include Xianhecao(Agrimoniae Herba),Nvzhenzi(Ligustri Lucidi Fructus),Mohanlian(Ecliptae Herba),Zhongjiefeng(Sarcandrae Herba),etc.,and the prescription usually used to treat ITP include Guipi Decoction(归脾汤),Xijiao Dihuang Decoction(犀角地黄汤),Bazhen Decoction(八珍汤),Erzhi Pill(二至丸),and Xiaochaihu De-coction(小柴胡汤).The main development trends toward retrospective study,TCM treatment mechanism,and data mining.
基金the National Program on Key Basic Research Project(2015CB554403)
文摘Objective: To investigate the biological basis of qi, blood and vessel in immune thrombocytopenia(ITP) patients with syndrome of qi failing to govern blood(SQFGB) based on traditional Chinese medicine.Methods: A total of 52 ITP patients with SQFCB were enrolled and divided into bleeding group(38 cases) and non-bleeding group(14 cases).Bleeding group was further divided into mild qi deficiency group(25 cases) and moderate/severe qi deficiency group(13 cases) based on Chinese Medicine syndrome score.20 healthy volunteer were recruited as control group.The count of platelet(PLT) was taken as the blood related indicator.The expressions of cytokines including IL-1β, IL-17 A, TNF-α, CD40 L, and TGF-β, detected by Aim Plex Multiple Immunoassays for Flow, were taken as the qi related indicators.The expressions of VEGF-A, detected by Aim Plex Multiple Immunoassays for Flow and NO, NOS, and ET-1 detected by ELISA, were taken as the vessel related indicators.Results: As compared to the control group, the count of PLT, taken as the blood related indicator, was significantly lower in ITP group patients with SQFCB(P<0.05).The expression levels of IL-17 A and TNF-α, taken as the qi related indicators, were significantly higher, while those of CD40 L, IL-1β, and TGF-β, also taken as the qi related indicators, were significantly lower in ITP patients with SQFCB, respectively(P<0.05).The expression levels of NO and ET-1, taken as the vessel related indicators, were significantly higher, while the expression levels of NOS and VEGF-A also taken as the vessel related indicators, were significantly lower in ITP patients with SQFCB, respectively(P<0.05).The count of PLT, taken as the blood related indicator, was significantly lower in moderate/severe group than those in mild group(P<0.05).The expression levels of CD40 L and TGF-β, taken as the qi related indicators, were also significantly lower in moderate/severe group than those in mild group, respectively(P<0.05).Conclusion: The count of PLT might be the biological basis of blood.The expressions of NO, NOS, ET-1 and VEGF-A might be the biological basis of vessel.The expressions of IL-1β, IL-17 A, TNF-α, TGF-β, and CD40 L may be the biological basis of qi.The expressions of CD40 L and TGF-β could reflect the degree of qi deficiency in ITP patients based on the theory of qi and blood.
文摘Immune thrombocytopenia (ITP) is a chronic disease resulting from increased platelet destruction and impaired platelet production. Secondary ITP can be a manifestation of chronic graft-versus-host disease (GVHD) and represent a lymphoproliferative disorder. A boy with chronic graft-versus-host disease after cord blood stem cell transplantation who had severe refractory immune-mediated thrombocytopenia received infusion of rituximab weekly, 375 mg/m2, for 4 weeks. Platelets count of the patient was recovered, and rituximab was well tolerated with no severe toxicity observed during treatment.
文摘Immune Thrombocytopenic purpura(ITP)is a haematologicimmune-mediated disorder in which the amount of platelet in the blood decreases abnormally.Single-agent therapies for ITP have not proven successful in achieving long-term remission,with relapse occurring in about half of the patients(p/t).Treatment options which include Rituximab with Dexamethasone as frontline therapy,have durable response rates ranging from 58%to 76%.In this study,we have used‘Total therapy’as treatment which includes low-dose Rituximab in combination with Thrombopoietin receptor agonist(TPO-RA)(Romiplostim)and high-dose Dexamethasone.In this case series study,each patient received romiplostim(250 mcg weekly s/c,4 doses)in combination with low-dose rituximab(100 mg weekly IV,4 doses)and high-dose dexamethasone(40 mgIV on days 1-4and days 15-18).This treatment combination demonstrated rapid response rates and a low rate of side effects,making it a good alternative for individuals with ITP.
文摘Objective: To detect the expression and significance of regulatory B cells in patients with immune thrombocytopenia. Methods: 73 ITP patients were divided into glucocorticoids treatment group (n = 42) and recombinant human thrombopoietin (rhTPO) treatment group (n = 31). According to the therapeutic effect, it was divided into effective group and ineffective group. The expression of CD19+ CD24hiCD38hi Breg in peripheral blood was detected by flow cytometry before and after treatment. The expression levels of transforming growth factor (TGF)-β1, interleukin (IL-10) and interferon (IFN)-γ were detected by ELISA before and after treatment. 30 volunteers were selected as the control group. Results: The expression of CD19+ CD24hiCD38hi Breg and cytokines IL-10 and TGF-β1 in 73 ITP patients before treatment was lower than that in the control group, while the expression of IFN-γ was higher than that in the control group (p < 0. 05). The expression levels of CD19+ CD24hiCD38hi Breg, IL-10 and TGF-β1 in the effective group were significantly higher than before treatment, while the expression of IFN-γ was significantly lower than before treatment (p < 0. 05). The expression of CD19+ CD24hiCD38hi Breg, IFN-γ, IL-10 and TGF-β1 in the invalid group had no significant change compared with before treatment. Conclusion: Abnormal expression of CD19+ CD24hiCD38hi Breg and related cytokines is involved in the pathogenesis of ITP.
基金supported by the National Natural Science Foundation of China(82230004,81970113,82300149)the National Key Research and Development Program of China(2021YFC2500304)+1 种基金Capital Health Research and Development of Special(2022-1-4082)Peking University Medicine Fund for world's leading discipline or discipline cluster development(71003Y3035).
文摘To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia(ITP),this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight(CyTOF).Thirtysix patients with ITP and nine healthy volunteers were enrolled in the study.As soluble immunomodulatory molecules,more sCD25 and sGalectin-9 were detected in ITP patients.On the cell surface,co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells.In contrast,co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets.Taking a platelet count of 30×10^(9)L^(−1)as the cutoff value,ITP patients with high and low platelet counts showed different T cell immune profiles.Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions,respectively,and participate in the pathogenesis of ITP.In conclusion,the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP.They may offer novel targets to develop personalized immunotherapies.
基金Capital’s Funds for Health Improvement and Research:Grant/Award Number:2022-2Z-2099 Beijing Municipal Administration of Hospitals Incubating Program:Grant/Award Number:PX2023044National Natural Science Foundation of China:Grant/Award Number:81970111Funding for Reform and development of Beijing Municipal Health Commission National Key R&D Program of China:Grant/Award Number:2023YFC2706100。
文摘Importance:Eltrombopag has been recommended for pediatric immune thrombocytopenia(ITP).Response and adverse drug reactions(ADRs)varied widely between individuals,even at the same dose of eltrombopag.The appropriate eltrombopag concentration in ITP has not been reported.Objective:This study aims to explore the appropriate eltrombopag concentration in pediatric ITP.Methods:This was a single-center,prospective cohort study.Children diagnosed with refractory persistent/chronic ITP and platelet count<30×10^(9)/L were treated with eltrombopag and followed up for at least 2 months.Concentration was detected by high-performance liquid chromatography-mass spectrometry at least 2 weeks after eltrombopag.The clinical characteristics-concentration,concentration-response,and concentration-ADRs were analyzed.Results:A total of 30 patients were enrolled,comprising 13 males and 17 females,with a median age of 72(45-94)months.The median dose and concentration were 1.39(1.09-1.56)mg/kg and 2.70(2.25-4.13)mg/L,respectively.Of the enrolled patients,14 responded to treatment,whereas 16 did not.Additionally,five experienced adverse drug reactions.No linear correlation was observed between eltrombopag concentration and clinical characteristics.The concentration was lower in the response group than in the nonresponse group,but there was no significant difference(t=0.755,P=0.457).Patients who experienced ADRs had a higher concentration than those without ADRs(t=2.538,P=0.017).The area under the receiver operating characteristic curve of ADRs was 0.78(95%confidence interval:0.56-1.00).Youden’s index identified the cutoff point as 4.33 mg/L,with a sensitivity of 88%and a specificity of 60%.Logistic regression analysis demonstrated that a higher platelet count before eltrombopag predicted a favorable response.Interpretation:Eltrombopag proves efficacious and well-tolerated for treating pediatric ITP.However,prolonged and high-dose administration may increase the likelihood of ADRs.Thus,examining the appropriate eltrombopag concentration assists in directing individualized management of pediatric ITP.
基金supported by grants from the National Natural Science Foundation of China(82370130,81870098,82300146)the Program of the Shanghai Academic/Technology Researcher Leader(20XD1401000)+2 种基金the Shanghai Engineering Research Center of Tumor Multi-Target Gene Diagnosis(20DZ2254300)the Key Subject Construction Program of the Shanghai Health Administrative Authority(ZK2019B30)the Science and Technology Commission of the Shanghai Municipality(21ZR1459000).
文摘Primary immune thrombocytopenia(ITP)is an autoimmune hemorrhagic disorder in which macrophages play a critical role.Mammalian sterile-20-like kinase 4(MST4),a member of the germinal-center kinase STE20 family,has been demonstrated to be a regulator of inflammation.Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive.The expression and function of MST4 in macrophages of ITP patients and THP-1 cells,and of a macrophage-specific Mst4−/−(Mst4ΔM/ΔM)ITP mouse model were determined.Macrophage phagocytic assays,RNA sequencing(RNA-seq)analysis,immunofluorescence analysis,coimmunoprecipitation(co-IP),mass spectrometry(MS),bioinformatics analysis,and phosphoproteomics analysis were performed to reveal the underlying mechanisms.The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients,and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment.The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages.Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines,and impaired phagocytosis,which could be increased by overexpression of MST4.In a passive ITP mouse model,macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid,attenuated the expression of M1 cytokines,and promoted the predominance of FcγRIIb in splenic macrophages,which resulted in amelioration of thrombocytopenia.Downregulation of MST4 directly inhibited STAT1 phosphorylation,which is essential for M1 polarization of macrophages.Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.
基金supported by the National Key Research and Development Program of China(No.2020YFC2002706)the Army Health Care Special Project(No.19BJZ28).
文摘Immune thrombocytopenia(ITP)is common in the elderly.Because of the coexistence of multiple diseases,there are many reservations regarding corticosteroid use in the elderly.Thrombopoietin(TPO)and its analogs can promote platelet production,but it is often difficult to correct TP in a short period.Recombinant human TPO(rh-TPO)acting on the cell membrane and the small-molecule TPO-receptor(MPL)agonist acting on the transmembrane receptor may have synergistic effects and accelerate platelet production because of different sites of action in the signaling pathway.In this study,two elderly patients with refractory ITP were successfully treated with two TPO-MPL signaling pathway agonists:recombinant human thrombopoietin(rh-TPO)and eltrombopag.This combination is safe with rapid and lasting effects.However,in elderly patients with refractory,recurrent,and glucocorticoid contraindications,the combination of different TPO agonists'clinical efficacy and adverse reactions needs to be further evaluated.
基金Supported by the National Natural Science Foundation of China(No.81072928)
文摘Objective： To measure the proportions of blood T cel subsets, Th1, Th2, Th17, Th22, and Treg cel s, and other parameters in patients with chronic immune thrombocytopenia（CITP） before and after treatment with Yiqi Tongyang Decoction（益气通阳方, YTD） to explore T cel status of patients with CITP, and to define the mechanism of action of YTD. Methods： The changes in peripheral blood T lymphocyte subsets, and those of Th1, Th2, Th17, Th22, and Treg cel s in 30 patients with CITP（22 females and 8 males） were analyzed using multiparametric flow cytometry before and after treatment with YTD for 6 months, and 26 healthy volunteers（14 males and 12 females） acted as a control. T-box expressed in T-cel s（T-bet） and GATA binding protein 3（GATA-3） m RNA levels in patients and controls were analyzed using real-time reverse transcription-polymerase chain reaction. Results： The proportions of Th1, Th17, Th22, Th1/Th2, and Th17/Treg cells increased in the peripheral blood of patients with CITP compared to those in controls before YTD therapy（P〈0.05）. Th1 cel numbers and the Th1/Th2 ratio fel in the treated patients with CITP to approximate the values of the control group（P〉0.05）. Th17 cel numbers and the Th17/Treg ratio also decreased in the treatment group（P〈0.05）, but not to the levels of the controls. The number of Treg cel s in the peripheral blood of patients with CITP before treatment was lower than that in the control group（P〈0.05）, but increased after YTD treatment（P〈0.05）, but not to the level of controls. T-bet and GATA-3 m RNA levels in peripheral blood were initially higher in patients before treatment than controls（P〈0.05）, but decreased after YTD therapy（P〈0.05）. Conclusions： Imbalances in T lymphocyte levels, particularly those of Th1/Th2 and Th17/Treg cel s, play important roles in the pathogenesis of CITP. YTD efficiently regulated the dynamics of Th1/Th2 and Th17/Treg equilibria.
文摘Background The management of patients with refractory immune thrombocytopenia （ITP） is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin （rhTPO） in combination with cyclosporin A （CsA） for the management of patients with corticosteroid-resistant primary ITP.
基金Beijing Municipal Science and Technology Commission(Z171100001017084)Natural Science Foundation of Beijing Municipality(7171013 and H2018206423)+2 种基金Key Program of National Natural Science Foundation of China(81730004)the National Natural Science Foundation of China(81670116 and 81970113)National Key Research and Development Program of China(2017YFA0105503)。
文摘Quantitative metagenomic studies have linked the gut microbiota to autoimmune disorders.Here,we performed deep shotgun metagenomic sequencing of fecal samples from 99 immune thrombocytopenia(ITP)patients and 52 healthy controls.Dysbiosis in the gut microbiome of ITP was detected phylogenetically and functionally,and classifier based on species markers distinguished individuals with ITP from healthy controls.In particular,the abundance of Ruminococcus gnavus,Bifidobacterium longum and Akkermansia muciniphila was markedly increased in treatment-na?ve ITP patients,and the alterations of microbial species were correlated with clinical indices.Functionally,the secondary bile acid biosynthesis and flagellar assembly were depleted in the gut microbiota of ITP,which may contribute to the onset of ITP by affecting the immune system.Furthermore,we found that corticosteroid treatment affected the gut microbiome of ITP.Compared with corticosteroid-sensitive ITP patients,we identified that the corticosteroid-resistant ITP patients displayed a distinct gut microbiome,which was different from that of the treatment-na?ve ITP patients.Together,we provided support for the critical role of gut microbiota in the development of ITP and established a foundation for further research characterizing gut microbiota in relation to corticosteroid resistance of ITP.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81900121,81770133,81973994,and 81770114)Major Research Plan of National Natural Science Foundation of China(No.91942306)+3 种基金Clinical Research Center of Shandong University(No.2020SDUCRCC009)Graduate Education Reform Project of Shandong University(No.XYJG2020141)State Key Clinical Specialty of China for Blood DisordersYoung Taishan Scholar Foundation of Shandong Province(No.tsqn201909175).
文摘Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity.Intracellular metabolic changes in MDSCs exert a direct immunological influence on their suppressive activity.Our previous study demonstrated that high-dose dexamethasone(HD-DXM)corrected the functional impairment of MDSCs in immune thrombocytopenia(ITP);however,the MDSC population was not restored in nonresponders,and the mechanism remained unclear.In this study,altered mitochondrial physiology and reduced mitochondrial gene transcription were detected in MDSCs from HD-DXM nonresponders,accompanied by decreased levels of carnitine palmitoyltransferase-1(CPT-1),a rate-limiting enzyme in fatty acid oxidation(FAO).Blockade of FAO with a CPT-1 inhibitor abolished the immunosuppressive function of MDSCs in HD-DXM responders.We also report that MDSCs from ITP patients had lower expression of the glucocorticoid receptor(GR),which can translocate into mitochondria to regulate the transcription of mitochondrial DNA(mtDNA)as well as the level of oxidative phosphorylation.It was confirmed that the expression of CPT-1 and mtDNA-encoded genes was downregulated in GR-siRNA-treated murine MDSCs.Finally,by establishing murine models of active and passive ITP via adoptive transfer of DXM-modulated MDSCs,we confirmed that GR-silenced MDSCs failed to alleviate thrombocytopenia in mice with ITP.In conclusion,our study indicated that impaired aerobic metabolism in MDSCs participates in the pathogenesis of glucocorticoid resistance in ITP and that intact control of MDSC metabolism by GR contributes to the homeostatic regulation of immunosuppressive cell function.
基金Natural Science Foundation of Jiangsu Higher Education Institution-Key Program under 21KJA310002(H.L.)the Suzhou Key Program Special Funds in XJTLU under KSF-A-21 and KSF-E-30(H.L.)+2 种基金Soochow University Research Development Funds under Q424900220(H.L.)National Natural Science Foundation of China(NSFC)under Grant 31470840(H.L.)the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Heightened platelet phagocytosis by macrophages accompanied by an increase in IFN-γplay 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 importinα5.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-importinα5 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-importinα5 module as a promising therapeutic target in the treatment of ITP.
基金supported by grants from Independent Innovation Foundation of Shandong University(No.2082012TS134)National Natural Science Foundation of China(No.81200344,No.81070411)National Science Fund for Distinguished Young Scholars(No.81125002).
文摘Primary immune thrombocytopenia(ITP)is an autoimmune disorder characterized by immune-mediated accelerated platelet destruction and/or suppressed platelet production.Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP,several abnormalities involving the cellular mechanisms of immune modulation have been identified,and the pathways behind the immune-mediated destruction of platelets have opened new avenues for the design of specific immunotherapies in an attempt to reduce the platelet destruction.This review is primarily focused on the recent literature with respect to immunopathological mechanisms in patients with ITP.
基金Beijing Natural Science Foundation(No.H2018206423)National Natural Science Foundation of China(No.81970113)+1 种基金Key Program of National Natural Science Foundation of China(No.81730004)National Key Research and Development Program of China(No.2017YFA0105503)。
文摘Background:Recombinant human thrombopoietin(rh-TPO)and eltrombopag are two distinct TPO receptor agonists(TPO-RAs)with different mechanisms.During the pandemic,when immunosuppressive medications are controversial,switching to another TPO-RA may be worth exploring in patients who do not benefit from their first TPO-RA.We investigated the outcomes of switching from rh-TPO to eltrombopag or vice versa in immune thrombocytopenia(ITP)patients.Methods:This prospective,open-label,observational investigation included 96 adult ITP patients who needed to switch between rh-TPO and eltrombopag between January 2020 and January 2021 at Peking University People’s Hospital in China.The study evaluated response rates and platelet counts at different time points after the switch,bleeding events,time to response,duration of response,and adverse events.Results:At 6 weeks after switching,response was observed in 21/49 patients(43%)who switched for inefficacy and 34/47 patients(72%)who switched for non-efficacy-related issues.In the inefficacy group,9/27 patients(33%)responded to eltrombopag,and 12/22 patients(55%)responded to rh-TPO.In the non-efficacy-related group,21/26(81%)and 13/21(62%)patients in the eltrombopag and rh-TPO groups maintained their response rates at 6 weeks after switching,respectively.Response at 6 months was achieved in 24/49 patients(49%)switching for inefficacy and 37/47 patients(79%)switching for non-efficacy issues.In the inefficacy group,13/27 patients(48%)responded to eltrombopag,and 11/22 patients(50%)responded to rh-TPO.In the non-efficacy-related group,22/26 patients(85%)and 15/21 patients(71%)in the eltrombopag and rh-TPO groups maintained their response rates at 6 months after switching,respectively.Both eltrombopag and rh-TPO were well tolerated.Conclusions:Our study confirmed the safety and effectiveness of switching between rh-TPO and eltrombopag for ITP patients who had no response to or experienced adverse events with their first TPO-RA.When the switch was motivated by other reasons,including patient preference and platelet count fluctuations,the probability of response was high.Registration:ClinicalTrials.gov,NCT04214951.
文摘Primary immune thrombocytopenia （ITP） is the most common hemorrhagic disorder characterized byisolated thrombocytopenia in the absence of conditions known to cause thrombocytopenia. The incidence rate of ITP is similar in males and females; the incidence was significantly higher among patients older than 60 years） The clinical manifestation of bleeding varies with patient. The severity of bleeding ranges from mild mucocutanous bleeding （petechiae and ecchymoses） to life-threatening hemorrhages （intracranial or gastrointestinal bleeding）; some patients have no bleeding manifestations. Fatal and major nonfatal hemorrhages were extremely higher in patients older than 60 years old.2 The thrombocytopenia in ITP has been traditionally thought to be caused by the production of autoantibodyies targeting platelet antigens. Autoantibodies attach to the platelets and are destructed by macrophages in the reticuloendothelial system. Understanding of the mechanisms of thrombocytopenia in ITP has greatly expanded in recent years. The pathogenesis of ITP is heterogeneous and complex. The thrombocytopenia in ITP is caused not only by increased platelet destruction but also by impaired platelet production. The advances in the understanding of ITP have led to the development of a novel nonimmunologic therapeutic approach by stimulating platelet production and even revised guidelines in the diagnosis and treatment of ITE3 In the process of exploring the pathogenesis of ITP, the researchers from all over the world have done a lot of studies. This review will provide an insight into the pathogenesis-oriented treatment of ITP, mainly focusing on the studies of Chinese researchers.
