We used resting-state functional magnetic resonance imaging to measure the amplitude of low-frequency fluctuations (ALFF) of intrinsic brain activity in 23 patients with moderate Alzheimer's disease (AD) and 27 age- and gender-matched healthy controls. Two different frequency bands were analyzed (slow-5:0.01-0.027 Hz; slow-4:0.027-0.073 Hz). In many brain regions, widespread ALFF differences between the two frequency bands were observed, including predominantly the posterior cingulate cortex/precuneus (PCC/PCu), hippocampus/parahippocampal gyrus (Hip/PHG), insula, thalamus, and basal ganglia. Compared to controls, AD patients showed decreased ALFF values in the bilateral PCC/PCu, inferior parietal lobe, and several temporal regions, and increased ALFF values mainly in the bilateral Hip/PHG, and middle and inferior temporal gyri. Intriguingly, the ALFF abnormalities in the left PCu, left supramarginal gyrus, and several temporal regions were greater in the slow-5 band compared to the slow-4 band. Moreover, correcting for gray matter volume loss significantly affected the functional analytical results, suggesting that gray matter loss can partially account for the functional imaging analytical results obtained in AD. Finally, we showed that regions with changes in ALFF demonstrated a significant correlation with patient cognitive performance as measured using Mini-Mental State Examination scores. The results also demonstrated a significant correlation between hippocampal volume and the ALFF in slow-5 band in the AD group. This study demonstrated widespread ALFF abnormalities of intrinsic brain activity in AD and revealed that the ALFF abnormalities in severe specific regions were frequency-dependent. Taken together, our findings provided novel insights into the pathophysiological mechanism of AD and may be helpful in the development of imaging biomarkers for disease diagnosis.

Key Points• TPO-RAs shift monocyte FcgR balance toward the inhibitory FcgRIIb and correct the enhanced phagocytic capacity of macrophages in ITP.Elevated expression of the activating Fcg receptor (FcgR) I and FcgRIIa together with decreased expression of the inhibitory FcgRIIb are involved in the pathogenesis of primary immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) have been used clinically for the management of ITP; however, little is known about the effect of TPO-RAs on FcgR modulation in ITP. In this prospective study, we measured the alteration in monocyte FcgR expression from 21 corticosteroid-resistant/relapsed patients with chronic ITP receiving eltrombopag therapy. Results showed that the mRNA and protein levels of FcgRIIb were significantly elevated after 6-week eltrombopag treatment. Concurrently, FcgRI and IIa levels decreased remarkably, whereas FcgRIII expression did not change. In vitro phagocytosis assays indicated that a shift in the balance of FcgR toward inhibitory FcgRIIb on monocytes was accompanied with a considerable decrease in monocyte/macrophage phagocytic capacity. The response to eltrombopag therapy in patients with ITP was associated with FcgR phenotype and functional changes of monocytes/macrophages. Moreover, the plasma transforming growth factor-b1 (TGF-b1) concentrations increased significantly in eltrombopag responders. Modulation of monocyte FcgR balance by TPO-RAs was also found in a murine model of ITP established by transferring splenocytes from immunized CD61 knockout mice into CD61 1 severe combined immunodeficient mice. Romiplostim administration in ITP mice significantly upregulated inhibitory FcgRII expression and downregulated activating FcgRI expression. These findings showed that recovery of platelet counts after TPO-RA treatment in ITP is associated with the restoration of FcgR balance toward the inhibitory FcgRIIb on monocytes, and suggested that thrombopoietic agents have a profound effect on immune modulation in ITP. This study is registered at ClinicalTrials.gov as #NCT01864512. (Blood. 2016;128(6):852-861)

In addition to antiplatelet autoantibodies, CD8+ cytotoxic T lymphocytes (CTLs) play an important role in the increased platelet destruction in immune thrombocytopenia (ITP). Recent studies have highlighted that platelet desialylation leads to platelet clearance via hepatocyte asialoglycoprotein receptors (ASGPRs). Whether CD8+ T cells induce platelet desialylation in ITP remains unclear. Here, we investigated the cytotoxicity of CD8+ T cells towards platelets and platelet desialylation in ITP. We found that the desialylation of fresh platelets was significantly higher in ITP patients with positive cytotoxicity of CD8+ T cells than those without cytotoxicity and controls. In vitro, CD8+ T cells from ITP patients with positive cytotoxicity induced significant platelet desialylation, neuraminidase-1 expression on the platelet surface, and platelet phagocytosis by hepatocytes. To study platelet survival and clearance in vivo, CD61 knockout mice were immunized and their CD8+ splenocytes were used. Platelets co-cultured with these CD8+ splenocytes demonstrated decreased survival in the circulation and increased phagocytosis in the liver. Both neuraminidase inhibitor and ASGPRs competitor significantly improved platelet survival and abrogated platelet clearance caused by CD8+ splenocytes. These findings suggest that CD8+ T cells induce platelet desialylation and platelet clearance in the liver in ITP, which may be a novel mechanism of ITP.

Key Points• The impaired suppressive function of myeloid-derived suppressor cells plays a role in the pathogenesis of immune thrombocytopenia.• The effect of dexamethasone in correcting dysfunction of myeloid-derived suppressor cells suggests a new therapeutic mechanism of high-dose dexamethasone in patients with immune thrombocytopenia.Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. In this study, the MDSC population was evaluated in adult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCs were impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor b was significantly upregulated in DXM-modulated MDSCs compared with the unmodulated cultures. DXMmodulated MDSCs inhibited autologous CD4 1 T-cell proliferation and significantly attenuated cytotoxic T lymphocyte-mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61 1 platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce a murine model of severe ITP. We passively transferred the DXM-modulated MDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo compared with those receiving splenocyte engraftment alone. These findings suggested that impaired MDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1.

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