Altered Homeostasis of Regulatory T Lymphocytes and Differential Regulation of STAT1/STAT5 in CD4+ T Lymphocytes in Childhood-onset Systemic Lupus Erythematosus.
改变了儿童期发病的系统性红斑狼疮中调节性 T 淋巴细胞的稳态和 CD4 + T 淋巴细胞中 STAT1/STAT5 的差异调节。
- 作者列表："Holcar M","Goropevšek A","Avčin T
OBJECTIVE:Childhood-onset systemic lupus erythematosus (cSLE) is usually a more severe and aggressive disease than adult-onset SLE (aSLE), but cellular and subcellular reasons for these differences are not well understood. The present study analyzed Th subsets, STAT1/STAT5 signaling response, and cytokine profiles of cSLE. METHODS:FOXP3+ regulatory (Treg) and effector Th subsets, expression and phosphorylation of STAT1/STAT5 in Th, and cytokine profiles were measured in the peripheral blood of patients with cSLE and healthy controls (HC), using flow cytometry and immunoassay on a biochip. RESULTS:Significant correlation between expression of the activation marker HLA-DR and decreased Th counts, an increase in the percentage of FOXP3+ Th, and a decrease in the activated Treg (aTreg) subset among them were found in cSLE. In contrast to our previous findings in aSLE, no significant differences in percentages and a significant decrease in the numbers of the naive-resting Treg (rTreg) subset compared to HC were found. The percentages of CD25- cells, possibly reflecting interleukin 2 depletion, were significantly increased in cSLE aTreg, but not in the rTreg subset. Consistent with the results of our previous studies in aSLE, increased expression of STAT1, along with significant correlation between decreased Th counts and their increased basal phosphorylation of STAT5, were also found in cSLE. CONCLUSION:Our results suggest that the key difference in Treg homeostasis between cSLE and aSLE is in the rTreg subset. However, perturbed aTreg homeostasis, increased levels of STAT1 protein, and homeostatic STAT5 signaling appear to be intrinsic characteristics of the disease, present in cSLE and aSLE alike.
目的: 儿童期发病的系统性红斑狼疮 (cSLE) 通常是一种比成人期发病的 SLE (aSLE) 更严重、更具侵袭性的疾病,但是这些差异的细胞和亚细胞原因还不是很清楚。本研究分析了 cSLE 的 Th 亚群、 STAT1/STAT5 信号反应和细胞因子谱。 方法: FOXP3 + 调节性 (Treg) 和效应因子 Th 亚群，Th 中 STAT1/STAT5 的表达和磷酸化,在 cSLE 患者和健康对照 (HC) 患者的外周血中，使用生物芯片上的流式细胞术和免疫分析法测量细胞因子谱。 结果: 活化标记物 HLA-DR 的表达与 Th 计数减少、 FOXP3 + Th 百分比增加、活化 Treg (aTreg) 减少之间存在显著相关性在 cSLE 中发现了其中的子集。与我们之前在 aSLE 的研究结果相反，与 HC 相比，未发现初始静息 Treg (Treg) 亚群的百分比差异和数量显著减少。CD25-细胞的百分比，可能反映白细胞介素 2 耗竭，在 cSLE aTreg 中显著增加，但在 treg 亚群中不显著增加。与我们以前在 aSLE 中的研究结果一致，在 cSLE 中也发现了 STAT1 的表达增加，以及 Th 计数减少与其 STAT5 基础磷酸化增加之间的显著相关性。 结论: 我们的研究结果表明，cSLE 和 aSLE 之间 Treg 稳态的关键差异在于 Treg 亚群。然而，受到干扰的 aTreg 稳态、 STAT1 蛋白水平升高和稳态 STAT5 信号似乎是疾病的内在特征，在 cSLE 和 aSLE 中同样存在。
METHODS:OBJECTIVE:To report the incidence of prion disease in the United States. METHODS:Prion disease decedents were retrospectively identified from the US national multiple cause-of-death data for 2003-2015 and matched with decedents in the National Prion Disease Pathology Surveillance Center (NPDPSC) database through comparison of demographic variables. NPDPSC decedents with neuropathologic or genetic test results positive for prion disease for whom no match was found in the multiple cause-of-death data were added as cases for incidence calculations; those with cause-of-death data indicating prion disease but with negative neuropathology results were removed. Age-specific and age-adjusted average annual incidence rates were then calculated. RESULTS:A total of 5,212 decedents were identified as having prion disease, for an age-adjusted average annual incidence of 1.2 cases per million population (range 1.0 per million [2004 and 2006] to 1.4 per million ). The median age at death was 67 years. Ten decedents were <30 years of age (average annual incidence of 6.2 per billion); only 2 of these very young cases were sporadic forms of prion disease. Average annual incidence among those ≥65 years of age was 5.9 per million. CONCLUSIONS:Prion disease incidence can be estimated by augmenting mortality data with the results of neuropathologic and genetic testing. Cases <30 years of age were extremely rare, and most could be attributed to exogenous factors or the presence of a genetic mutation. Continued vigilance for prion diseases in all age groups remains prudent.
METHODS::The conformational conversion of the cellular prion protein (PrPC) to the misfolded and aggregated isoform, termed scrapie prion protein (PrPSc), is key to the development of a group of neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). Although the conversion mechanism is not fully understood, the role of gene polymorphisms in varying susceptibilities to prion diseases is well established. In ovine, specific gene polymorphisms in PrPC alter prion disease susceptibility: the Valine136-Glutamine171 variant (Susceptible structure) displays high susceptibility to classical scrapie while the Alanine136-Arginine171 variant (Resistant structure) displays reduced susceptibility. The opposite trend has been reported in atypical scrapie. Despite the differentiation between classical and atypical scrapie, a complete understanding of the effect of polymorphisms on the structural dynamics of PrPC is lacking. From our structural bioinformatics study, we propose that polymorphisms locally modulate the network of residue interactions in the globular C-terminus of the ovine recombinant prion protein while maintaining the overall fold. Although the two variants we examined exhibit a densely connected group of residues that includes both β-sheets, the β2-α2 loop and the N-terminus of α-helix 2, only in the Resistant structure do most residues of α-helix 2 belong to this group. We identify the structural role of Valine136Alanine and Glutamine171Arginine: modulation of residue interaction networks that affect the connectivity between α-helix 2 and α-helix 3. We propose blocking interactions of residue 171 as a potential target for the design of therapeutics to prevent efficient PrPC misfolding. We discuss our results in the context of initial PrPC conversion and extrapolate to recently proposed PrPSc structures.Communicated by Ramaswamy H. Sarma.
METHODS::Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]-Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains.