Expression and functions of cellular prion proteins in immunocytes.

Prion diseases are fatal neurodegenerative processes caused by the accumulation of the pathological prion protein, PrPSc . While pathological lesions are limited to the central nervous system (CNS), disease-specific proteins accumulate and replicate in secondary lymphoid organs prior to neuroinvasion, and their replication there depends on the abundance of cellular prion protein (PrPC ). PrPC is expressed in both central and peripheral lymphoid tissues, and up- or downregulates innate and adaptive immune responses. In addition to prion diseases, PrPC is also immunologically involved in other neurological disorders and infectious diseases, including Alzheimer's disease and human immunodeficiency virus infection. Herein, we summarize the expression and functions of PrPC in various immunocytes, as well as its immunological and pathological roles in neurodegeneration and infection.

Cellular Prion Protein Attenuates OGD/R-Induced Damage by Skewing Microglia toward an Anti-inflammatory State via Enhanced and Prolonged Activation of Autophagy.

Modulation of microglial pro/anti-inflammatory states and autophagy are promising new therapies for ischemic stroke, but the underlying mechanisms remain largely unexplored. The objective of the study is to determine the intrinsic role of PrPC (cellular prion protein) in the regulation of microglial inflammatory states and autophagy in ischemic stroke. PrPC was expressed in murine microglia, and an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model was established in microglia of different PRNP genotypes. During reperfusion following OGD, wild-type (WT) microglia had significantly increased pro/anti-inflammatory microglial percentages and related cytokine [interleukin [IL]-6, IL-10, IL-4, tumor necrosis factor, and interferon-gamma] release at reperfusion after 48 or 72 h. WT microglia also showed greater accumulation of the autophagy markers LC3B-II/I (microtubule-associated protein B-light chain 3), but not of p62 or LAMP1 (lysosome-associated membrane protein) at reperfusion after 24 h and 48 h. Inhibition of autophagy using 3-methyladenine or bafilomycin A1 aggravated the OGD/R-induced pro-inflammatory state, and the effect of 3-methyladenine was significantly stronger than that of bafilomycin A1. Concomitantly, PRNP knockout shortened the accumulation of LC3B-II/I, suppressed microglial anti-inflammatory states, and further aggravated the pro-inflammatory states. Conversely, PRNP overexpression had the opposite effects. Bafilomycin A1 reversed the effect of PrPC on microglial inflammatory state transformation. Moreover, microglia with PRNP overexpression exhibited higher levels of LAMP1 expression in the control and OGD/R groups and delayed the OGD/R-induced decrease of LAMP1 to reperfusion after 48 h. PrPC attenuates OGD/R-induced damage by skewing microglia toward an anti-inflammatory state via enhanced and prolonged activation of autophagy.

Construction of a Prognostic and Early Diagnosis Model for LUAD Based on Necroptosis Gene Signature and Exploration of Immunotherapy Potential.

Necroptosis is a type of programmed necrosis that is different from apoptosis and necrosis. Lung cancer has the highest incidence and mortality worldwide, and lung adenocarcinoma is the most common subtype of lung cancer. However, the role of necroptosis in the occurrence and development of LUAD remains largely unexplored. In this paper, four NRGs and nine NRGs determined by big data analysis were used to effectively predict the risk of early LUAD (AUC = 0.994) and evaluate the prognostic effect on LUAD patients (AUC = 0.826). Meanwhile, ESTIMATE, single-sample gene set enrichment analysis (ssGSEA), genomic variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune checkpoint analysis were used to explore the enrichment characteristics and immune research related to the prognostic model. In deep data mining, we were surprised to find that prognostic models also regulate the immune microenvironment, cell cycle, and DNA damage repair mechanisms. Thus, we demonstrated a significant correlation between model evaluation results, ICI treatment, and chemotherapeutic drug sensitivity. The low-risk population has a stronger tumor immune response, and the potential for ICI treatment is greater. People at high risk respond less to immunotherapy but respond well to chemotherapy drugs. In addition, PANX1, a core gene with important value in immune regulation, prognosis assessment, and early diagnosis, has been identified for the first time, which provides a new target for the immunotherapy of LUAD as well as a new theoretical basis for the basic research, clinical diagnosis, and individualized treatment of LUAD.

Novel Necroptosis-Related Gene Signature for Predicting Early Diagnosis and Prognosis and Immunotherapy of Gastric Cancer.

Necroptosis is a kind of programmed necrosis, which is different from apoptosis and pyroptosis. Its molecular mechanism has been described in inflammatory diseases. Gastric cancer (GC) is one of the most common malignancies worldwide with the third highest mortality. However, the role of necroptosis in the occurrence and progression of GC remains largely unexplored. Therefore, we investigated necroptosis-related genes (NRGs) by analyzing public transcriptomic data from GC samples. Our results indicate that 83 of 740 NRGs are dysregulated in GC tissues. Next, we identified necroptosis-associated early diagnosis and prognostic gene signatures for GC using machine learning. 2-NRGs (CCT6A and FAP) and 4-NRGs (ZFP36, TP53I3, FAP, and CCT6A), respectively, can effectively assess the risk of early GC (AUC = 0.943) and the prognosis of GC patients (AUC = 0.866). Through in-depth analysis, we were pleasantly surprised to find that there was a significant correlation between the 4-NRGs and GC immunotherapy effect and immune checkpoint inhibitors (ICIs), which could be used for the evaluation of immunosuppressants. Finally, we identified the core gene FAP, and established the relationship between FAP and ICIs in GC. These findings could provide a new target for immunotherapy for GC and a more effective treatment scheme for GC patients.

Characteristics and Management of Autoimmune Disease-Associated Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis (CVST) is a central nervous system disease characterised by thrombosis in cerebral venous or dural sinuses. Autoimmune diseases, a series of diseases caused by immune responses to autoantigens, are important causes of CVST. The most common diseases that lead to CVST are Behçet's syndrome, systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren's syndrome. Each of these diseases have different clinical and imaging manifestations and treatment for CVST varies by aetiology. This review summarises the characteristics and the current management strategies for autoimmune disease-associated CVST and emphasises controversial therapeutic strategies to provide informative reference information for diagnosis and treatment. Risk factors of autoimmune antigens should not be neglected when unconventional CVST occurs, and both drugs and interventional therapy need further standardisation and discussion with more prospective clinical studies.

Role of cellular prion protein in splenic CD4+ T cell differentiation in cerebral ischaemic/reperfusion.

OBJECTIVE: Cellular prion protein (PrPC ), the primary form of prion diseases pathogen, has received increasing attention for its protective effect against ischaemic stroke. Little is known about its role in peripheral immune responses after cerebral ischaemia/reperfusion (I/R) injury. This study is to detect the variation of splenic CD4+ T lymphocytes differentiation and the concentration of inflammatory cytokines after murine cerebral I/R injury in the context of PRNP expression as well as its influence on the ischaemic neuronal apoptosis. METHODS: We established the cerebral ischaemic murine model of different PRNP genotypes. We detected the percentage of splenic CD4+ PrPC+ T cells of PRNP wild-type mice and the ratio of splenic Th1/2/17 lymphocytes of mice of different PRNP expression. The relevant inflammatory cytokines were then measured. Oxygen glucose deprivation/reperfusion (OGD/R) HT22 mouse hippocampal neurons were co-cultured with the T-cell-conditioned medium harvested from the spleen of modelled mice and then the neuronal apoptosis was detected. RESULTS: CD4+ PrPC+ T lymphocytes in wild-type mice elevated after MCAO/R. PRNP expression deficiency led to an elevation of Th1/17 phenotypes and the promotion of pro-inflammatory cytokines, while PRNP overexpression led to the elevation of Th2 phenotype and upregulation of anti-inflammatory cytokines. In addition, PrPC -overexpressed CD4+ T cells weakened the apoptosis of OGD/R HT-22 murine hippocampal neurons caused by MCAO/R CD4+ T-cell-conditioned medium, while PrPC deficiency enhanced apoptosis. INTERPRETATION: PrPC works as a neuron protector in the CNS when I/R injury occurs and affects the peripheral immune responses and defends against stroke-induced neuronal apoptosis.

Rare genetic Creutzfeldt-Jakob disease with E196A mutation: a case report.

Genetic Creutzfeldt-Jakob disease (gCJD) accounts for approximately 10-15% of human prion diseases. It is an autosomal dominant disease caused by missense or insertion mutations of the gene that encodes prion protein (PRNP). In general, the manifestations and neuropathological changes of gCJD are similar to those of sporadic CJD (sCJD), and the diagnostic sensitivities of cerebrospinal fluid (CSF) markers, electroencephalography (EEG), and magnetic resonance imaging (MRI) are generally lower in gCJD than sCJD. Here we report on a 56-year-old Chinese woman who was diagnosed with gCJD and suspected to have thyroid cancer. The patient carried the glutamate to alanine substitution at codon 196 (E196A) of PRNP, which is quite a rare mutation and has only been reported in China. To our knowledge, this is the fourth case of E196A gCJD in the world. Here, we compared the manifestations and assistant examinations of the current patient with those of three previously reported Chinese patients with E196A gCJD in order to illustrate the common features of E196A gCJD.