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关键词： iPS cell   retinal pigment epithelium   transplantation   MHC class   rejection  

摘要： PURPOSE. We previously reported that suspensions of CIITA-/- monkey induced pluripotent stem cell-derived retinal pigment epithelium (moiPSC-RPE) that lacks expression of major histocompatibility complex (MHC) class II avoided rejection without systemic immunosuppression. RPE strips represent a novel graft formulation for RPE impairment diseases that may enable mass engraftment but potentially increase rejection risk. This study evaluated host immune responses to allogeneic CIITA+'+ and CIITA-'-moiPSC-RPE strips in MHC-mismatched transplantation in monkey eyes with RPE damage, without systemic immunosuppression. METHODS. RPE strips were generated from CIITA+'+ and CIITA-'-moiPSC-RPE. Following RPE ablation using a microsecond pulse laser, two RPE strips were transplanted into each eye at 1-to 3-week intervals. One monkey received CIITA+'+ moiPSC-RPE strips, while another received CIITA-'-moiPSC-RPE strips. Graft status was monitored through routine ophthalmic examinations, and immunohistologic evaluation was conducted after 5 months. RESULTS. Fluorescein angiography revealed evident leakage in eyes with CIITA+'+ RPE strips beginning 1 to 2 months posttransplantation, with optical coherence tomography showing bulging at the graft site, indicating immune cell accumulation. Immunostaining confirmed the presence of immune cells (CD4, CD8, Iba1, IFN-gamma, MHC class II, and CD20) at CIITA+'+ RPE strip grafts. In contrast, CIITA-'- RPE strip transplants showed no signs of rejection in either eye over 5 months and minimal immune cell presence at the graft site. CONCLUSIONS. Allogeneic transplantation of CIITA-'- RPE strips may reduce rejection risk in RPE-ablated disease model eyes, suggesting potential clinical benefits of MHC class II-deficient RPE grafts, particularly for diseases with inflammatory pathology.

关键词： Antimicrobial peptides   Atopic dermatitis   Barrier function   Innate immunity   Keratinocyte biology  

摘要： Skin barrier dysfunction initiates or deteriorates various cutaneous problems, such as atopic dermatitis. At high concentrations, the nonreducing disaccharide trehalose (a-d-glucopyranosyl a-d-glucopyranoside) induces a transient senescence-like state in fibroblasts and promotes wound repair. In this study, we investigated the effect of trehalose on normal human keratinocytes and demonstrated its specific role in the skin barrier. RNA-sequencing analysis revealed that trehalose regulates the expression of many skin barrier-associated genes. T helper 2 cytokines IL-4/IL-13 were observed to downregulate several differentiation markers (FLG, loricrin, keratin 1, and keratin 10) and epidermal antimicrobial proteins in monolayer-cultured keratinocytes and living skin equivalents and impaired skin barrier function in living skin equivalents, all of which were significantly upregulated or restored by trehalose. Trehalose inhibited IL-33 expression and reduced nuclear IL-33 levels by activating MAPK/extracellular signal-regulated kinase kinase 5-extracellular signal-regulated kinase 5 and suppressing extracellular signal-regulated kinase kinase 1/2-extracellular signal-regulated kinase pathway. It also increased NRF2 activation to trigger antioxidant enzyme production through JNK, thus neutralizing IL-4/IL-13-mediated oxidative stress. Trehalose prevented IL-4/IL-13-mediated signal transducer and activator of transcription 3/signal transducer and activator of transcription 6 activation and restored IL-4/IL-13-suppressed skin barrier molecules through IL-33 downregulation and NRF2 activation. This study demonstrated that trehalose may play a role in skin barrier repair in atopic dermatitis.

关键词： Autoantibodies   Synovium   omics   Innate immunity   Adaptive immunity  

摘要： Background: Around 30% of the patients with rheumatoid arthritis (RA) are seronegative for both rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). In this subset of patients, the lack of biological markers complicates diagnosis and could delay treatment initiation. Seronegative RA presents with a weaker HLA-DRB1 association [1, 2] and a lower infiltration of CXCL13 + CD4 + T cells in the synovium compared to ACPA+ RA [3, 4], suggesting that the adaptive immune system plays a less prominent role in the pathogenesis of seronegative RA. Objectives: We hypothesized that innate immune mechanisms may play a more prominent role in ACPA- RA. Our overall objective was to uncover molecular pathways involved in the pathogenesis of ACPA-RA by identifying unique transcriptomic signatures in synovial mononuclear myeloid cells. Methods: We performed 10X single cell RNA sequencing on immune cells from paired synovial fluid and peripheral blood (PB) from patients with ACPA+ and ACPA- RA (n=4 in each group). We confirmed our finding in a published single cell dataset comprising synovial biopsies from patients with ACPA- (n=6) and ACPA+ RA (n=21), naïve to treatment. We performed full spectrum flow cytometry on synovial fluid mononuclear cells from patients with ACPA- RA, ACPA+ RA and psoriatic arthritis (PsA) as a disease control group (n=8 to 9 in each group). Here, we assessed the frequency of dendritic cell populations and their capacity to produce pro-inflammatory cytokines upon Toll-Like Receptor stimulation. Finally, we measured interferon (IFN) cytokines in synovial fluid and sera of patients with ACPA- RA, ACPA+ RA and PsA (n=9 to 12 in each group). Results: Our analysis revealed an elevated expression of type I IFN-stimulated genes (ISG) and a higher IFN score in SF of ACPA- RA as compared to ACPA+ RA. This IFN signature was derived from synovial dendritic cells, macrophages and T cells and was not detected in PB of ACPA- RA. We also identified a type I

关键词： Adaptive immunity   biological DMARD   Clinical Trial   Biomarkers  

关键词： Chronic Obstructive Pulmonary Disease (COPD)   Small airway disease   Biomass smoke   IL-17a   IL-17a   NR1D1  

摘要： Introduction: Biomass smoke (BS) exposure is a critical environmental risk factor for Chronic Obstructive Pulmonary Disease (COPD). In this study, mechanisms of biomass smoke (BS)-induced small airway disease are explored, with a focus on the roles of Interleukin-17a (IL-17a) and Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1). Methods: This study included 20 BS exposure COPD (BS-COPD) patients and 13 controls, who underwent chest high-resolution computed tomography (HRCT) scans to assess emphysema and small airway disease. The control group was divided into a low- and high BS exposure control group. Serum IL-17a levels were measured. Wild-type and IL-17a-/- B6/C57 mice were exposed to wood smoke to establish a COPD model in mice. Airway pathology was evaluated by histological analysis. The effects of IL-17a and NR1D1 on cell proliferation of BEAS-2b cells exposed to wood smoke particulate matter 2.5 were assessed in vitro using flow cytometry and Western blotting. Results: HRCT revealed significantly higher small airway disease and emphysema in BS-COPD patients compared to controls (p < 0.01). Small airway disease exhibited the strongest negative correlation with FEV1%predicted (r = -0.61, p = 0.004). High-exposure control group showed significant BS Index correlations with small airway disease (r = 0.81, p = 0.049) and emphysema (r = 0.87, p = 0.025). Serum IL-17a levels correlated with small airway disease in BS-COPD (r = 0.48, p = 0.033). The mouse model demonstrated higher airway wall thickness and small airway disease in IL-17a-/- mice exposed to wood smoke. In vitro, IL-17a promoted BEAS-2b cell proliferation, an effect enhanced by NR1D1 downregulation. Conclusions: BS exposure drives emphysema and small airway disease in non-COPD individuals. NR1D1 downregulation exacerbates IL-17a-mediated remodeling in vitro, suggesting therapeutic potential. Trial registration: ChiCTR-OOC-16008692

关键词： Bipolar disorder   Schizophrenia   sHLA-E   Inflammation   Natural killer cells  

摘要： Objectives. - Schizophrenia (SZ) and bipolar disorders (BP) are chronic and severe neuropsychiatric diseases. These disorders are tightly related to immune deregulations. In the current study, we intended to replicate the previously reported involvement of the soluble HLA-E isoforms (sHLA-E) in the risk of developing the two conditions along with disease severity in a Tunisian population group. Patients and methods. - One hundred and twenty-four patients with schizophrenia and 121 with bipolar disorder meeting the DSM-IV criteria along 111 healthy controls were included in this present case-control study. The soluble HLA-E isoforms circulating levels were measured using the ELISA method. The statistical analyses were performed using Kruskal-Wallis and Wilcoxon rank sum tests by R software and GraphPad prism 9. Results. - We found that the sHLA-E circulating levels were significantly higher in BP patients as compared to healthy controls (P < 0.0001) and that such increases were mainly observed in patients during an acute phase of their disease (P < 0.0001). In SZ patients, while we failed to observe an association with the levels of sHLA-E in the entire SZ sample, we found that high sHLA-E levels characterized stabilized patients in comparison with those during an acute episode (P = 0.022). Finally, we did not observe any association between sHLA-E circulating levels and symptoms assessed by the classical clinical scales either in BP or SZ patients. Conclusion. - Overall, the present findings replicate in a Tunisian population group the previously demonstrated implication of sHLA-E circulating levels in the risk of developing BP or SZ in a French patient cohort. Such replication allows to consider HLA-E as a potent and true inflammatory marker in the context of the two disorders. (c) 2024 L'Encephale, Paris.

关键词： Syringomyelia   TNF-alpha   Necroptosis   Reactive astrocytes   Infliximab   Sensory dysfunction  

摘要： Syringomyelia is a severe and progressive disease characterized by fluid-filled cavities that form within the spinal cord, leading to progressive neurological deterioration. However, the molecular mechanisms that cause neuronal death and subsequent dysfunction remain incompletely understood. This study demonstrates that tumor necrosis factor-alpha (TNF-alpha)-mediated necroptosis plays a crucial role in neuronal death during syringomyelia progression. RNA-seq analysis revealed significantly elevated necroptosis scores at both 14 and 28 days after syrinx formation, with identified disease-related differentially expressed necroptosis genes primarily enriched in TNF-alpha-related signaling pathways. Through establishing a rat model of syringomyelia with central canal dilation, significant activation of necroptosis markers, phosphorylated receptor-interacting protein kinase 3 (p-RIPK3) and phosphorylated mixed lineage kinase domain-like protein (p-MLKL), was observed in the area surrounding the syrinx, with their expression predominantly localized to neurons. Concurrently, we found markedly elevated TNF-alpha levels around the syrinx, and primarily originating from reactive astrocytes (70.29 %). Upregulation of TNF receptor 1 (TNFR1) in perilesional neurons suggested enhanced sensitivity to TNF-alpha-mediated death signals. Subsequently, administration of the TNF-alpha inhibitor infliximab at day 14 post-modeling significantly alleviated the expression of necroptosis markers and attenuated the progression of sensory dysfunction at day 28, even in the presence of persistent syrinx. This study is the first to reveal TNF-alpha-mediated neuronal necroptosis as a crucial mechanism in neurological deterioration in syringomyelia, providing novel molecular targets for treatment. These findings suggest that targeting this pathway, particularly in combination with conventional surgical approaches, may offer therapeutic benefits for patients with syringomyelia.

关键词： Interleukin-6   gp130   BACE1   Long-term potentiation   Neuronal activity   Verubecestat   AZD3839  

摘要： The pleiotropic cytokine IL-6 regulates numerous processes in the body, including neuronal functions. IL-6 either binds to membrane-bound receptor (mIL-6R) and triggers signaling via heteromerization with the signal transducer gp130 (classical signaling), or binds to its soluble form (sIL-6R) to act on cells that do not express mIL-6R (trans-signaling). The ss-secretase BACE1 can cleave gp130 as well as IL-6R and we hypothesized that BACE1 may alter neuron activity and synaptic transmission via modulation of IL-6 signaling. We used multielectrode array (MEA) recordings to monitor electrical activity of neuronal networks in acute cerebellar slices as well as long-term potentiation (LTP) induced by high-frequency stimulation in the hippocampus and to assess how exposure to IL-6 affects these processes. A pharmacological approach was applied to elucidate the contribution of trans-signaling involving BACE1. Spontaneous neuronal activity in cerebellar slices significantly decreased upon perfusion with IL-6 but not LIF and recovered during wash out. BACE1 inhibitors verubecestat or AZD3839 abolished the inhibitory effects of IL6. Furthermore, IL-6 and LIF reversibly inhibited LTP in hippocampal slices, and in contrast to cerebellar neurons, BACE1 inhibitors verubecestat or AZD3839 did not abolish the inhibitory effect of IL-6 on LTP. Interestingly, a dramatic rebound effect on excitatory postsynaptic potentials was observed with BACE1 inhibitor AZD3839 but not verubecestat during wash out. Our results support relevant and differential roles of IL-6, LIF and BACE1 in pathways modulating neuronal discharge activity in the cerebellum and the synaptic plasticity in the hippocampus, and a possible involvement of this interaction in deficits of memory and learning.

关键词： biological DMARD   Outcome measures   Observational studies/ registry  

关键词： alleles   breast neoplasms   high-throughput nucleotide sequencing   HLA-DP antigens   point mutation  

摘要： Identification of the novel alleles HLA-DPA1*02:142 and HLA-DPA1*01:03:01:92.