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摘要： Neuroimmune conditions in children often present with overlapping clinical features, making early diagnosis and therapeutic decisions challenging. Given the urgency of initiating timely treatments in severe cases, there is a pressing need for reli...

摘要： Plasmacytoid dendritic cells (pDCs) are major producers of type I interferon (IFN-I), an important antiviral cytokine, and activity of these cells must be tightly controlled to prevent harmful inflammation and autoimmunity. Evidence exists that one regulatory mechanism is a fate-switching process from an IFN-I-secreting pDC to a professional antigen-presenting conventional dendritic cell (cDC) that lacks IFN-I-secreting capacity. However, this differentiation process is controversial owing to limitations in tracking the fate of individual cells over time. Here we use single-cell omics and functional experiments to show that activated human pDCs can lose their identity as IFN-I-secreting cells and acquire the transcriptional, epigenetic and functional features of cDCs. This pDC fate-switching process is promoted by tumor necrosis factor but blocked by IFN-I. Importantly, it occurs in vivo during human skin inflammatory diseases and injury, and physiologically in elderly people. This work identifies the pDC-to-cDC reprogramming trajectory and unveils a mechanistic framework for harnessing it therapeutically.

关键词： Non-HLA antibodies   Threshold cut off   Sensitization  

摘要： Background: Measuring non-HLA antibodies is a potentially important tool in assessing allograft dysfunction and needs to be correlated with clinical outcomes. Thus, determining the antibody distribution in healthy populations is important before correlating with clinical events. Using male blood donors, we selected a low immunological risk control cohort. Methods: We analyzed samples from 92 male, non-transfused blood donors (donors) to assess the detection of antibodies in a normal population cohort using a non-HLA 33 antigen multiplex commercial assay. Results: At manufacturer's suggested cutoff threshold (COT) of 75 % percentile, no donors had negative results and at 95 % percentile only three donors were negative across all 33 antigens. At each of the manufacturer's COT, the median (IQR) number positive antibody bead tests per donor was 13 (10-17), 11 (8-13) and 7 (5-10) at 75th, 85th and 95th percentile COT, respectively. There was poor correlation between manufacturer's COT and locally generated COT (range r = 0.520 to 0.595). The percentage of donors who had three or more positive antibody bead tests was: 98.9 % at 75th COT;95.7 % at 85th COT and 93.5 % at 95th COT. Conclusions: Considering the high proportion of positive results in a low immunological risk cohort, application of non-HLA antibody measurement in a diseased cohort is not optimal, and difficult to correlate with clinical events. Further studies to determine normal detection rates are needed for assay COT and clinical application in diseases.

关键词： autoimmunity   LADA   latent autoimmune diabetes in adults   T1D   type 1 diabetes   IFN-alpha   neutralizing antibody  

摘要： Context Autoantibodies against interferon-alpha (AAb-IFN-alpha) might be associated with the less aggressive autoimmunity in latent autoimmune diabetes in adults (LADA) compared to early-onset type 1 diabetes (T1D).Objective To investigate the presence and clinical relevance of the positivity to AAb-IFN-alpha in people with LADA compared to *** Design and Methods Serum levels of AAb-IFN-alpha isoforms were measured using a cell-based approach in 41 subjects with LADA and 90 subjects with *** The primary and secondary outcomes were the difference between LADA and T1D in the proportion of participants testing positive for autoantibodies (AAb) against >= 2 and against 3 interferon-alpha (IFN-alpha) isoforms, respectively. The presence and levels of AAb-IFN-alpha were related to clinical and biochemical features of participants with *** Seven (17.1%) and 5 (12.2%) participants with LADA and 3 (3.3%) and 0 participants with T1D showed positivity for AAb against >= 2 and 3 IFN-alpha isoforms (P = .011 and P = .0025, respectively). Fasting blood glucose and hemoglobin A1c levels were numerically lower among people with LADA testing positive for AAb against >= 2 IFN-alpha isoforms than among those who were either negative or positive for AAb against 1 IFN-alpha isoform. Among LADA-positive individuals, levels of AAb-IFN-alpha 2 isoform were inversely correlated with glutamic acid decarboxylase antibodies levels (rho = -0.513;P = .025).Conclusion Autoimmunity against IFN-alpha is peculiar to autoimmune diabetes and appears to be distinctive to its slowly progressive forms. Understanding the underlying molecular mechanisms and clinical significance of this novel autoimmunity could lead to the development of new therapeutic strategies in autoimmune diseases, advancing personalized medicine.

关键词： Non-classical MHC   L lineage   Salmonids   Molecular evolution  

摘要： Non-classical MHC class I molecules, which are encoded by a diverse gene family, have a wide range of functions that can be immune-or non-immune related. From an evolutionary perspective, different non-classical MHC class I genes are typically specific to smaller phylogenetic groups and are often not well conserved among species within these groups rendering non-classical MHC phylogeny difficult to establish. Here we perform a comparative analysis spanning non-classical MHC class I L lineage gene content, organization, phylogeny and variability across divergent salmonid species, providing insight into L lineage immune system variation and species-specific adaptations. Based on evolutionary relationships and sequence analysis, salmonid L lineage genes can be classified into three clades, each with distinct features. Clade I gene sequences exhibit significant variation within species, comprising multiple haplotypes and null alleles, as well as notable variations between species, including highly flexible gene numbers and patterns of pseudogenization. Clade I genes comprise eleven subclades, each displaying separate evolutionary patterns, characteristic phylogenetic marker motifs and subclade specific promoter regions, indicative of unique regulatory patterns and subclade specific functional roles. Our study reveals two distinct phylogenetic patterns among these genes: some subclades display a high degree of flexibility, as demonstrated by species specific expansions and contractions, whereas others have been maintained as mono-genic subfamilies with remarkably few changes in their nucleotide sequence across divergent species. Comparably, clade II L lineage genes consist of four subclades, among which LIA and LLA genes are full length genes with species specific pseudogenization patterns. We report compelling evidence that the LIA gene lineage is highly conserved and present in all 23 Salmonidae species examined as well as in representative Esociformes. This suggests t