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摘要： At the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2024 annual meeting, Drs. Dennis McGonagle and Wilson Liao discussed "MHC-I-opathies," a class of immune-mediated diseases genetically associated with major histocompatibility complex class I (MHC-I) and class I peptide processing. MHC-I-opathies demonstrate epistatic interactions, genetic associations, and immunopathology that are distinct from classic B cell and autoantibody-driven autoimmune diseases. Investigations into the pathomechanisms of MHC-I-opathies have revealed a blend of tissue-specific innate immunity and CD8 T cell responses. Several functional pathomechanisms by which MHC-I molecules increase psoriasis (PsO) susceptibility were presented by McGonagle and Liao, and there were multiple associations within the HLA-C locus. Antigen presentation to T cells, HLA regulation of natural killer cells and CD8 T cells through killer immunoglobulin-like receptors, and HLA regulation of dendritic cells through leukocyte immunoglobulin-like receptors were discussed. Interestingly, MHC-I associations are not only linked to excessive inflammation in MHC-I-opathies but also to the spontaneous suppression of infection (eg, HIV-1 elite controllers). This striking prominence of MHC-I in PsO and antiviral immunity provides insight into why autoimmune alleles are maintained in the human genome and how protective antiviral pathways may be linked to aberrant activation of MHC-I-opathies. Outside of spinal inflammation in HLA-B27-positive axial psoriatic arthritis (PsA), the basis for MHC-I genetics in PsA remains less clear and is at least partly linked to greater PsA heterogeneity. Understanding the contribution of MHC-I in PsO and PsA may have important implications for therapy development.

关键词： ELISA   interleukin 17A   psoriasis   secukinumab   therapeutic drug monitoring  

摘要： Secukinumab has been approved for the treatment of psoriasis. Off-label high-dose regimens have been used for certain patients. Therapeutic drug monitoring can assist in adjusting treatment plans. This study aimed to determine the therapeutic threshold of secukinumab and evaluate the influence of patient characteristics on secukinumab concentrations in patients with psoriasis. Patients with psoriasis (n = 36) treated with secukinumab during the maintenance therapy were enrolled in this cross-sectional study. Disease activity was determined using the psoriasis area and severity index (PASI) score, with an optimal response (OR) defined as <= 2. Secukinumab trough concentrations were measured using an in-house developed sandwich ELISA method. The median secukinumab concentrations in patients with OR were significantly higher than in those without (35.08 vs. 25.94 mu g/mL, p < 0.05). Secukinumab levels greater than 35.43 mu g/mL were associated with OR (sensitivity of 50.00%, specificity of 89.89%, AUC = 0.70 and p < 0.05). Multivariate logistic regression showed that secukinumab concentrations were significantly associated with OR (odds ratio: 1.02;95% CI: 1.01-1.12;p = 0.04). Linear mixed-effects analysis indicated that an increase in body weight and a decrease in albumin were associated with a decrease in secukinumab concentrations. IL-17A levels showed no correlation with PASI score or secukinumab concentrations. Secukinumab concentrations over 35.43 mu g/mL were associated with OR in patients with psoriasis. When determining the treatment dose, attention may be paid to patients with higher body weight and lower albumin levels in order to prevent underdosing.

关键词： MHC   Nsp1   ORF8  

摘要： Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition.

关键词： Host-directed therapy   Staphylococcus aureus   Intracellular infection   Immune regulation   Drug-target interaction   AD   atopic dermatitis   ADAM   a disintegrin and metalloproteinase   AMP   antimicrobial peptides   AMPK   adenosine monophosphate-activated protein kinase   AP1   activation protein 1   APCs   antigen-presenting cells   CADD   computer-aided drug design   CAR   chimeric antigen receptor   Cas   caspase   Clf   clumping factor   CLR   C-type lectin receptor   Cna   Cn adhesin   CRSwNP   chronic rhinosinusitis with nasal polyps   DC   dendritic cell   EGFR   epidermal growth factor receptor   ERK   extracellular signal-related kinase   FcɛRI   high affinity receptor for IgE   FLA   flagellin   FnBP   fibronectin-binding protein   FPR2   formyl peptide receptor 2   GABA   gamma-aminobutyric acid   GAPDH   glyceraldehyde-3-phosphate dehydrogenase   G/M-CSF   granulocyte/macrophage colony-stimulating factor   HCAR2   hydroxycarboxylic acid receptor 2   HDAD   host-directed antimicrobial drug   HDT   host-directed therapy   HLA-Cw6   human leukocyte antigen Cw6   HMG-CoA   3-hydroxy-3-methylglutaryl coenzyme A   IFN   interferon   IKK   IκB kinase   IL   interleukin   IL-5R   IL-5 receptors   ILC   innate lymphoid cell   IRAK   IL-1 receptor-associated kinase   ITAM   immunoreceptor tyrosine-based activation motif   ITIM   immunoreceptor tyrosine-based inhibition motif   JNK   Jun amino terminal kinase   LPS   lipopolysaccharide   MAPK   mitogen-activated protein kinase   MBL   mannose-binding lectin   MDP   muramyl dipeptide   Myd88   myeloid differentiation primary response 88   MRSA   methicillin-resistant   S. aureus   MSSA   methicillin-susceptible   S. aureus   NADPH   nicotinamide adenine dinucleotide phosphate   NE   neutrophils   NEMO   NF-κB essential modulator   NET   neutrophil extracellular trap   NF-κB   nuclear factor-kappa B   NLRP   NOD-, LRR- and pyrin domain-containing protein   NOD   nucleotide-binding oligomerization domain   OPG   osteoprotegerin   PAMP   pathogen-associated molecular patterns   PDIA3   protein disulfide isomerase family A member 3   PRR   pattern-recognition receptor   PSM   phenol-soluble modulin   PVL   Panton-Valentine leucocidin   RANKL   receptor activator of nuclear factor-κB ligand   RIP2   recep  

摘要： Background Staphylococcus aureus poses a significant global threat to both human and animal health. Bacterial-targeted therapies are limited by strong selective pressures (e.g., mecA -mediated β-lactam resistance) and the pathogen’s remarkable capacity for phagocyte intracellular survival—a strategy that allows them to evade antibiotics and the immune system, ultimately leading to persistent infections. These factors highlight the urgent need for alternative strategies to combat bacterial infections. Aim of review This review explores host-directed therapies (HDTs) as alternative strategies for combating S. aureus infections, aiming to overcome limitations of current treatments and contribute to the development of novel or combination therapies. Key scientific concepts of review HDTs offer several advantages, including a reduced risk of bacterial resistance, a broad antimicrobial spectrum, and the potential for synergy with antibiotics to shorten treatment duration and even treat persistent intracellular infections. Target-based precision drug design shows strong promise in addressing off-target effect challenges. This review provides an overview of key host factors involved in S. aureus pathogenesis, emphasizing therapeutic agents targeting these factors, their mechanisms of action, and pharmacological profiles. These recent advancements are crucial in the ongoing efforts to combat S. aureus infections.

关键词： non-human leukocyte antigen antibodies   angiotensin II type 1 receptor antibody   endothelin-type A receptor antibody   kidney   cytokines   pediatric   AT1R   angiotensin II type 1 receptor   DSA   donor specific antibody   eGFR   estimated glomerular filtration rate   ETAR   endothelin-type A receptor   HLA   human leukocyte antigen  

摘要： Activating antibodies to angiotensin II type 1 receptor and endothelin type A receptor (AT1R and ETAR-Abs) have been associated with rejection, allograft loss, decline in allograft function, and development of HLA donor specific antibodies in kidney transplantation. Understanding immune dysregulation and inflammatory signatures associated with these antibodies is important for generating targeted investigations of pathogenesis. We investigated a panel of 38 cytokines in a multicenter cohort of 133 pediatric kidney transplant recipients with 1 to 2 years of follow up to further elucidate AT1R and ETAR-Ab associated inflammatory signatures. Pre- and post-transplant blood samples (n=483) were tested for AT1R-Ab, ETAR-Ab, and 38 cytokines. The relationship between AT1R and/or ETAR-Ab positivity and cytokine elevations were evaluated accounting for demographic and clinical factors. AT1R and/or ETAR-Ab positivity was associated with elevations in 33/38 cytokines, with some elevations resolving or intensifying on post- vs pre- transplantation samples. Interrogation of this data using z-score comparisons and principal component analyses revealed a strong signal for IL-9, IL-13, IL-5, IL-4, IL-6, lymphotoxin alpha and granulocyte-macrophage colony-stimulating factor (GMCSF): cytokines involved with antibody formation and Type 2 immune responses. The relationship of this signal to transplant outcomes and impact of adjunctive receptor blockade requires additional investigation.

关键词： diversity   genetics   haematopoietic cell transplant   HLA-E   non-classical HLA  

摘要： HLA-E is a non-classical HLA class I gene with limited reported genetic variability and few published studies into full-gene sequencing or population allele frequencies. Two protein variants, HLA-E*01:01 and HLA-E*01:03, are very common, accounting for 94%-100% of observed alleles in most studies performed to date. Frequently utilised exon-based sequencing strategies have led to the assumption of HLA-E being a near bi-allelic gene;however, recent full-gene sequencing studies have shown a greater degree of genetic variability than initially imagined. We carried out a literature review of HLA-E genotype and ethnicity data, which suggested HLA-E*01:03 is more common in Asian and, in particular, East Asian populations. Furthermore, HLA-E*01:03:02 is more frequently observed than HLA-E*01:03:01 in European and American populations, whereas HLA-E*01:03:01 is found at higher frequencies in Asian populations. It has been proposed that HLA-E may have a role in Haematopoietic Cell Transplantation (HCT) due to its interaction with NK and CD8+ T cells and its non-canonical peptide binding repertoire. Here we also review published literature into the effects of HLA-E genetics on HCT outcomes. Heterogeneity between cohorts muddies the waters;hence, studies report confounding effects of HLA-E genotype and matching on HCT outcomes. The need for further HLA-E sequencing of larger cohorts is evident to gain useful insight into the true genetic variability of HLA-E and its impact on HCT.

关键词： Clonal haematopoiesis   Angina pectoris   Unstable angina pectoris   Interleukin-1β   Atherosclerotic plaque stability   AP   angina pectoris   CHIP   clonal haematopoiesis of indeterminate potential   CVDs   cardiovascular diseases   EAF   effect allele frequency   GWAS   genome-wide association study   ICD   International Classification of Diseases   IL   interleukin   IVW   inverse-variance weighted   LD   linkage disequilibrium   MR   Mendelian randomization   PSM   propensity score matching   SAP   stable angina pectoris   SD   standard deviations   UKB   UK Biobank   VAF   variant allele fraction  

摘要： Introduction Clonal haematopoiesis of indeterminate potential (CHIP) has been reported to increase the risk of various diseases, including cardiovascular diseases (CVDs). In contrast, a newly published study suggests that CHIP itself may not directly contribute to the risks of CVDs or other age-related conditions. CHIP could also serve as a protective factor against certain diseases, such as Alzheimer’s disease. However, protective effects of CHIP against CVDs have rarely been investigated. Objectives To demonstrate the associations with CHIP and lower angina pectoris (AP) risk especially unstable angina pectoris (UAP), and explore potential mechanisms. Methods This study was carried out based on UK Biobank cohort. General linear models adjusted for covariates were used to detect associations between CHIP and AP. Propensity score matching models were used for validation. Mendelian randomization was utilized for causality inference. Mediation analysis was conducted to explore underlying mechanisms of cytokines level. Results In covariate models, large overall CHIP was associated with reduced AP and UAP risk. Large TET2 CHIP reduced AP and UAP risk. Propensity score matching models confirmed that large TET2 CHIP protected against AP and UAP. Mendelian randomization supported the effects of large TET2 CHIP against UAP. Large TET2 CHIP was linked to increased IL-1β levels, with IL-1β mediating the protection against UAP. Conclusions CHIP protected against AP, with large TET2 CHIP specifically protecting against UAP. Elevated IL-1β levels might mediate this effect via plaque stabilization.

关键词： Fungal infections   Immunology   Infectious disease   Neutrophils  

摘要： Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling the local expression of a subunit required for NADPH oxidase assembly and activity in the lung.

关键词： aged MSCs   autologous stem cell therapies   CD74   immunogenicity   MHC class II   young microenvironment  

摘要： Older adults are the primary population for cell-based therapies for age-related diseases, but the efficacy of administering autologous mesenchymal stem cells (MSCs) is impaired due to biological aging. In the present study, we cultured aging adipose (AD)-derived MSCs from > 65-year-old donors on extracellular matrix (ECM) synthesized by human amniotic fluid-derived pluripotent stem cells (ECM Plus) versus tissue culture plastic (TCP) and hypothesized that ECM Plus provided an ideal "young" microenvironment for reactivating and preserving early-stage progenitor cells within aging AD-MSCs. To test our hypothesis, we serially sub-cultured aging AD-MSCs on ECM Plus or TCP and characterized the cells both phenotypically and functionally, and then analyzed the cells at the single-cell transcriptomic level for the mechanisms that control cell fate. The results showed that the maintenance of aging AD-MSCs on ECM Plus significantly restored their quantity and quality. The mechanisms responsible for these effects were associated with a remarkable up-regulation of intracellular CD74 when cells were maintained on ECM Plus compared to TCP, which triggered activation of the phosphoinositide-3-kinase (PI3K) pathway as a key modulator of cell survival (anti-apoptosis) and suppression of cellular senescence. Moreover, AD-MSCs maintained on ECM Plus increased their expression of HLA-DR and stimulated T cell activity. These findings challenge the "immune privilege" of allogeneic MSCs as a universal source for MSC-based therapies. The present study leads to a new paradigm for treating age-related diseases: serial administration of rejuvenated autologous MSCs, which may not only replace aged MSCs but also gradually reverse the aged microenvironment.

关键词： atherosclerosis   cardio-oncology   endothelial cells   imatinib mesylate   inflammation  

摘要： BACKGROUND:Imatinib, the first Abl-tyrosine kinase inhibitor (TKI), improved leukemia outcomes without cardiovascular side effects. Newer agents, including ponatinib, addressed imatinib resistance, improving cancer remission, but substantially increased arterial thrombotic events, including myocardial infarction (MI) and stroke. The mechanism behind ponatinib-induced thrombosis and the cardiovascular effect of asciminib, a newly approved Abl-TKI, remain unknown. METHODS:The effect of clinically relevant plasma concentrations of imatinib, ponatinib, and asciminib were compared with vehicle in vivo using SR-BI-mut/LDLR-knockout (KO) mice to assess spontaneous MI and stroke risk. The mechanism was interrogated in C57BL/6J mice, assessing leukocyte trafficking and thromboinflammation by intravital microscopy and flow cytometry, respectively, and in ApoE-KO mice, assessing plaque phenotype by flow cytometry and histology. In vitro effect on human umbilical vein endothelial cells (ECs) and human coronary artery ECs was determined by flow cytometry, PCR, and immunoblotting. The role of TNF (tumor necrosis factor) signaling was evaluated by pharmacological inhibition and small interfering RNA knockdown. RESULTS:In SR-BI-mut/LDLR-KO mice, ponatinib significantly accelerated death from MI and stroke compared with vehicle, imatinib, and asciminib. In human ECs, only ponatinib increased expression of TNF receptors (TNFRs) and adhesion molecules (P-selectin, ICAM1 [intercellular adhesion molecule 1], and VCAM1 [vascular cell adhesion molecule 1]). Ponatinib rapidly induced TNFR2 membrane trafficking and TNF signaling in human umbilical vein ECs. TNFR inhibition or TNFR2 knockdown prevented ponatinib induction of EC adhesion molecules. In vivo, ponatinib increased mesenteric vessel adhesion molecules, leukocyte rolling and adhesion to vessels, leukocyte and platelet activation, and platelet-leukocyte aggregates. In ApoE-KO mice, ponatinib increased plaque necrotic core and inflam