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关键词： Ankylosing Spondylitis   Arthritogenic Peptides   HLA-B*14   HLA-B*27   Mass Spectrometry   Peptide Repertoires   cross-reactivity  

摘要： The human major histocompatibility complex class I gene HLA-B*27 is the main risk factor for ankylosing spondylitis (AS) through a mechanism that remains unknown. In African populations, where B*27 is rare, the B*14:03 allotype is strongly associated with AS, whereas B*14:02, which differs at only one residue (L156R), is not associated. Using large-scale mass spectrometry-based peptide sequencing, we analyzed the peptidomes of HLA-B*14:03, HLA-B*14:02, and HLA-B*27:05, obtaining more than 2000 ligands for each. Remarkably, we identified 1011 peptides shared by the AS-associated HLA-B*27:05 and B*14:03 alleles but not by the non-AS-associated B*14:02 allele. Surprisingly, although B*14:03 and B*27:05 differ by 15 amino acids in their peptide-binding domain, they share a large portion of their ligands (64 and 43%, respectively), while B*14:03 and B*14:02, differing by only one residue, show less overlap (33-35%). The B*14:03 peptide repertoire most closely resembles that of B*27:05 at the P1, P2, and P5 peptide positions but diverges at the C-terminus, where B*14:03 is more selective. Structural modeling suggests that the L156R difference between B*14 alleles may induce long-range effects on peptide binding at P1, P2, and P5 residues, explaining the distinct repertoires. Most of the 1011 shared ligands contained R/K/A/G at P1, R at P2, and L/F at the C-terminus. Of these, ten peptides were previously identified as ligands of the three HLA-B*27 subtypes most strongly associated with AS and are absent in nonassociated subtypes, while four peptides from the HLA 169 to 181 region-previously implicated in AS pathogenesis-were also identified, suggesting that differential peptide binding may influence disease development. In summary, the AS-associated allotypes B*14:03 and B*27:05, but not the non-AS-associated allotype B*14:02, share similar peptide repertoires and binding characteristics, supporting specific common peptide ligands of HLA-B*27:05 and B*14:03 as a mechanism

关键词： IFN-γ   helminth   microbiota   intestinal immunity   stroma   neutrophils  

摘要： IFN-gamma function during a type-2 helminth infection remains enigmatic. Westfall et al. found an unexpected role for IFN-gamma in limiting tissue damage during intestinal infection by Heligmosomoides polygyrus bakeri (Hpb). IFN-gamma produced by CD8+ T cells stimulates stromal cells directly to recruit neutrophils, where they prevent tissue damage caused by the worms.

关键词： IL-17C   PPP6C   psoriasis   SMURF2   ubiquitination  

摘要： Psoriasis, a persistent inflammatory skin condition, affects approximately 2%-3% of the world's population. Increased IL-17C levels are noted in psoriatic lesions, alongside IL-17's ability to diminish protein phosphatase 6 catalytic subunit (PPP6C) expression in keratinocytes. Additionally, SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) facilitates the degradation of specific substrates through ubiquitination. However, the precise mechanisms of action involving IL-17C, SMURF2, and PPP6C in psoriasis remain unclear. Therefore, this study aims to delve into how IL-17C, SMURF2, and PPP6C contribute to psoriasis development. A psoriasis mice model was established using 5% imiquimod cream. And the expression of IL-17C, SMURF2, and PPP6C was tested. Further, an investigation was conducted using experimental techniques such as CCK-8, flow cytometry, colony formation assay, ELISA, qRT-PCR, western blot assay, co-immunoprecipitation, and ubiquitination assays. Employing both lentiviral transfection and plasmid transfection methods, an in-depth investigation was conducted into the contributions of IL-17C, SMURF2, and PPP6C to psoriasis. The results showed that the IL-17C, Keratin 17 and SMURF2 were increased, and PPP6C was decreased in psoriasis mice model. Further, IL-17C enhanced the cell viability of human epidermal keratinocytes (HaCaT), induced inflammatory responses, and upregulated SMURF2 and Keratin 17 expression. When SMURF2 was silenced, the effects of IL-17C on HaCaT cells were significantly inhibited. Moreover, SMURF2 interacted with PPP6C, promoting its ubiquitination and degradation. Overexpression of SMURF2 further enhanced the effects of IL-17C on HaCaT cells by targeting PPP6C. In conclusion, our study uncovered the upregulation of SMURF2 mediated by IL-17C, leading to psoriasis-like alterations in keratinocytes through the promotion of PPP6C ubiquitination. This novel finding not only provides crucial insights into the molecular mechanisms of psoriasi

关键词： IL1B   Single-nucleotide polymorphism   ANCA-associated vasculitis   Guangxi population  

摘要： Neutrophils and monocytes are involved in the pathogenesis of AAV(antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis), and secreted IL-1 beta is also closely related to the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This study aimed to investigate the association between IL1B gene polymorphisms and AAV susceptibility in the Guangxi *** collected peripheral blood from 271 AAV patients and 297 healthy controls for DNA extraction. Genotyping of rs1143627, rs16944, and rs2853550 was performed via multiplex polymerase chain reaction combined with high-throughput sequencing. This study revealed that the allele frequencies of rs1143627 and rs16944 varied significantly between the case groups and the healthy controls (p = 0.015, p = 0.036). There was an increased risk of homozygous mutations in the rs1143627 codominant and recessive models (p = 0.046, p = 0.025). Similarly, the risk of a homozygous rs16944 mutation was increased (p = 0.08, p = 0.03). In particular, in Han Chinese women, the risk of disease development is increased. There is strong linkage disequilibrium between rs1143627 and rs16944. Among the five haplotypes,no haplotype was associated with the occurrence of disease (p > 0.05). IL1B gene polymorphisms (rs1143627, rs16944) may increase the risk of ANCA-associated vasculitis in the Guangxi population.

关键词： Phellodendrine chloride   Gouty arthritis   Chondrocytes   STAT3   Proteoglycan  

摘要： Background: Phellodendrine, a primary bioactive constituent of Phellodendron chinense Schneid (PCS), is crucial in its pharmacological profile. Phellodendrine exhibits potent anti-nephritic properties and demonstrates a marked inhibitory effect on the cellular immune response. However, the effects of phellodendrine on proteoglycan depletion and cartilage degeneration in gouty arthritis remain insufficiently understood. Therefore, the objective of this study is to elucidate the therapeutic potential and underlying mechanisms of phellodendrine chloride (PC) in the treatment of gouty arthritis. Methods: A monosodium urate (MSU)-induced arthritis model in rats, along with a peritonitis model in mice, was developed, in combination with a chondrocyte model. Neutrophil proportions were quantified using flow cytometry. The expression levels of MMP-3, STAT3, and phosphorylated STAT3 (p-STAT3) in chondrocytes were determined by Western blot analysis. Proteoglycan levels in chondrocytes were assessed using toluidine blue staining and quantitative reverse transcription PCR (qRT-PCR). Joint swelling rates were monitored at 0-24 h in rats, and histopathological changes in joint tissues were subsequently analyzed. Results: Phellodendrine chloride mitigated the rise in neutrophil proportions within MSU-induced peritoneal lavage fluid in mice and decreased inflammatory cell infiltration in rat ankle tissues. Treatment with phellodendrine chloride led to a downregulation of MMP-3 protein levels and inhibited IL-1 beta-induced proteoglycan degradation in chondrocytes. Additionally, results from experiments combining IL-1 beta with AG490 or IL-6 demonstrated that phellodendrine chloride attenuated IL-1 beta-induced MMP-3 expression and proteoglycan degradation. Conclusion: Our findings suggest that phellodendrine chloride mitigates gouty arthritis (GA) by modulating the IL-6/STAT3 signaling pathway.

关键词： HLA class II   italic>HLA-DRB5*01:133   HLA-typing   new HLA allele   next-generation sequencing  

摘要： A transition in codon 16 in the peptide-binding domain results in the novel HLA-DRB5*01:133 allele.

关键词： ankylosing spondylitis (as)   ectopic ossification   guillain-barré syndrome (gbs)   hla-b27   neurogenic heterotopic ossification (nho)  

摘要： We report an exceptional case of neurogenic heterotopic ossification (NHO) developing in a 28-year-old female with pre-existing human leukocyte antigen B27 (HLA-B27) positive ankylosing spondylitis (AS), following a severe course of Guillain-Barré syndrome (GBS). Seven days postpartum, she developed acute GBS requiring three months of intensive care, intubation, mechanical ventilation, and plasmapheresis, leading to flaccid tetraplegia and prolonged immobilization. Four months post-GBS onset, she presented with bilateral hip pain and severely restricted range of motion. Radiographs and CT scans confirmed extensive heterotopic ossification around both femoral heads. Biological workup revealed significant elevations in alkaline phosphatase (ALP), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), alongside hypercalcemia. This case uniquely highlights the rare occurrence of NHO after GBS (reported in only 6% of GBS patients), compounded by a potential genetic predisposition from HLA-B27-positive AS. We discuss the intricate interplay of neuroinflammation, prolonged immobility, and genetic factors in NHO pathogenesis, emphasizing the diagnostic challenges and the need for a multidisciplinary approach in such complex presentations. This report underscores the importance of considering NHO in GBS patients, especially those with pre-existing inflammatory conditions, and contributes to understanding the broader risk factors for this debilitating complication.

关键词： Adipocyte browning   Macrophage polarization   TNF alpha   Mitochondrial respiration   Palmitic acid   LPS  

摘要： Obesity and its associated pro-inflammatory activity contribute significantly to metabolic dysfunction. In contrast, browning of white adipose tissue (WAT) generally improves metabolic health. Our prior research suggested that macrophage-derived pro-inflammatory cytokines suppress key regulators of browning-adrenergic receptor beta 3 (Adrb3) and peroxisome proliferator-activated receptor gamma (Pparg)-as well as energy metabolism mediators-insulin receptor substrate 1 (Irs1) and hormone-sensitive lipase (Lipe)-in dietinduced obese mice. To explore this mechanism, we developed an in vitro model using RAW264.7 macrophages and 3T3-L1 adipocytes exposed to palmitic acid (PA) and/or lipopolysaccharide (LPS). PA (200 mu M) and LPS (1.0 mu g/ml) synergistically promoted M1 polarization of macrophages and secretion of pro-inflammatory cytokines, with tumor necrosis factor-alpha (TNF alpha), C-C motif chemokine ligand 2 (CCL2), CCL5, and interleukin6 (IL-6) being predominant. Conditioned media from both control and PA-treated macrophages, when exposed to LPS >= 0.01 mu g/ml, significantly downregulated Adrb3, Pparg, Irs1, and Lipe in adipocytes. At physiologically relevant LPS levels (<= 0.001 mu g/ml), PA-treated macrophage media exerted greater suppression of these genes than controls. Among the cytokines, TNF alpha emerged as the primary mediator, significantly reducing expression of the four key regulators. Furthermore, adipocytes treated with TNF alpha exhibited significant reductions in both uncoupling protein 1 (Ucp1) expression and mitochondrial respiration. These findings demonstrate that exposure to obesity-associated factors (PA and LPS) induces macrophage-derived TNF alpha, which suppresses browning and mitochondrial function in adipocytes. This mechanism may inform new therapeutic strategies targeting TNF alpha to alleviate obesity-related metabolic disorders.

关键词： cell proliferation   homeostasis   interleukins   lipoproteins, LDL   lymphatic vessels  

摘要： BACKGROUND:The lymphatic system functions by removing fluid, macromolecules, and immune cells to maintain tissue homeostasis. The structural organization of junctional protein complexes is vital to lymphatic function where initial lymphatics have permeable button junctions and collecting lymphatics have relatively impermeable zipper junctions. During inflammation, this junctional morphology appears to reverse, contributing to overall lymphatic malfunction. Little is known about the effects of immunomodulatory cytokines on lymphatic vessel formation and function during inflammation. The purpose of this study is to test the hypothesis that IL (interleukin)-19 promotes lymphangiogenesis and proper lymphatic function during ***:We used cultured human dermal lymphatic endothelial cells to determine IL-19 expression and its effects on lymphangiogenesis assays. Immunocytochemistry and electric cell-substrate impedance sensing determined effects on junctional morphology as it relates to permeability in vitro. RNA sequencing determined the effects of IL-19 on gene expression. Il19-/- Ldlr-/- double knockout mice were used to determine IL-19 effects on lymphatic function and lymphatic vessel visualization in ***:Endogenous IL-19 expression is induced by exogenous IL-19 and VEGF (vascular endothelial growth factor) C stimulation. IL-19 is lymphangiogenic, increasing human dermal lymphatic endothelial cell migration, network formation, and proliferation. IL-19 induces expression of transcription factors and permeability-associated genes. IL-19 induces rapid VE-cadherin (vascular endothelial cadherin) phosphorylation, increases permeability of human dermal lymphatic endothelial cell monolayers, and mitigates oxidized low-density lipoprotein-associated decrease in human dermal lymphatic endothelial cell permeability. In vivo, Il19-/- Ldlr-/- double knockout mice on a high-fat diet have impaired lymphatic drainage, decreased lymphatic branch points, and i

关键词： HLA   HLA-B*35:606   new allele   next-generation sequencing  

摘要： The HLA-B*35:606 allele differs from the HLA-B*35:01:01:02 allele by a single nucleotide at codon 254 in exon 4.