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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： CD154   CD40   IL-4   macrophage   peritoneal cavity  

摘要： Stimulation of macrophages via CD40 promotes their classical activation. Therefore, CD154 (CD40 ligand) can be expected to oppose macrophage polarization and proliferation induced by IL-4. However, there are limited experimental data to support this, which is additionally complicated by the possibility of differential effects of CD40 agonists in different formats/contexts. Whereas canonically CD4+ T cells upregulate CD154 strongly following exposure to cognate antigen, na & iuml;ve CD4+ cells constitutively express significant levels of CD154, which could be a tonic signal. Soluble CD154 and agonistic CD40 antibodies also trigger CD40 signaling. We explored these questions in a reductionist model of IL-4 delivery to mouse peritoneal cavity cells in vitro and in vivo. Soluble CD40 agonists inhibited M(IL-4) polarization, with a stronger effect on RELM-alpha than on Ym1 (Chil3), as well as inhibiting IL-4-induced proliferation. CD154 provided by CD4+ cells in the context of an antigen-specific interaction blunted macrophage RELM-alpha expression but did not affect Ym1. Macrophages negatively regulated, via CD40, constitutive cell-surface CD154 on na & iuml;ve CD4+ cells, both in vitro and in vivo. The large peritoneal macrophages of CD40 KO mice showed a moderately enhanced RELM-alpha response to IL-4, but this was not a cell-autonomous effect. No differences between WT and CD40 KO mice were detected in IL-4-induced macrophage proliferation. We conclude that strong CD40 stimulation, including stimulation by CD154 expressed by antigen-specific CD4+ cells, blunts selected macrophage responses to IL-4, and that constitutive CD4+-cell CD154, in spite of interacting with CD40 on macrophages, does not directly influence macrophage responses to IL-4. Constitutive CD40 ligand expressed by CD4 cells interacts with macrophage CD40 but does not affect macrophage responses to IL-4, whereas stronger CD40 agonists inhibit these responses.

关键词： pIgRL4.2   IFN   SVCV   CRISPR/Cas9   Zebrafish  

摘要： The mucosal immune system plays a critical role in defending the body against external pathogens and preserving homeostasis. The polymeric immunoglobulin receptor (PIGR) is a critical component of this system, responsible for facilitating the transport and secretion of soluble polymeric immunoglobulins across epithelial cells, thereby contributing to immune defense. In zebrafish, a pIgR-like (pIgRL) family exists, among which pIgRL4.2 is highly expressed in multiple immune organs, suggesting its potential role in immunity. In this study, spring viremia of carp virus (SVCV) infection significantly downregulates pIgRL4.2 expression. Conversely, overexpression of pIgRL4.2 in EPC cells markedly delays SVCV-induced cytopathic effects and effectively suppresses SVCV replication. Additionally, overexpression of pIgRL4.2 enhances IFN activation induced by both poly (I:C) treatment and SVCV infection. Furthermore, CRISPR/Cas9 was used to generate pIgRL4.2-null zebrafish, and disruption of pIgRL4.2 in zebrafish has been demonstrated to result in a reduction in survival rates following SVCV challenge. This is accompanied by a consistent downregulation of antiviral responsive genes, concomitant with an increase in SVCV replication in pIgRL4.2-deficient zebrafish. Therefore, this study demonstrates that pIgRL4.2 inhibits viral replication by positively regulating the IFN signaling pathway.

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： 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   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.