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关键词： allergy   basophils   B cells   germinal center   IL-1   sensitization   Tfh cells   type I hypersensitivity   IL-1R1  

摘要： Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on IL6R missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints. Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease and ischemic atherosclerotic stroke in individuals of European and East Asian ancestry. Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns.

摘要： Genetic associations within the human leukocyte antigen (HLA) gene complex and linked genes in TB-IRIS outcomes remains population specific and not well understood. Here, we conducted a study including well characterised HIV-TB coinfected patients with (n = 86) and without (n = 124) TB-IRIS from the randomized, double-blind, prophylactic prednisone trial (PredART study) with HLA, ERAP and KIR genotyping data. We confirmed the association of TB-IRIS with lower CD4 counts pre-ART initiation. We identified nine classical class I and II HLA alleles protective against TB-IRIS, while four alleles were linked to increased risk. Associations ranged from strongly protective (HLA-DQB1*05:01, OR: 0.07, 95%CI: 0.02-0.28, Pc < 0.001) to strongly risk associated (notably DRB1*01:02, OR: 5.92, 95%CI: 1.36-26.7, Pc = 0.028), with conflicting signals at the HLA-DRB1 locus. Conditional regression analysis revealed that residue E71 at the polymorphic position 71 within the HLA-DRB1 peptide-binding groove was critical, and grouping of HLA-DRB1 alleles by the residue at position 71 corresponded with differential TB-IRIS association. In conclusion, this study identifies population-specific genetic factors influencing TB-IRIS susceptibility and highlights a potential mechanistic role for specific HLA-DRB1 residues in modulating immune responses during ART.

关键词： Myofascial pain syndrome   Myofascial trigger points   Isoliquiritigenin   IL-17   Inflammation  

摘要： Background: Myofascial trigger points (MTrPs) are a primary cause of myofascial pain syndrome. Current studies suggest that MTrPs consist of persistent sarcomere contraction and an inflammatory microenvironment. IL-17 has been implicated in the progression of inflammation. However, its expression of IL-17 in MTrPs and the underlying mechanisms remain unclear. Purpose: This study aimed to characterise IL-17 signalling and elucidate the associated molecular mechanisms in the context of MTrPs, and evaluate the therapeutic effects of isoliquiritigenin (ISL) on MTrPs. Methods: We examined IL-17A signalling expression using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blot analysis in MTrPs rat. Haematoxylin and eosin staining and transmission electron microscopy were used to assess muscle fibre and sarcomere morphology. The Randall-Selitto test was employed to evaluate pain-like behaviours in rats. Dihydroethidium staining, JC-1 assay, and ATP quantification were used to assess inflammation-associated mitochondrial function in vitro and in vivo. Additionally, molecular docking, cellular thermal shift, and drug affinity responsive target stability assays were conducted to examine the interaction between ISL and the IL-17 receptor subunit A (IL-17RA) protein. Results: IL-17A and IL-17RA were significantly expressed in rats with MTrPs. These rats exhibited elevated oxidative stress level and reduced ATP production. Studies on IL-17A stimulated myotubes and gastrocnemius muscle indicated that IL-17RA signalling contributes to inflammation, abnormal sarcomere contraction and mitochondrial dysfunction in MTrPs. Lentivirus-mediated IL-17RA knockdown in the rats further confirmed these findings. Inhibition of the mitogen-activated protein kinase p38 and subsequent rescue experiments highlighted the critical role of IL-17RA/Act1/p38 signalling. Notably, molecular docking and validation experiments revealed that ISL binds to and in

关键词： Autoimmune   HLA   Immunogenetics   Stevens-Johnson syndrome   Toxic epidermal necrolysis  

摘要： Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very rare dermatologic disorders characterized by extensive detachment of the epidermis. Although some drugs, infectious agents, HLA genes, malignancy and connective tissue diseases are thought to play a role in the development of the disease, the pathogenesis has not been fully elucidated. Type IV hypersensitivity reactions are thought to be the underlying cause of these diseases. Inflammatory changes such as purulent erosion, ulcers and crusting can be seen in the gastrointestinal system, urinary tract and genital mucosa. Some immunologic biyomarkers like as HLA-B* 1502, Granulysin and CCL-27 are used in clinical diagnosis, prognosis, treatment, and personalized new drug development that could further explain the pathogenesis of SJS and TEN. This review focuses on the pathophysiology of the SJS and TEN and presents it in light of current data on this subject. We recommend further in vivo and in vitro studies to unravel the underlying immunological mechanisms to determine appropriate intervention strategies.

关键词： Ultrasound   Piezoelectric   Programmed immunomodulation   Macrophage polarization   Boneregeneration  

摘要： In craniomaxillofacial bone defect repair, both classically (M1) and alternatively (M2) activated macrophages coexist and are crucial to the repair process. However, recent studies focus on regulating macrophage M2 repolarization to promote osteogenic differentiation, overlooking the significant role of the M1 phenotype in bone marrow-derived mesenchymal stem cells (BMSCs) recruitment. Consequently, this research reports a programmed macrophage polarization therapy that is based on natural immunoregulatory. First, ultrasounddriven piezoelectric potential from beta-phase polyvinylidene fluoride (beta-PVDF) film activates M1 polarization. In vitro results show that the M1 phenotype exhibits a remarkable ability to recruit BMSCs and promote osteogenic differentiation. Subsequently, the rapid and potent M2 repolarization was achieved after interleukin-4 (IL-4) treatment, which promoted osteogenic differentiation. In vivo results indicate that the piezo-IL-4 programmed immunomodulatory system effectively facilitated the rapid repair of bone defects. This study first combined ultrasound piezoelectricity with IL-4 to promote programmed regulation of macrophage polarization and promote BMSCs recruitment and differentiation. This approach offers an effective strategy based on natural immunoregulatory for modulating the immune microenvironment, which is essential for the design and development of bone repair materials, provides a significant theoretical foundation for the optimisation of immune regulation strategies in the field of bone tissue engineering.