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摘要： Little information is available about CCR5-Δ32 and HLA-B*57:01 alleles in the Peruvian population, especially in human immunodeficiency virus (HIV)-negative people with high-risk sexual behavior. Here we describe the prevalence of these alleles in HIV-exposed seronegative individuals (PS) and HIV-seropositive individuals (PVV). For this purpose, 300 individuals were recruited: 150 from each group, and the selected alleles were characterized by endpoint PCR, real-time PCR and DNA sequencing. According to our results, the prevalence of CCR5/CCR5-Δ32 heterozygous was 2.7%, and no homozygous cases were found. The population was in Hardy-Weinberg equilibrium for the CCR5 locus. Regarding HLA-B*57:01, one case was identified in the PS group, while no cases were observed in the PVV group. No statistical difference was detected between groups (P > 0.05). In conclusion, we showed a low prevalence for CCR5-Δ32 as HLA-B*57:01 in the Peruvian population. As these alleles were found at similar frequencies among both HIV-positive and HIV-negative Peruvian individuals with high-risk sexual behavior, it is possible that other genetic factors play an important role in preventing HIV transmission in this population. The low frequency of the HLA-B*57:01 allele in the Peruvian population suggests that routine genotyping tests for abacavir hypersensitivity should be reevaluated in the public health policies of Peru's Ministry of Health, based on national epidemiological data.

关键词： CTLA‐4 gene (rs 231775)   HLA   SLE   anti‐C1q  

摘要： This study was performed to determine anti-C1q serum level, genetic polymorphism in cytotoxic T lymphocyte-associated antigen 4 gene (CTLA-4 gene) (rs 231775), and HLA class II genes in susceptibility and early prediction of systemic lupus erythematosus (SLE) and lupus nephritis (LN) in Upper Egyptian patients. A total of 60 unrelated cases of SLE (30 cases with LN) and 60 healthy controls were studied for HLA-DQB1, HLA-DQA1, and HLA-DRB1 (DR4 subtypes) alleles. Anti-C1q level was estimated by ELISA. CTLA-4 gene genotypes were detected by PCR-RFLP. The means of age of SLE patients without nephritis and LN patients were 24 ± 5.09 and 32 ± 7.26, respectively. Most of the patients were females (93.3%). Anti-C1q serum level was significantly higher in LN patients (24.11 ± 4.26) versus SLE patients without nephritis (18.17 ± 1.35) (p value < 0.001). The AA genotype of the CTLA-4 gene was significantly higher in patients with LN versus SLE patients without nephritis (53.5% vs. 26.5%; p value = 0.035). (DR7)-DQA1*02-DQB1*0303 haplotype was higher in SLE patients versus the control group and showed the highest odds ratio (7.37) with a significant p value (0.031). Odds ratios of DRB1*0405-DQA1*03-DQB1*0302 and DRB1*0405-DQA1*03-DQB1*02 were 6.263 and 4.214, respectively. DRB1*0405-DQA1*03-DQB1*02 haplotype was detected in 11.7% of LN patients versus 1.7% of SLE patients without nephritis (OR = 8.82, p value = 0.02). DRB1*0405-DQA1*03-DQB1*02 haplotype, in addition to CTLA-4 gene (AA genotype), and high anti-C1q serum level can predict the progression of SLE Upper Egyptian patients to LN.

关键词： 猪流行性腹泻病毒   单克隆抗体   多克隆抗体   双抗体夹心酶联免疫吸附试验  

摘要： 猪流行性腹泻病毒（PEDV）是导致仔猪腹泻的主要病原之一，给养猪业造成了严重危害。本试验以PEDV N蛋白单克隆抗体（mAb）为捕获抗体，兔抗PEDV多克隆抗体（pAb）为检测抗体，建立双抗体夹心酶联免疫吸附检测方法（DAS-ELISA）并确定其最佳反应条件，随后对该方法的特异性，敏感性和重复性进行评价，并通过对96份临床样本的检测，评价该方法与逆转录聚合酶链式反应（RT-PCR）方法的符合率。结果显示，本试验建立的DAS-ELISA检测方法对PEDV的最佳反应条件为：0.478 mg/L mAb于4 ℃包被12 h，3%牛血清白蛋白37 ℃封闭60 min，待检病毒37 ℃孵育20 min，3.75 mg/L兔抗PEDV pAb 37 ℃孵育45 min，1:5 000倍稀释的辣根过氧化酶（HRP）标记的羊抗兔免疫球蛋白G（IgG）37 ℃孵育30 min；该方法对猪繁殖与呼吸综合征病毒（PRRSV）、猪传染性胃肠炎病毒（TGEV）、猪德尔塔冠状病毒（PDCoV）和猪圆环病毒（PCV）等均无交叉反应，具有较好的特异性；最低检测限为1.65×102TCID50/mL(4.7×10-4mg/mL)，具有较高的敏感性；批内和批间变异系数分别为3.3%～5.9%和3.0%～6.2%，具有良好的重复性；采用DAS-ELISA和RT-PCR分别对临床样本检测，阳性符合率为91.67%（22/24），阴性符合率为98.61%（71/72），总符合率为96.88%（93/96）。以上结果表明，本试验建立的DAS-ELISA方法具有良好的特异性、敏感性和重复性，适用于PEDV的临床检测。

摘要： Astragalus polysaccharide, a bioactive substance with significant immunomodulatory functions, has not yet had its specific configuration–function relationship fully elucidated. In the present study, four Astragalus polysaccharide fractions with different polarities were successfully obtained through DE52 anion exchange column separation technology, and their pharmacological activities were screened. Homogeneous Astragalus polysaccharide was isolated and purified using DE52 polarity separation columns and gel column purification techniques. The types of glycosidic bonds in Astragalus polysaccharide were identified through monosaccharide composition analysis, infrared spectroscopy, molecular weight determination, and polysaccharide methylation analysis. The probable disaccharide repeating unit structure of AMPS-0.2A polysaccharide was determined to be α-(1,2)-l-Rha-α-(1,4)-d-GalA. Astragalus polysaccharide was found to induce the polarization of macrophages from the M2 phenotype to the M1 phenotype. This effect was primarily mediated through the regulation of the JNK/MAPK signaling pathway and the NLRP3/IL-1β signaling pathway, thereby promoting the polarization of M1 macrophages.

摘要： AbstractSection

The development of new drugs through structural bioinformatics plays a crucial role in the pharmaceutical industry, aiming to reduce both the cost and time required for drug development. Psoriasis is a chronic autoimmune skin disease with complex etiology for which new therapeutic options are needed. This study presents an in silico pipeline combining large-scale virtual screening and bioisosterism. This methodological integration allows not only the identification but also the chemical refinement of lead compounds, addressing both binding efficacy and predicted toxicity.

A comprehensive pipeline was developed for the identification of potential drug candidates targeting five key proteins (A2Ar, BTK, P38-MAPK, PAD-4 and TNF- α) involved in psoriatic symptomatology. Initially, a systematic review was conducted to identify studies that had employed drug repositioning for these target proteins in psoriasis. Subsequently, protein structures were retrieved from the Protein Data Bank, and 80,617 ligands derived from natural products were obtained from Zinc20. Virtual screening was applied by analyzing binding energies and molecular interactions with AutoDock Vina. Additionally, the evaluation of absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) properties was conducted using the pkCSM server to ensure drug-like behavior. When necessary, molecular optimization through bioisosterism was performed using MB-Isoster software.

We identified eight potential compounds capable of targeting the A2Ar, BTK, P38-MAPK, PAD-4, and TNF-α receptors. These compounds exhibited binding energies superior to those of the respective controls for each receptor, interacting with the same amino acids and displaying ADME-Tox properties, making them promising candidates f

关键词： Gag   MHC   Qa-1   endogenous retrovirus   epitope  

摘要： The interactions between endogenous retroviruses (ERVs) and major histocompatibility complex molecules may significantly influence autoimmune diseases due to their common roles in the evolution and development of the adaptive immune system. Notably, regions within the Gag antigens of a specific group of ERVs, similar to murine leukemia retroviruses, exhibit patterns of sequence conservation, variation, and mutation. One highly conserved peptide of Gag, p5-13 (VTTPLSLTL), binds with high affinity to a nonclassic major histocompatibility complex molecule, Qa-1, and is preferentially recognized by T cells enriched in the pancreas of nonobese diabetic (NOD) mice, which spontaneously develop autoimmune type 1 diabetes. Interestingly, deep sequencing analysis of the Gag genes expressed in NOD mice has revealed numerous mutations flanking the conserved Qa-1-binding sequences. This includes 1 epitope, p310-328, which contains both conserved and mutated residues that can elicit autoreactive T cells in NOD mice. A specific residue, D316, within this epitope accumulates multiple mutations as the disease progresses, leading to a reduction in the consensus score in sequence alignment at this position during the later stages of prediabetes. Consistently, the substitution of the D316 residue with a dominant mutant, G316, enhances the antigenicity of this epitope, stimulating autoreactive T cells in prediabetic NOD mice to release interferon-γ . Thus, sequence variants of ERV Gag antigens encode overlapping conserved and highly mutated epitopes that can be recognized by T cells and utilized for biomarker discovery.

关键词： Inflammation   Low back pain   Myofascial release   Pain   Tumor necrosis factor-alpha  

摘要： BACKGROUND:Non- specific low back pain (NSLBP) is a common musculoskeletal disorder that leads to disability. Its development has been associated with inflammatory responses including cytokines such as TNF-α. Various management approaches, including manual therapy and exercise therapy to treat NSLBP. Manual therapy including myofascial release (MFR) has shown to reduce the pain and improve soft tissue flexibility and mobility. It was therefore hypothesized that three-dimensional MFR (3D-MFR) would reduce TNF-α levels in individuals with NSLBP. This present study aimed to investigate the effect of three-dimensional myofascial release (3D-MFR) on inflammation as indicated by TNF-α level, as well as on pain intensity and quality of life in individuals with NSLBP. METHODOLOGY:A double-blinded randomized controlled trial was conducted over a 6 month period in the tertiary care centre. 40 participants aged 18-50 years with a clinical diagnosis of nonspecific low back pain. Participants were randomly allocated into two groups using a computer-generated randomization sequence with allocation concealed through sealed opaque envelopes, one receiving 3D-MFR and the other a sham group intervention, both over 4 weeks. Outcomes included concentration of TNF-α level (in blood and urine), Visual Analogue Scale (VAS) scores for pain intensity and Modified Oswestry Disability Index (MODI) scores for quality of life assessed before and after the intervention. RESULTS:Post-intervention, the blood TNF-α in 3D-MFR group (p = 0.001; CI- LL = 5.62, UL = 14.69) compared to the Sham group (p = 0.85; CI- LL = 9.97, UL = 20.09) and urine TNF-α levels in 3D-MFR group (p = 0.003; CI- LL = 0.61, UL = 1.33) compared to the Sham group (p = 0.744; CI- LL = 1.36, UL = 2.63). VAS scores in 3D- MFR group (p < 0.001; CI- LL = 2.2, UL = 3.39) versus the Sham group (p = 0.001; CI- LL = 4.06, UL = 5.31), MODI scores for 3D-MFR group (p < 0.001; CI- LL = 23.69, UL = 34.09) compared to the Sham group (p < 0.

关键词： CHPE   in-silico docking   Metformin   MHC   Sjögren’s Disease  

摘要： Sjögren’s disease (SjD) is a chronic autoimmune disorder predominantly affecting females, characterized by exocrine gland dysfunction. This study investigates the therapeutic potential of 2-chloro-1-(4-hydroxy-phenyl)-ethanone (CHPE) and metformin in the C57BL/***- Aec1Aec2 mouse model, which closely mirrors human SjD. Molecular docking identified CHPE and metformin as high-affinity binders to the MHC class II I-A b antigen-binding groove, suggesting their ability to inhibit antigen presentation and modulate immune responses. In-vitro assays confirmed their effectiveness in reducing T cell activation. In-vivo studies demonstrated that both preventative and therapeutic regimens of CHPE and metformin significantly reduced lymphocytic infiltration in the lacrimal glands, with metformin showing a more pronounced effect in females. Salivary gland infiltration was less responsive, though some reduction in focal scores was observed in male mice treated preventatively with CHPE. Both drugs altered the composition of lymphocytic infiltrates, particularly by reducing B cell populations, with notable sex-specific differences in response to treatment. CHPE and metformin also reduced anti-nuclear antibody levels, with CHPE showing stronger effects in females. Additionally, both drugs improved saliva and tear secretion, with metformin being more effective in the preventative regimen, especially in females. T cell receptor transductant assays revealed that CHPE and metformin exert their therapeutic effects through antigen-specific pathways, inhibiting T cell responses to SjD-associated autoantigens. Overall, this study provides compelling evidence that CHPE and metformin can modulate immune responses and improve gland function, with effectiveness varying by sex and age. These findings support the potential of these compounds as personalized treatments for SjD tailored to individual patient characteristics.

关键词： B-Lymphocytes   Vaccination   Tumor Necrosis Factor Inhibitors   T-Lymphocytes   Autoimmune Diseases  

摘要： Objectives Tumour necrosis factor inhibitors (TNFi) are widely used and effective as treatment for immune-mediated inflammatory diseases (IMIDs). However, TNFi therapy causes a faster waning of antibody responses following vaccination. The underlying cause by which TNFi affect humoral immunity remains to be elucidated. The formation of long-lasting, high-affinity antibodies after vaccination results from germinal centre (GC)-derived, T cell-dependent B-cell responses. Therefore, this study investigated how TNFi affect the formation and maintenance of antigen-specific B- and CD4+ T-cell responses following SARS-CoV-2 mRNA *** SARS-CoV-2 spike-specific B-cell responses were characterised using spectral flow cytometry. Spike-specific CD4+ T cells were measured using an activation-induced marker assay. 15 patients with inflammatory bowel disease (IBD) treated with TNFi were compared with 9 IBD patients without systemic immunosuppression and 10 healthy *** Spike-specific CD4+T-cell frequency and phenotype, including T follicular helper cells, were not affected by TNFi. Total spike-specific B-cell frequencies were reduced in TNFi-treated patients. Deep phenotyping revealed lower IgG+memory B-cell frequencies in TNFi-treated patients 3-6 months after vaccination. These data were confirmed in TNFi-treated rheumatoid arthritis patients. Interestingly, already at day 7 after the second vaccination, TNFi therapy reduced the induction of class-switched CD11c- CD71+activated B cells, which are believed to be GC-derived. Conversely, CD11c+B cells, associated with extrafollicular B-cell responses, were not affected by TNFi *** These data suggest that TNFi therapy affects the differentiation of GC-derived B cells, which may explain its effect on humoral immune responses.