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关键词： Leptospira spp.   Bull   Preputial smegma   Receptor   Cytokine  

摘要： Leptospirosis, a zoonosis with a wide worldwide distribution, causes significant reproductive losses in cattle. The genital presentation of the disease has been reported, and its understanding is crucial for the implementation of adequate sanitary measures. Although Leptospira spp. modulate innate immunity, the response in the genital mucosa of bulls is unknown. The objective of this work was to evaluate the expression of innate immune receptors and cytokines in smegma from bulls with genital infection by Leptospira spp. To do so, routine preputial scraping samples were selected from breeding bulls from four establishments in the Azul District, Buenos Aires, Argentina with no reproductive problems, which were previously evaluated for the presence of Leptospira spp. DNA by qPCR detection of the secY gene. The relative gene expression of TLR2, TLR4, IFN-beta and IFN-lambda in the smegma samples of animals infected with Leptospira spp. was determined by RT-qPCR, with subsequent analysis of the results using REST software. The expression of TLR2 was significantly increased in animals infected with Leptospira spp. compared to uninfected control animals (4-fold), while TLR4 did not show differences. Likewise, both IFN-beta and IFN-lambda were significantly increased in smegma of infected animals (3.5 and 3.1-fold, respectively). Therefore, this work shows that genital infection of Leptospira spp. in bulls generates and modulates a local innate immune response, with an association between the presence of Leptospira spp. DNA and the expression levels of TLR2, IFN-beta and IFN-lambda.

关键词： human leukocyte antigen (HLA)   HLA typing   HLA inferences from sequencing data   long-read sequencing for HLA prediction   next-generation sequencing-based HLA analysis  

摘要： Long-read sequencing platforms such as the Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio) platforms now offer sufficient read lengths, throughput, and accuracy at competitive costs to analyze polymorphic regions of the human genome, including the highly complex human leukocyte antigen (HLA) gene cluster-a cornerstone of human immunity. Here, we present a streamlined protocol for predicting HLA signatures from whole-genome shotgun (WGS) long-read sequencing data by directly streaming sequence alignments into HLAminer. This method is as simple as running minimap2, scales efficiently with the number of sequences, and works with any read aligner compatible with the SAM file format-eliminating the need to store bulky alignment files on disk. We provide a step-by-step guide for predicting HLA class I and class II alleles from third-generation long-read sequencing data and demonstrate the robustness of predictions even with older, less accurate WGS nanopore datasets and relatively low (10x) sequencing coverage. Code availability: HLAminer is available under the BC Cancer software license agreement (academic use) at . (c) 2025 The Author(s). Current Protocols published by Wiley Periodicals *** Protocol: HLA prediction from streamed ONT or PacBio long-read alignments

关键词： Haploidentical   transplantation   Haplotypes   HLA-E ligand   NKG2 receptor   Relapse   Survival  

摘要： Background: Recurrence of blood malignancy is the major cause of mortality after hematopoietic cell transplantation. NKG2 receptor/HLA-E ligand complexes play a fundamental role in the surveillance and elimination of transformed cells but their role in the control of leukemia in transplantation is unknown. Objective: We tested the hypothesis that gene variation of patient and/or donor HLA-E ligand and donor NKG2C-NKG2A receptors are associated with the risks of relapse and mortality (primary endpoints) and GVHD and non-relapse mortality (secondary endpoints) after haploidentical transplantation. Study Design: We retrospectively defined donor NKG2 receptor haplotypes and patient HLA-E ligands in 1629 haploidentical related transplantations. HLA-E residue 107 was genotyped in patients and donors. Single nucleotide polymorphisms descriptive of NKG2C and NKG2A haplotypes were characterized in donors. Overall mortality, relapse, nonrelapse mortality and chronic GVHD were studied using Cox regression models. Acute GVHD was studied by logistic regression. Results: The hazard of relapse for patients transplanted from NKG2C-del/del donors was 51% lower than that from wt/wt donors (hazard ratio, HR, .49 [95% CI, .26 to .89) contributing to a HR for mortality of .62 (95% CI, .38 to 1.02). The HR of mortality among patients transplanted from a donor with 2 vs. 0 copies of the NKG2A rs35909400-rs2734440rs12824474 CCC haplotype was HR 2.28 (95% CI, 1.34 to 3.86). The HRs of mortality for ArgArg and ArgGly patients compared to GlyGly patients were 1.42 (95% CI, 1.11 to 1.82) and 1.43 (95% CI, 1.13 to 1.81), respectively. Hazard ratios for nonrelapse mortality for patients with ArgGly or ArgArg genotypes compared to patients with GlyGly genotype were HR 1.60 (95% CI, 1.06 to 2.41) and HR 1.79 (95% CI, 1.21 to 2.66), respectively. Assessment of donor receptor/patient ligand pairings showed that among Arg-positive patients, the HR of mortality from donors with any wt-CCC/CCC haplotyp

关键词： Atopic dermatitis   Genetics   HLA   ERAP1  

摘要： Atopic dermatitis (AD) is one of the most common dermatoses. According to current data 2.6 % of the world's population suffer from AD. Atopic dermatitis is a multifactorial disease. The immune genes polymorphism is also associated with an increased risk of AD. The human leukocyte antigen (HLA) system is a group of genes that plays a crucial role in the immune response. The endoplasmic reticulum aminopeptidases ERAP (1 and 2) are trimming longer peptides to an optimal length for binding to HLA-I molecules. HLA class I (HLA-B) and class II (HLA-DRB1) typing and ERAP1-rs7063 genotyping were performed for 152 patients suffering from AD and 187 control subjects. Frequencies of HLA-B allele group and majority of HLA-DRB1 allele group did not differ between patients and controls. The exception was HLA-DRB1*07 allele group (OR = 0.34;95 % CI = 0.20;0.61, p = 0.0039) whose frequency was lower in patients than in controls. ERAP1 19-exon to 20- exon ratio, governed by rs7063, did not seem to affect the susceptibility to AD.

关键词： HLA   MHC   next-generation sequencing   structural variation  

摘要： The Major Histocompatibility Complex (MHC) of human chromosome 6 contains multiple genes critical for immunity. The exceptional polymorphism of this genomic region that establishes and maintains immune diversity can be technically challenging to characterise and analyse. In this study, we present a family where the mother and one of her children have no HLA-B allele in common, implying the absence of HLA-B from the maternal haplotype. Homozygosity of the mother and child was confirmed using three independent PCR-based methods and high throughput DNA sequencing. Through probe-based MHC region enrichment, sequencing, and read mapping, we located the breakpoints of a large (36.5 kbp) deletion encompassing the entire HLA-B gene. Accordingly, the deletion was present on the maternal haplotype and transmitted to the child. This study demonstrates strategies for locating large deletions in complex genomic regions and highlights the dynamic nature of MHC structure and variation.

关键词： Gene expression   GF   Hepapoietin A   Psoriasis   Scatter factor  

摘要： Hidradenitis suppurativa (HS) is a chronic inflammatory disease that is difficult to control, and its mechanism remains unclear. Hepatocyte GF (HGF) has been reported to be significantly upregulated in the serum and skin of patients with HS, especially in the lesions with tunnels. In this study, we examined the transcriptome of HGF-treated keratinocytes and compared it with genetic profiling of HS lesions. HGF was highly expressed in HS skin, especially in the deep dermis, compared with that in healthy controls, and its source was mainly fibroblasts. HGF upregulated more genes in keratinocytes than IL-17A or TNF-a, and these genes included multiple epithelial-mesenchymal transition-related genes. Differentially expressed genes in HGF-stimulated keratinocytes were involved in activation of epithelial-mesenchymal transition-related pathways. These HGF-induced genes were significantly upregulated in HS lesions compared with those in healthy skin and nonlesions and were more strongly associated with HS tunnels. In summary, HGF was highly expressed in HS and induced epithelial-mesenchymal transition-related genes in keratinocytes;HGF-induced genes were highly associated with gene profiling of HS with tunnels, suggesting that HGF may be involved in HS tunnel formation through epithelial-mesenchymal transition.

关键词： Premature menopause   Prophylactic surgical   procedure   Fimbriectomy   Ovarian neoplasm   HBOC syndrome   Adnexa uteri  

摘要： Risk reducing salpingo-oophorectomy has long been the gold standard for preventing the development of tubo-ovarian cancers in high-risk population such as BRCA1/2 mutation carriers. Although a clear survival benefit has been demonstrated of these prophylactic procedures, important side effect from the associated surgical menopause have been described. Given that recent evidence suggests that most high-grade serous carcinomas (HGSC), the majority of all ovarian carcinomas, and especially for patients with a genetic predisposition originate in the fallopian tube, where also precursor lesions such as STIC can be found, an alternative risk reduction strategy has emerged, the prophylactic fimbriectomy with delayed oophorectomy. Multiple studies have already investigated the acceptability, side effects and safety of this procedure, with promising results. And currently multiple studies are ongoing to investigate the long-term effects on sexuality and the risk of developing subsequent tubo-ovarian carcinomas. A long-term follow-up in a large population is essential given the latency of 4-5 years between precursor lesions and HGSC. In this review, we provide an overview of the current knowledge on the origin, screening, and risk-reducing surgery for the prevention of tubo-ovarian cancers in high-risk women.

关键词： Rheumatoid arthritis   IL-6 receptor   Janus kinase (JAK)   Signal transducer and activator of transcription   (STAT)   Preferential inhibition  

摘要： Interleukin-6 (IL-6) is a relevant cytokine in rheumatoid arthritis (RA) pathogenesis, potentially activating Janus kinases (JAK)-1, -2, and tyrosine kinase 2 (TYK2), and thus, three signal transducer and activator of transcription (STAT)-1, -3 or - 5 pathways. This pilot study aims to explore differences in phosphorylated (p)STAT3 levels among patients with RA, those not classified as RA (nRA), and healthy donors (HD), providing some clues on the relative contribution of each JAK protein to the downstream of the IL-6-induced STAT3 pathway. Clinical data and blood samples from 80 subjects (41 RA, 14 nRA, and 25 HD) were collected. The activity of the JAKSTAT3 pathway was assessed by Western Blot and Real Time-PCR analysis for the quantification of STAT3 in peripheral blood mononuclear cells (PBMC). Furthermore, the impact of JAK-1, -2, and TYK2 inhibitors on pSTAT3 was assessed in vitro by FACS, with and without IL-6 stimulation in RA patients na & iuml;ve to treatment with DMARD and steroids. The pSTAT3 (%) was significantly higher in PBMC from RA compared to nRA patients and HD. Furthermore, pSTAT3 (%) was significantly associated with inflammation and disease activity (ESR, CRP, and DAS28). The JAK-1 inhibitor was more effective in reducing pSTAT3 expression in CD14pos cells of RA patients, while the JAK-2 selective compound was more effective in CD4pos cells of RA patients. On the contrary, the TYK2 selective agent showed no significant effects. This study highlights the importance of the JAK/STAT3 pathway in RA. Some differences among various JAK proteins have been pointed out, with JAK1 and JAK2 standing as the most relevant mediators of the STAT3 pathway in this in-vitro model after IL-6R activation.