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关键词： acute rejection   allelic mismatch   HLA antigens   kidney transplantation   predictive models   random survival forest  

摘要： Deceased donor kidney allocation relies on HLA compatibility at the antigen level, as optimal matching reduces the risk of acute rejection. Whether HLA allele-level mismatches improve, the prediction of acute rejection after transplantation remains unclear. Using data from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) from 2017 to 2020, HLA antigenic and allelic mismatches between recipients and deceased donors were calculated with imputation of two-field allelic equivalents undertaken where required. The discordance between antigen and allele mismatches was calculated, and oblique random survival forest models were used to predict acute rejection. Predictive performance of antigen (HLA-A, -B, -DRB1 and -DQB1), allele (HLA-A, -B, -DRB1 and -DQB1) and extended allele (HLA-A, -B, -C, -DRB1, -DQA1 and -DQB1) models was examined using concordance index and integrated Brier scores, with variable importance calculated using permutation-based methods. Among 2644 recipients followed for a median of 1.7 years, 521 recipients (20%) experienced acute rejection. Discordant numbers of antigenic and allelic mismatches occurred in 8%, 9%, 24% and 17% of HLA-A, -B, -DRB1 and -DQB1 loci, respectively. Predictive performances were similar across all models, with concordance indices of 0.62-0.63 and integrated Brier scores of 0.09. HLA-DRB1 and -DQB1 mismatches were the strongest predictors of acute rejection across models. In patients matched at the HLA-DRB1 or -DQB1 antigen, those with allelic mismatches had similar incidences of rejection compared to those without. Allelic-level assessment of HLA compatibility did not improve the prediction of acute rejection and may disadvantage certain recipients by reclassifying them into higher mismatch categories in allocation algorithms without providing clear clinical benefit.

关键词： DQA1   Eplets   HLA   Imputation   Machine Learning   Transplantation  

摘要： Donor/recipient mismatched HLA antigens can lead to the production of Donor-Specific Antibodies by the recipient, which are deleterious to organ transplants. The HLA-DQ locus is the most frequent target, with both the DQ beta and alpha chains involved. For deceased donors in particular, while HLA-DQB1 has been typed in emergencies for a long time, HLA-DQA1 has only recently been included. No imputation algorithmic tool was available to impute HLA-DQA1 until the development of HaploSFHI, trained on 61,393 two-field typings by NGS methods. We evaluated the accuracy of two-field HLA-DQA1 imputation from serological and two-field level HLA-A, B, DRB1, and DQB1 typings. We report a highly accurate two-field HLA-DQA1 prediction using a French test cohort of 7696 individuals, respectively reaching 92.30% and 96.45% accuracy. The average 'False Positive eplet load' stood at 0.19 and 0.07, respectively, and the average 'False Negative eplet load' at 0.18 and 0.08, respectively. A similar performance was obtained on three independent test cohorts of European ancestry (from the USA, the UK, and Portugal). Interestingly, performance was only slightly inferior on five independent test cohorts of other ethnicities (from Hong Kong and the USA) whereas it was significantly lower for two-field DRB1 imputation from its serological level. These results suggest that DQA1 can reliably be imputed even when information is totally missing, with low error risk at both antigen and eplet levels, even if the reference population is not matched. Similar additional initiatives would be welcome to confirm these findings.

关键词： HLA   HLA-DQA1*01:169   novel allele   sequencing-based typing  

摘要： HLA-DQA1*01:169 differs from HLA-DQA1*01:01:01:09 by one nucleotide substitution in codon 175 in exon 3.

关键词： EBV   HLA   MHC   mononucleosis   multiple sclerosis  

摘要： Background: Epstein-Barr Virus (EBV) and its clinical manifestation, infectious mononucleosis (IM), are strongly linked to MS risk. A recent in vitro study suggests that HLA-E*01:03, in contrast to HLA-E*01:01, may protect against MS through more effective immune responses against EBV-infected B cells. However, the role of HLA-E*01 in MS remains unclear. Methods: We investigated if HLA-E*01:01 was significantly associated with higher MS risk in individuals with a history of IM diagnosis, using 487,144 individuals from the UK Biobank's cohort. We estimated the interaction between HLA-E*01:01 and IM using Cox proportional hazard models, adjusting for demographics, smoking, childhood body size, older siblings, and MS-related HLA alleles (e.g., HLA-DRB1*15:01). Results: HLA-E*01:01 allele alone was not significantly associated with IM or MS (p > 0.05). However, a significant interaction between HLA-E*01:01 and IM history was observed in relation to MS risk (p < 0.001). Specifically, MS risk was significantly higher in both HLA-E*01:01 heterozygotes (HR = 1.74 [95% CI: 1.36, 1.97], p < 0.001) and homozygotes (HR = 3.01 [95% CI: 1.81, 3.88], p < 0.001) with IM history, compared to HLA-E*01:03 homozygotes. Conversely, these associations were non-significant in individuals without IM history (p > 0.05). The estimated proportion of the combined risk attributable to interaction effects was 40% in HLA-E*01:01 heterozygotes and 65% in HLA-E*01:01 homozygotes. Conclusions: HLA-E*01:01 carriers diagnosed with IM are at significantly increased risk of MS, independently from other MS-related HLA alleles. This supports the hypothesis that HLA-E*01:01 may contribute to MS susceptibility due to weaker immune control over EBV infection. Incorporating HLA-E*01:01 into existing MHC-based MS risk models could then enhance personalized risk assessments in individuals with IM history.

摘要： The early innate host immune response is crucial in the susceptibility to tuberculosis (TB). This study aimed to investigate the potential role of Toll-interacting protein (TOLLIP), a negative regulator of the human innate immune response, and interleukin-10 (IL-10), an anti-inflammatory cytokine, in susceptibility to TB. The peripheral blood mononuclear cells of 30 active pulmonary TB patients and 30 healthy volunteers were included. TOLLIP mRNA expression levels, single nucleotide polymorphisms (SNPs) of the TOLLIP gene, such as rs5743899A/G and rs3750920C/T, and IL-10 -1082G/A SNP were detected using real-time PCR, PCR-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system-PCR (ARMS-PCR), respectively. TOLLIP mRNA expression levels were significantly higher in TB patients than in healthy controls (expression fold difference = 2.72, the delta-delta Ct method, also known as the 2-triangle triangle Ct method). The heterozygous (GA) genotype of the IL-10 -1080G/A polymorphism was significantly predominant among the patient group (p = 0.02, Hardy-Weinberg equilibrium). However, the Kruskal-Wallis analysis found no significant relationship between TOLLIP mRNA expression levels and SNPs. TOLLIP mRNA and IL-10 -1082G/A SNP were assessed as potential biomarkers to predict TB susceptibility. For more significant results, they should be examined with other negative regulators of innate immunity and other immune factors associated with susceptibility to TB. Our study is the first to investigate the association of TOLLIP polymorphisms and expression levels with TB susceptibility in Turkey.

关键词： Alzheimer's disease   IL-34   microglia   neuroinflammation   NLRP3   TREM2  

摘要： Background: As a recently identified cytokine, interleukin-34 (IL-34) is predominantly produced by neurons and functions as a modulator for glial functions. Emerging evidence indicates that IL-34 exerted neuroprotective effects in Alzheimer's disease (AD), but the underlying mechanism remained elusive. Objective: To uncover the mechanisms by which IL-34 provides neuroprotection in AD. Methods: Using senescence-accelerated mouse prone substrain 8 (SAMP8) mice, a well-established model for sporadic AD, we investigated the dynamic changes in brain IL-34 concentrations during AD progression. Afterwards, SAMP8 mice received a 4-week continuous intracerebroventricular infusion of IL-34. Morris water maze test was employed to assess the spatial cognitive functions. Neuronal and synaptic markers, oxidative stress makers, pro-inflammatory cytokines and glial activation markers in the brains of SAMP8 mice were measured. Finally, amyloid-beta (A beta)(42)-stimulated primary microglia, lentivirus-mediated gene knockdown strategy and co-immunoprecipitation assay were utilized to uncover the possible mechanisms by which IL-34 exerted neuroprotection in AD. Results: In SAMP8 mice, we revealed that brain IL-34 concentrations gradually decreased during AD progression. A 4-week continuous intracerebroventricular infusion of IL-34 rescued spatial cognitive impairments, ameliorated neuronal and synaptic damage, and suppressed oxidative stress and microglia-mediated inflammation in the brains of SAMP8 mice. Using A beta(42)-stimulated primary microglia, we demonstrated for the first time that IL-34 suppressed microglial NLRP3 inflammasome activation and pro-inflammatory cytokines release by interacting with triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial functions. Conclusions: These findings uncover the mechanisms by which IL-34 provides neuroprotection in AD, indicating that IL-34/TREM2 signaling may represent a novel therapeutic strategy for th

关键词： HLA-DQB1*04:01:07   next-generation sequencing   novel allele  

摘要： HLA-DQB1*04:01:07 differs from HLA-DQB1*04:01:01:01 by one nucleotide substitution at position 735 in exon 4.

关键词： Osteoarthritis   Curcumin   Chondrocytes   Bmp2/Smad5/Runx2 pathway   Oxidative stress   Inflammation   Apoptosis   Gene silencing  

摘要： A core role of chondrocyte survival/death has been suggested in the pathogenesis of osteoarthritis. We explored the underlying molecular mechanism of curcumin protecting against interleukin-1 beta (IL-1 beta)-induced chondrocyte injury via the bone morphogenetic protein 2 (Bmp2)/small mothers against decapentaplegic homolog 5 (Smad5)/runt-related transcription factor 2 (Runx2) pathway. Chondrocytes ATDC5 in vitro inflammatory model was established by IL-1 beta induction, and treated with curcumin, or Smad5 small interfering RNA. Levels of extracellular matrix (ECM) type II collagen (Col-II) and aggrecan, reactive oxygen species (ROS), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha) and IL-6 were determined by immunocytochemistry, kits and ELISA. Apoptosis and necrosis were assessed by Annexin V/PI and TUNEL. Matrix metalloproteinase 13 (MMP13), A disintegrin and metalloproteinase with thrombospondin 5 (ADAMTS5), Bmp2/Smad5/Runx2 expression and Smad5 phosphorylation levels were determined by qPCR and western blot. IL-1 beta-treated ATDC5 cells showed decreased Col-II, aggrecan in ECM and SOD and GSH-Px levels, as well as increased apoptosis and levels of MMP13, ADAMTS5, Bmp2, Runx2, ROS, COX-2, TNF-alpha and IL-6 and Smad5 phosphorylation (all p < 0.05), whilst curcumin treatment brought about the opposite trends, suggesting that curcumin inhibited oxidative stress, inflammatory response and apoptosis, and inactivated the Bmp2/Smad5/Runx2 pathway in IL-1 beta-treated chondrocytes. Additionally, Smad5 silencing also caused suppressed oxidative stress, inflammatory response and apoptosis in IL-1 beta-treated chondrocytes. Curcumin reduced IL-1 beta-induced chondrocyte oxidative stress, inflammation, and apoptosis, and increased ECM secretion by inactivating the Bmp2/Smad5/Runx2 pathway, thereby exerting a protective effect on injured chondrocytes.

关键词： HLA-A*26:01:80   next-generation sequencing   novel allele  

摘要： The sequence of HLA-A*26:01:80 differs from HLA-A*26:01:01 by one single nucleotide substitution.