Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in \"carrier\" or \"pathogenic\" states. HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S. aureus infection. However, the contribution of HLA DP to S. aureus infection is unknown yet.
In this study, we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes. Neo-floxed IAβ+/- mice were crossbred with Ella-Cre and further crossbred with HLA DP401 or HLA-DRA0101 humanized mice. After several rounds of traditional crossbreeding, we finally obtained HLA DP401-IAβ-/- and HLA DRA-IAβ-/- humanized mice, in which human DP401 or DRA0101 molecule was introduced into IAβ-/- mice deficient in endogenous murine MHC class II molecules. A transnasal infection murine model of S. aureus pneumonia was induced in the humanized mice by administering 2 × 108  CFU of S. aureus Newman dropwise into the nasal cavity. The immune responses and histopathology changes were further assessed in lungs in these infected mice.
We evaluated the local and systemic effects of S. aureus delivered intranasally in HLA DP401-IAβ-/- and HLA DRA-IAβ-/- transgenic mice. S. aureus Newman infection significantly increased the mRNA level of IL 12p40 in lungs in humanized mice. An increase in IFN-γ and IL-6 protein was observed in HLA DRA-IAβ-/- mice. We observed a declining trend in the percentage of F4/80+ macrophages in lungs in HLA DP401-IAβ-/- mice and a decreasing ratio of CD4+ to CD8+ T cells in lungs in IAβ-/- mice and HLA DP401-IAβ-/- mice. A decreasing ratio of Vβ3+ to Vβ8+ T cells was also found in the lymph node of IAβ-/- mice and HLA DP401-IAβ-/- mice. S. aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ-/- genetic background mice.
These humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S. aureus pneumonia and study what role DP molecule plays in S. aureus infection.

BACKGROUND: Mass vaccination has dramatically reduced the incidence of severe COVID-19, with most cases now presenting as self-limiting upper respiratory tract infections. However, those with co-morbidities, the elderly and immunocompromised, as well as the unvaccinated, remain disproportionately vulnerable to severe COVID-19 and its sequelae. Furthermore, as the effectiveness of vaccination wanes with time, immune escape SARS-CoV-2 variants could emerge to cause severe COVID-19. Reliable prognostic biomarkers for severe disease could be used as early indicator of re-emergence of severe COVID-19 as well as for triaging of patients for antiviral therapy.
METHODS: We performed a systematic review and re-analysis of 7 publicly available datasets, analysing a total of 140 severe and 181 mild COVID-19 patients, to determine the most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients. In addition, we included an independent cohort where blood transcriptomics of COVID-19 patients were prospectively and longitudinally monitored previously, to track the time in which these gene expression changes occur before nadir of respiratory function. Single cell RNA-sequencing of peripheral blood mononuclear cells from publicly available datasets was then used to determine the immune cell subsets involved.
RESULTS: The most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients were MCEMP1, HLA-DRA and ETS1 across the 7 transcriptomics datasets. Moreover, we found significantly heightened MCEMP1 and reduced HLA-DRA expression as early as four days before the nadir of respiratory function, and the differential expression of MCEMP1 and HLA-DRA occurred predominantly in CD14+ cells. The online platform which we developed is publicly available at https://kuanrongchan-covid19-severity-app-t7l38g.streamlitapp.com/, for users to query gene expression differences between severe and mild COVID-19 patients in these datasets.
CONCLUSIONS: Elevated MCEMP1 and reduced HLA-DRA gene expression in CD14+ cells during the early phase of disease are prognostic of severe COVID-19.
BACKGROUND: K.R.C is funded by the National Medical Research Council (NMRC) of Singapore under the Open Fund Individual Research Grant (MOH-000610). E.E.O. is funded by the NMRC Senior Clinician-Scientist Award (MOH-000135-00). J.G.H.L. is funded by the NMRC under the Clinician-Scientist Award (NMRC/CSAINV/013/2016-01). S.K. is funded by the NMRC under the Transition Award. This study was sponsored in part by a generous gift from The Hour Glass.

Hepatitis is an inflammation of the liver that has several potential causes; however, the genetic association has recently begun to be studied.
Human leukocyte antigen (HLA) is an essential component of the immune response, and in this study, we conducted a correlation analysis to determine whether genetic polymorphisms of HLA and drinking habits affect hepatitis development.
Genetic polymorphisms of HLA were investigated using Korean genomic and epidemiological data. A gene association study was performed using PLINK version 1.07. Other statistical analyses and multivariate logistic regression analyses were performed using PASW Statistics version 18.0.
Thirteen single nucleotide polymorphisms (SNPs) in HLA-DRA showed significant statistical correlations with hepatitis. In particular, rs9268645 showed the highest statistical association with hepatitis (P = 3.97 × 10-5, odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.61-0.84). In multivariate logistic regression analysis, when considering only genetic factors, the A allele of rs9268644 showed a reduced hepatitis OR of approximately 0.52-fold. However, the group carrying the minor A allele (AA + AC) with alcohol consumption had an approximately 1.58-fold OR of hepatitis compared to that of the group carrying the same allele with no alcohol consumption. This implies that the A allele of rs9268644 has a protective effect on hepatitis by genetic factors and shows sensitivity to alcohol.
Our results showed that hepatitis is influenced by both genetic and external factors (drinking habits), which can provide new guidelines for the prevention or treatment of hepatitis.

BACKGROUND: Immune checkpoint blockade (ICB) only works well for a certain subset of patients with non-small cell lung cancer (NSCLC). Therefore, biomarkers for patient stratification are desired, which can suggest the most beneficial treatment.
METHODS: In this study, three datasets (GSE126044, GSE135222, and GSE136961) of immunotherapy from the Gene Expression Omnibus (GEO) database were analyzed, and seven intersected candidates were extracted as potential biomarkers for ICB followed by validation with The Cancer Genome Atlas (TCGA) dataset and the in-house cohort data.
RESULTS: Among these candidates, we found that human leukocyte antigen-DR alpha (HLA-DRA) was downregulated in NSCLC tissues and both tumor and immune cells expressed HLA-DRA. In addition, HLA-DRA was associated with an inflamed tumor microenvironment (TME) and could predict the response to ICB in NSCLC. Moreover, we validated the predictive value of HLA-DRA in immunotherapy using an in-house cohort. Furthermore, HLA-DRA was related to the features of inflamed TME in not only NSCLC but also in most cancer types.
CONCLUSIONS: Overall, HLA-DRA could be a promising biomarker for guiding ICB in NSCLC.

BACKGROUND: Low-grade gliomas (LGG) are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults. Currently, LGG treatment involves either or a combination of surgery, radiation therapy, and chemotherapy. Despite the knowledge of constitutive genetic risk factors contributing to gliomas, the role of single genes as diagnostic and prognostic biomarkers is limited. The aim of the current study is to discover the predictive and prognostic genetic markers for LGG.
METHODS: Transcriptome data and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We first performed the tumor microenvironment (TME) survival analysis using the Kaplan-Meier method. An analysis was undertaken to screen for differentially expressed genes. The function of these genes was studied by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Following which a protein-protein interaction network (PPI) was constructed and visualized. Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes. The key genes were selected by an intersection of core and prognostic genes. A clinical correlation analysis of single-gene expression was undertaken. GSEA enrichment analysis was performed to identify the function of key genes. Finally, a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG.
RESULTS: A total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA. Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment. The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified. Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG. Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration, positively related to macrophage M1 phenotype, and negatively related to activation of NK cells.
CONCLUSIONS: HLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients. It may also be associated with the immune infiltration phenotype in LGG.

OBJECTIVE: Reliable biomarkers to predict the outcome and treatment response of estrogen receptor (ER)-negative breast cancer (BC) are urgently needed. Since immune-related signaling plays an important role in the tumorigenesis of ER-negative BC, we asked whether Notch genes, alone or in combination with other immune genes, can be used to predict the clinical outcome and immune checkpoint blockade (ICB) for this type of cancer.
METHODS: We analyzed transcriptome data of 6918 BC samples from five independent cohorts, 81 xenograft triple-negative BC tumors that respond differently to ICB treatment and 754 samples of different cancer types from patients treated with ICB agents.
RESULTS: We found that among four Notch genes, the expression levels of NOTCH1 and NOTCH4 were positively associated with recurrence of ER-negative BC, and that combined expression of these two genes (named Notch14) further enhanced this association, which was comparable with that of the Notch pathway signature. Analysis of 1182 immune-related genes revealed that the expression levels of most HLA genes, particularly HLA-DMA and -DRA, were reversely associated with recurrence in ER-negative BC with low, but not high Notch14 expression. A combined expression signature of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA was more prognostic for ER-negative and triple-negative BCs than previously reported immune-related signatures. Furthermore, we found that the expression levels of these four genes were also synergistically associated with T cell exclusion score, infiltration of specific T cells and ICB efficacy in ER-negative BC, thereby providing a potential molecular mechanism for the synergistic effect of these genes on BC.
CONCLUSIONS: Our data indicate that a gene signature composed of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA may serve as a potential promising biomarker for predicting ICB therapy efficacy and recurrence in ER-negative/triple-negative BCs.

Background and Objectives: Abnormal expressions of CD74 and human leukocyte antigen-DR alpha (HLA-DRA) have been reported in various cancers, though their roles in cervical cancer remain unclear. This study aimed to evaluate the gene and protein expressions of CD74 and HLA-DRA in the progression from normal cervix to precancerous cervical intraepithelial neoplasia (CIN) and finally to squamous cell carcinoma (SCC). Materials and Methods: The gene expression profiles of CD74 and HLA-DRA were determined in formalin-fixed paraffin-embedded tissues, with three samples each from normal cervixes, human papillomavirus type 16/18-positive, low-grade CIN (LGCIN), high-grade CIN (HGCIN), and squamous cell carcinoma (SCC) using Human Transcriptome Array 2.0. Immunohistochemical expression of the proteins was semi-quantitatively assessed in another cohort of tissue microarray samples comprising 7 normal cervix cases, 10 LGCIN, 10 HGCIN, and 95 SCC. Results: The transcriptomics profile and proteins\' expression demonstrated similar trends of upregulation of CD74 and HLA-DRA from normal cervix to CIN and highest in SCC. There was a significant difference in both proteins\' expression between the histological groups (p = 0.0001). CD74 and HLA-DRA expressions were significantly associated with CIN grade (p = 0.001 and p = 0.030, respectively) but not with the subjects\' age or SCC stage. Further analysis revealed a positive correlation between CD74 and HLA-DRA proteins. Conclusions: CD74 appears to promote cervical carcinogenesis via oncogenic signalling mechanisms and may serve as a potential antitumour target. Additionally, the upregulation of HLA-DRA, often associated with stronger immunogenicity, could be a promising biomarker for developing immunotherapies.

Three novel HLA-DRA alleles, DRA*01:03, DRA*01:04, and DRA*01:05 alleles with unique amino acid sequences.

There is an increasing demand for prognostic immune biomarkers of cancer. The prognostic significance of immune markers has been shown for various cancers, but biomarkers of bladder cancer (BCa) have not been fully evaluated. To clarify the role of human leukocyte antigen DR alpha chain (HLA-DRA) in BCa development, we examined expression of HLA-DRA mRNA in tissue samples of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).
Tissues of 96 NMIBC, 43 MIBC and 59 controls comprising noncancerous BCa surrounding tissues were used to examine the expression of HLA-DRA gene by real-time polymerase chain reaction. The expression of up-stream genes regulating HLA-DRA were also measured to explain the role of HLA-DRA in BCa.
Patients with high grade NMIBC showed higher expression of HLA-DRA than those with low grade NMIBC (P < 0.05). In addition, NMIBC patients who progressed to MIBC showed high expression of HLA-DRA mRNA. Kaplan-Meier analysis showed that NMIBC patients with low expression of HLA-DRA had better progression-free survival than those with high expression (P = 0.004). Moreover, the expression of genes regulating HLA-DRA varied in NMIBC and MIBC, indicating a different immunoregulation effect of HLA-DRA in both cancers.
High expression of HLA-DRA in NMIBC patients has implications for patient stratification strategies, as well as for BCa tumor immunology.

UNASSIGNED: Parkinson\'s disease (PD) is a common progressive neurodegenerative disorder. Up to now, several single-nucleotide polymorphisms (SNPs) located in virulence gene sites have been reported linked to PD. Candidate gene association studies and genome-wide association studies have identified rs3129882, rs4248166 in HLA-DRA and rs34372695 in SYT11 as risk factors for familial or sporadic PD. However, the association between variants of HLA-DRA, SYT11 and PD are still controversial, especially in the Central Chinese population. We here performed a case-control study to investigate whether HLA-DRA and SYT11 genes could predispose to sporadic PD in the Chinese population.
UNASSIGNED: We investigate 486 PD patients and 457 age- and sex-matched controls from Central China to assess this association.
UNASSIGNED: In the allele model, the odds ratio (OR) result of rs3129882 was 0.905 (p = 0.287). Moreover, no significant difference was observed in the association between rs424816 (OR = 0.864, p = 0.106) and rs34372695 (p = 1.0) with PD risk. Genotypic analysis in SNP rs3129882, rs4248166 and rs34372695 indicated no significant association with PD. Subgroup analysis of our data showed age-onset and gender were not associated with either genotype or minor allele frequencies of rs3129882 and rs4248166. Moreover, the negative results were also observed in a meta-analysis of studies of rs3129882 from mainland China and Taiwanese population.
UNASSIGNED: Our results reveal that rs3129882, rs4248166 and rs34372695 do not confer significant risks for sporadic PD in the Central Chinese population.