Human Leukocyte antigen-DR Research Articles

Recent Advances of Precision Immunotherapy in Sepsis

Abstract Precision immunotherapy signifies the administration of the required type of immune intervention tailored to the state of immune activation at the appropriate time window. The classification of patients into the different states of immune activation is usually done by either a protein blood biomarker or a molecular blood endotype which is diagnostic of the precise immune state. Evidence coming from trials of the last decade suggests that immune interventions should be split into strategies aiming to attenuate the exaggerated immune responses, strategies aiming to restore sepsis-induced immunoparalysis (SII) and strategies aiming to restore the vascular tone. Suggested strategies to attenuate the immune responses are anakinra, nangibotide and tocilizumab. Biomarkers which guide their use are ferritin and sTREM-1 (soluble triggering receptor expressed on myeloid cells-1). Suggested strategies to restore SII are nivolumab, recombinant human interferon-gamma, CYT107 and GM-CSF (granulocyte macrophage colony stimulating factor). Biomarkers which guide their use are the expression of the human leukocyte antigen DR on blood monocytes, the absolute lymphocyte count, and blood levels of IgM. One recently suggested strategy to restore vascular tone is adrecizumab, the use is guided by the blood levels of bio-adrenomedulin. The use of these precision treatment strategies is still hampered by the need of large scale randomized controlled trials.

Human Leukocyte Antigen – DR (HLA-DR) Isotype Expression on Monocytes as a Prognostic Marker in Patients with Sepsis in Intensive Care Unit

Human Leukocyte Antigen – DR (HLA-DR) Isotype Expression on Monocytes as a Prognostic Marker in Patients with Sepsis in Intensive Care Unit

Human leukocyte antigen DR alpha inhibits renal cell carcinoma progression by promoting the polarization of M2 macrophages to M1 via the NF-κB pathway

Human leukocyte antigen DR alpha (HLA-DRA) is recognized for its inhibitory effect on the progression of clear cell renal cell carcinoma (ccRCC); high HLA-DRA expression levels are positively correlated with improved prognosis in patients with ccRCC. In this study, we evaluated HLA-DRA expression in ccRCCs, its effects on tumor-associated macrophage recruitment, and the influence of polarization. Clinical cohort analyses revealed that elevated HLA-DRA expression in ccRCC cells was correlated with enhanced tumor infiltration by M1-type macrophages. In addition, ccRCC prognosis was predicted by combining HLA-DRA expression level analysis and the M1/M2 macrophage ratio. In vitro studies demonstrated that ccRCC cells with increased HLA-DRA expression promoted THP-1 cell migration and induced macrophage polarization toward the M1 phenotype. The effect was further substantiated in a mouse xenograft model in which an increase in M1 macrophages was observed. In addition, co-culturing macrophages with the supernatant from cells overexpressing HLA-DRA induced the expression of proteins associated with both M1 and M2 macrophage polarization. HLA-DRA was intricately linked to the expression and secretion of chemokines, including CCL2, CCL5, MIP-1ɑ, and CXCL-10. Moreover, the NF-κB pathway activation promoted polarization to M1 macrophages. This study shows that HLA-DRA and the M1/M2 ratio are indicators of favorable prognosis in patients with ccRCC. HLA-DRA promotes M1-like polarization by regulating NF-κB, which can be used as a therapeutic target to enhance anti-tumor immunity.

Immune Profile and MRI-Detected Cardiac Fibrosis and Edema in Hypertensive and Non-Hypertensive Patients with COVID-19.

Cardiac involvement in 2019 coronavirus disease (COVID-19) survivors has been reported frequently. An exacerbated immune response may be the main mechanism of myocardial injury and late cardiac sequelae in this population. Background/Objectives: We investigated the immune profile in hypertensive and non-hypertensive patients with COVID-19 who developed late cardiac fibrosis and edema, as detected by magnetic resonance imaging (MRI). Methods: We evaluated associations of cytokine and immune-cell subset levels during hospitalization for COVID-19 with the presence of myocardial interstitial fibrosis [represented by the extracellular volume (ECV)] or edema (represented by the T2), detected by cardiac MRI examination after discharge, in hypertensive and non-hypertensive patients. Results: Patients with hypertension had reduced B-cell percentages, increased natural killer cell percentages, and higher interleukin (IL)-4, IL-5, IL-13, IL-17A, and tumor necrosis factor-β levels compared to patients without hypertension. Larger percentages of human leukocyte antigen DR isotope+ blood cells, reflecting CD8+ T-cell activation, correlated with increased T2 and ECV in hypertensive patients. The HLA-DR mean fluorescence intensity was associated with ECV in non-hypertensive patients. Conclusions: Our findings reveal cytokine and immune-cell dysregulation in both hypertensive and non-hypertensive patients with COVID-19, along with moderate correlations between CD8+ T-cell activation and increased cardiac MRI markers of myocardial interstitial fibrosis and edema. These results contribute to a deeper understanding of immune dysfunction mechanisms involved in myocardial remodeling.

The Antiviral Effects of Heat-Killed Lactococcus lactis Strain Plasma Against Dengue, Chikungunya, and Zika Viruses in Humans by Upregulating the IFN-α Signaling Pathway.

The growing risk of contracting viral infections due to high-density populations and ecological disruptions, such as climate change and increased population mobility, has highlighted the necessity for effective antiviral treatment and preventive measures against Dengue virus (DENV), Chikungunya virus (CHIKV), and Zika virus (ZIKV). Recently, there has been increasing attention on the use of probiotics as a potential antiviral option to reduce virus infections. The present study aimed to assess the immunomodulatory effects of heat-killed Lactococcus lactis strain plasma (LC-Plasma) on peripheral blood mononuclear cells (PBMCs) and its subsequent antiviral response against DENV, CHIKV, and ZIKV. To evaluate the immunomodulatory effects of LC-Plasma on PBMCs isolated from healthy individuals, PBMCs were cultured at a density of 2 × 105 cells/well and stimulated with 10 µg/mL of LC-Plasma. LC-plasma-stimulated PBMCs demonstrated elevated interferon-alpha (IFN-α) production and cluster of differentiation 86 (CD86) and human leukocyte antigen-DR isotype (HLA-DR) upregulation, potentially linked to plasmacytoid dendritic cell (pDC) activation. The replication of DENV, CHIKV, and ZIKV was dose-dependently inhibited when Huh-7 cells were stimulated with LC-Plasma-stimulated PBMC supernatant (LCP Sup). IFN-stimulated gene (ISG) expression, including IFN-stimulated gene 15 (ISG15), IFN-stimulated exonuclease gene 20 (ISG20), IFN-induced transmembrane protein 1 (IFITM-1), myxovirus resistance protein A (MxA), and radical S-adenosyl methionine domain-containing protein 2 (RSAD2), was significantly upregulated in LCP Sup-stimulated Huh-7 cells. Findings from this study indicate that LC-Plasma has the potential to induce IFN-α production, leading to an enhancement in the expression of ISGs and contributing to a broad-spectrum antiviral response. Thus, LC-Plasma may serve as a rational adjunctive treatment to ameliorate viral diseases, warranting future clinical trials.

Mediating role of circulating inflammatory proteins in the effect of immune cells on esophageal cancer risk: A Mendelian randomization study.

The immune system and inflammatory processes play crucial roles in the development of esophageal cancer (EC). This study aimed to investigate the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC, with a particular focus on the mediating role of circulating inflammatory proteins. Utilizing public genetic data, we applied a 2-sample Mendelian Randomization (MR) method to examine the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC. Comprehensive sensitivity analyses were conducted to assess the robustness, heterogeneity, and horizontal pleiotropy of the MR results. Additionally, a 2-step MR method was employed to quantify the impact and proportion of immune cell phenotypes mediated by circulating inflammatory proteins on EC. Eleven immune cell phenotypes and 1 inflammatory cytokine were found to have causal relationships with EC, with results stable across all sensitivity analyses. Mediation analyses revealed that only 2 cell phenotypes had causal relationships with EC through interleukin-10: CD3 on human leukocyte antigen-DR (HLA-DR)+ T cells (mediation effect = -0.009; mediation proportion = 12.01%) and monocytic myeloid-derived suppressor cell absolute count (mediation effect = 0.018; mediation proportion = 18.97%). This study enhances the understanding of the causal relationships between immune cells, circulating inflammatory proteins, and EC. The findings highlight the potential mediating role of interleukin-10, providing new insights into the mechanisms by which immune cells may influence esophageal tumorigenesis.

Autoimmune diseases and cardiovascular risk: Mendelian randomization analysis for the impact of 19 autoimmune diseases on 14 cardiovascular conditions

BackgroudAutoimmune diseases (AIDs) have been associated with various cardiovascular diseases (CVDs) in observational data. However, the causality of these associations remains uncertain. Therefore, a systematic assessment of the impact of AIDS on cardiovascular risk is required. ResultsWe assessed the impact of 19 common AIDs on 14 CVDs using bidirectional Mendelian randomization (MR). Celiac disease (odds ratio [OR] = 2.949, 95 % confidence interval [CI]: 1.111–7.827, P = 0.030) and type 1 diabetes mellitus (T1DM) (OR = 1.044, 95 % CI: 1.021–1.068, P = 1.82e-4) were associated with an increased risk of peripheral arterial disease (PAD). Additionally, celiac disease was linked to an increased risk of arrhythmia (OR = 1.008, 95 % CI: 1.002–1.013, P = 0.004), multiple sclerosis to venous thromboembolism (OR = 1.001, 95 % CI: 1.000–1.001, P = 0.010), and psoriasis to heart failure (OR = 1.048, 95 % CI: 1.021–1.077, P = 0.001). Sensitivity analyses were conducted to enhance the robustness of these findings. Predominantly, immune response and inflammation-related pathways were enriched in the aforementioned associations. Mediation analysis identified human leukocyte antigen-DR positive myeloid dendritic cells as partially mediating the effect of T1DM on PAD, with a mediated proportion of 16.61 % (P = 0.028). Potential therapeutic agents, such as tumor necrosis factor-alpha inhibitors and interferon, may have efficacy in treating AID-related CVDs. ConclusionsThis study presents genetic evidence of certain AIDs impacting specific CVDs and identifies potential mediators and drugs.

Decreased CD3+CD56+ Natural Killer T Lymphocytes and Increased Human Leukocyte Antigen-DR+ Cells in the Inflamed Area of Pouchitis in Ulcerative Colitis Patients.

Pouchitis is an inflammatory condition that affects the ileal pouch during ileal pouch-anal anastomosis surgery. Despite its clinical significance, precise immunological mechanisms underlying pouchitis remain unclear. This study aimed to investigate the lymphocyte profile in the ileal pouch of patients with pouchitis compared to those with familial adenomatous polyposis (FAP) and ulcerative colitis without pouchitis using flow cytometry and immunohistochemical techniques. We prospectively analyzed endoscopic biopsy specimens from the ileal pouches of 15 patients and categorized them into three groups: FAP, ulcerative colitis with an inflammation-free pouch (UC-I), and ulcerative colitis with ulcers and/or erosions in the pouch (UC-UE). Flow cytometry was used to assess various T-lymphocyte markers, including cluster of differentiation (CD) 4, CD8, CD56, and human leukocyte antigen (HLA)-DR. Immunohistochemistry was performed to visualize the spatial distribution of CD3+, CD56+, and HLA-DR+ cells in the pouch mucosa. We observed significantly reduced CD56+/CD3+ and CD8+/CD3+ ratios in the UC-UE group compared to those in the FAP group, indicating a disruption in natural killer T-cell populations. Immunohistochemical analysis revealed that the spatial distribution of lymphocytes differed among the non-inflamed mucosa, dense lymphocyte infiltration, and lymphoid follicles, with these components frequently intermingling. CD56 + cells were less abundant in areas with dense lymphocyte infiltration, whereas HLA-DR+ cells were more abundant. Our study revealed a decrease in CD56+ natural killer T cells and an increase in HLA-DR+-activated T cells in areas with dense lymphocyte infiltration, suggesting an association between these cells and pouchitis in ulcerative colitis. The distinct patterns observed in non-inflamed mucosa, areas with dense lymphocyte infiltration, and lymphoid follicles underscore the need for further analyses of these three segments to elucidate the immunological mechanisms underlying pouchitis.

A Systematic Review and Meta-Analysis of Human Leukocyte Antigen-DR (HLA-DR) in Onychomycosis: HLA-DR8 Confers Susceptibility.

Onychomycosis (OM) is a nail infection from various fungal species, representing a worldwide dermatologic health concern. The toenails are most often affected. Comorbid chronic health conditions and environmental and genetic factors play a role in the development of OM. It has been observed that certain populations have an increased risk of developing OM, suggesting an inherited component to its etiology. Recent studies have observed the impact of the human leukocyte antigen-DR (HLA-DR) profile on the likelihood of developing OM; however, none have aggregated these studies for a meta-analysis to determine a statistical effect. The literature was systematically reviewed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to determine the effect of the HLA-DR profile on OM susceptibility. Studies that contained HLA-DR allele frequency data on patients with OM were included. Studies that contained too much allele frequency data, did not contain HLA-DR allele frequency data, or were written in a non-English language were excluded. Google Scholar, PubMed, and Scientific Direct databases were searched. The risk of bias was assessed by using the National Institutes of Health (NIH) quality assessment case-control study tool. The results were generated using Review Manager version 5.4 by extracting and inputting HLA-DR allele frequency data into the program. The program created aggregated odds ratios that were visually represented in forest plots. A total of five articles were included in the analysis. One hundred fifty-six patients with OM were used in this analysis. Mexican mestizos and United States Caucasian populations were represented in this study. Overall, the NIH risk of bias tool revealed that most studies included did not justify their sample size, or the assessors were not blinded. Of all the HLA-DR alleles analyzed, only HLA-DR8 revealed a statistically significant result with an odds ratio of 1.70 with a 95% CI (1.05-2.76). This suggests that HLA-DR8 confers a 70% higher risk of susceptibility to OM. This finding can help identify these target populations and serve as the basis for personalized treatment solutions.

Report on post-transplantation cancer in southeast Asia from the Thai kidney transplantation cohort

Post-transplantation cancer is a significant cause of mortality among kidney transplant recipients (KTR). The incidence of post-transplantation cancer varies based on geographic region and ethnicity. However, data on KTR from South East Asia, where characteristics differ from other parts of Asia, is lacking. We conducted a retrospective cohort study at a transplant center in Thailand to investigate the incidence of post-transplantation cancer and mortality rates. Factors associated with post-transplantation cancer and patient outcomes were analyzed using competing-risks regression. The study included 1156 KTR with a post-transplant follow-up duration of 5.1 (2.7–9.4) years. The age- and sex-adjusted incidence rate of post-transplant cancer was highest for urothelial cancer (6.9 per 1000 person-years), which also resulted in the highest standardized incidence ratio (SIR) of 42.5 when compared to the general population. Kidney cancer had the second-highest SIR of 24.4. Increasing age was the factor associated with an increased risk of post-transplant cancer (SHR 1.03; 95% CI 1.01–1.05). Human leukocyte antigen (HLA) DR mismatch was associated with a decreased risk of post-transplant cancer (SHR 0.72; 95% CI 0.52–0.98). Post-transplantation cancer was significantly associated with patient mortality (HR 3.16; 95% CI 2.21–4.52). Cancer significantly contributes to KTR mortality, and the risk profile for cancer development in Thai KTRs differs from that of Western and most Asian counterparts. Further research is essential to explore appropriate screening protocols for countries with high rates of urothelial and kidney cancer, including Thailand.

Human Leukocyte Antigen-DR and Cluster Designation 34: Double-negative Acute Myeloid Leukemias – Our Experience in Clinical Setting

AbstractIntroduction:Dual negativity for cluster designation (CD) 34 and human leukocyte antigen (HLA)-DR antigen in leukemia panel is an important finding in clinical practice. The combination of this finding though seen classically in acute promyelocytic leukemia (APL) is not specific to it but can be seen in many other myeloid leukemias like the ones associated with nucleophosmin 1 (NPM1) or FMS-related tyrosine kinase 3 gene-internal tandem duplication (FLT3-ITD) abnormalities. It is important to identify APL from non-APL leukemia as treatment and prognosis vary.Aims and Objectives:We analyzed CD 34 and HLA-DR dual-negative acute myeloid leukemia (AML) cases presented to us over 2.5 years (26 cases) and segregated them into APL and non-APL groups to study their morphological/flow cytometric and cytogenetic profile and correlation with treatment response.Materials and Methods:It was a prospective study including all newly diagnosed AMLs showing CD 34 and HLA-DR dual negativity in flow cytometry profile. Cases in which complete information/cytogenetics/molecular profile were not available, were excluded from the study. The patients were followed up till the end of induction to look for morphological response to induction therapy. The clinical and treatment records were pulled out from the patient database after ethical committee clearance.Results:A total of 139 new AML cases were encountered during the study period out of which 28 (20%) were found to be dual negative for CD34 and HLA-DR. The non-APL group showed higher mean age, TLC at baseline, variable morphology, and more number of aberrant expression on flow cytometry profile. No significant difference was noted in terms of gender, presence of hepatosplenomegaly, DIC as complication, or percentage of blasts/blasts equivalent at baseline. Our study found that while all APL patients had PML-RARA, the associated molecular abnormalities were much lesser as compared to the non-APL group which showed a variety of abnormalities such as NPM1, FLT3, RAS mutation, and mutations involving epigenetic modifiers. The response rate to induction therapy was significantly lower in the non-APL group as compared to the APL group.Conclusion:The non-APL myeloid leukemia which is dual negative is commonly found to be associated with cup-shaped morphology, NPM, or FLT3-ITD mutation along with other abnormalities. These patients were older in age, showed higher TLC and higher blast counts, associated with poorer response to induction therapy as compared to the APL group.

The Impact of Donor-Recipient Human Leukocyte Antigen Matching on Bronchiolitis Obliterans-Free Survival Among Lung Transplant Recipients With Connective Tissue Diseases.

The development of connective tissue disease-associated lung diseases (CTD-LD) occurs in association with specific human leukocyte antigens (HLA). For CTD-LD patients who require lung transplant, it is unknown whether utilization of donor organs expressing these same HLA impacts posttransplant outcomes. Using the Scientific Registry of Transplant Recipients, we assessed whether CTD-LD lung transplant recipients in the United States have worse bronchiolitis obliterans (BOS)-free survival based on the degree of donor HLA matching. This included overall degree of donor-recipient HLA matching, donor-recipient matching at DR loci, and recipient matching with specific donor HLA antigens associated with the development of pulmonary disease in their condition. Among 1413 patients with CTD-ILD, highly HLA-matched donor-recipients did not have worse adjusted survival (hazard ratio [HR]=0.93, 95% confidence interval [CI]=0.58-1.51, p=0.77). Recipients who were fully matched at HLA DR did not have worse survival (HR=0.82, 95% CI=0.56-1.19, p=0.29). Finally, among individual CTD-LD, including rheumatoid arthritis, systemic sclerosis, the idiopathic inflammatory myopathies, and systemic lupus erythematous, transplant with a donor expressing HLA antigens associated with lung manifestations in these conditions was not associated with worse BOS-free survival. Among transplant recipients with CTD-LD, HLA donor-recipient matching, including at the DR loci, does not result in worse BOS-free survival. Based on these findings, there is no reason to treat these as unacceptable antigens when considering donor offers for CTD-LD candidates.

Löfgren syndrome, characteristics of Japanese cases: A case and a review of the literature.

Löfgren syndrome (LS) is a sarcoidosis subtype characterised by an acute disease course, bilateral hilar lymphadenopathy (BHL), erythema nodosum (EN), and ankle arthritis. LS in Caucasians appears to be self-limiting; however, our patients require glucocorticoid (GC) treatment. Here, we present a case of LS and review the literature to identify the characteristics of Japanese patients with LS. A 66-year-old woman was referred to Kobe City Medical Center General Hospital; she initially presented with an acute onset of low-grade fever and ankle arthritis, followed by EN. Skin biopsy revealed a noncaseating granuloma, and a chest computed tomography scan displayed BHL; she was diagnosed with LS. Her arthralgia ameliorated spontaneously, but the erythema persisted, necessitating GC treatment. A literature review revealed that the Japanese LS patients showed more fever, were more frequently treated with GCs, and more patients seemed to relapse, which may be explained by the absence of human leucocyte antigen-DR isotype 3, a good prognostic allele in Caucasians. Japanese LS may cause severe symptoms after development because of the differences in human leucocyte antigens from foreign countries. For early diagnosis, it is important to evaluate EN and BHL in patients with polyarthritis involving ankle arthralgia.

Monocytic Human Leukocyte Antigen-DR Expression Levels to Predict Outcome in Children With Severe Sepsis

Monocytic Human Leukocyte Antigen-DR Expression Levels to Predict Outcome in Children With Severe Sepsis

Causal Involvement of Immune Cells in Chronic Obstructive Pulmonary Disease: A Mendelian Randomization Study.

The immune cells play a substantial role in the development and progression of chronic obstructive pulmonary disease (COPD). We aim to investigate the causal involvement of immune cells in COPD via a Mendelian randomization (MR) analysis. Published genome-wide association studies (GWAS) statistics on immune cells were analyzed, with genetic variants identified as instrumental variables (IVs). Inverse-variance weighting (IVW), weighted median, and MR-Egger regression methods were employed, along with simple mode and weighted mode adopted in the two-sample MR analysis. Sensitivity analysis was conducted to examine the heterogeneity, horizontal pleiotropy, and stability of the causal relationship. IVW results suggested that CCR2 on CD62L+ plasmacytoid dendritic cells (DC), CCR2 on plasmacytoid DC, CD11b on CD66b++ myeloid cells, CD19 on CD20- CD38- CD24+ memory B cell subset, CD25 on transitional B cells, and CD25++CD8br %CD8br T cells were risk factors for the development of COPD. Besides, CD127 on effector memory-like cytotoxic T lymphocytes lacking expression of co-stimulatory molecule 28 (CD28-EM CTLs) and HLA DR+ NK ACs expressing human leukocyte antigen DR molecules while being natural killer cells (%NK ACs) were protective factors for COPD. This study unveiled a causal relationship between immune cell phenotype and COPD. These findings offer new insights for the prevention and treatment of COPD using COPD-associated immune cells.

IL-15 gene mutation as a molecular risk factor in acute lymphoid leukemia.

The present study investigated the relationship between single nucleotide polymorphisms in the interleukin (IL)-15 gene located (exon 8) on the chromosomal location 4q31.21 and acute lymphoblastic leukaemia (ALL) risk in Iraqi patients. A total of 78 (49 male -29 female) primary ALL (62B-cell, 16 T-cells lineages cases and 30 healthy control subjects (median age 11, age range were 4-21.5), were enrolled at the Nanakaly Hospital of Erbil Province between February 2021 and January 2022. The genotype analysis was performed using polymerase chain reaction (PCR) and Sanger DNA sequencing. The IL15 homozygous rs10833 (100%) and rs2291596 (63.6%) genotypes indicated high frequencies and were associated with a risk of developing ALL, while the remaining 16 novel mutations indicated in low frequency (9.1%) except for the 97270G>GT genotype (18.2%). High expression levels were noted for different clusters of differentiation (CD) biomarkers between both subtypes of ALL, including, CD10, CD19, CD22, CD79a, CD99, terminal deoxynucleotidyl transferase (TdT), and human leukocyte antigen DR (HLA-DR) isotype in B-cells lineages, while, CD2, CD3, CD5, CD7, CD13, CD117 and TdT are more specific to T-cells lineages. On the other hand, significant changes were noted in certain hematological parameters including red blood cells (RBCs), haemoglobin (g/dl), haematocrite (HCt %), red blood cell distribution width (RDW %), and platelet counts (PLT- 109/L) compared with those of healthy subjects. Finally, it was concluded that various novel mutations were recorded with different subtypes of ALL diseases, and mild anemia was observed among patients. Future studies will be towered to associate these mutations with prognosis and therapeutic response of diseases.

Adenosine 5'-Monophosphate-to-Threonine Ratio Promotes Abdominal Aortic Aneurysms via Up-Regulation of HLA-DR on Natural Killer Cells: A Bidirectional Mendelian Randomized Analysis.

Objective: Immune-metabolic interactions may have causal and therapeutic impacts on abdominal aortic aneurysms (AAAs). However, due to the lack of research on the relationship between immune-metabolic interactions and AAAs, further exploration of the mechanism faces challenges. Methods: A two-sample, two-step mediation analysis with Mendelian randomization (MR) based on genome-wide association studies (GWASs) was performed to determine the causal associations among blood immune cell signatures, metabolites, and AAAs. The stability, heterogeneity, and pleiotropy of the results were verified using a multivariate sensitivity analysis. Results: After multiple two-sample MRs using the AAA data from two large-scale GWAS databases, we determined that the human leukocyte antigen-DR (HLA-DR) levels on HLA-DR + natural killer (NK) cells (HLA-DR/NK) were associated with the causal effect of an AAA, with consistent results in the two databases (FinnGen: odds ratio (OR) = 1.054, 95% confidence interval (CI): 1.003-1.067, p-value = 0.036; UK Biobank: OR = 1.149, 95% CI: 1.046-1.261, p-value = 0.004). The metabolites associated with the risk of developing an AAA were enriched to find a specific metabolic model. We also found that the ratio of adenosine 5'-monophosphate (AMP) to threonine could act as a potential mediator between the HLA/NK and an AAA, with a direct effect (beta effect = 0.0496) and an indirect effect (beta effect = 0.0029). The mediation proportion was 5.56%. Conclusions: Our study found that an up-regulation of HLA-DR on HLA-DR/NK cells can increase the risk of an AAA via improvements in the AMP-to-threonine ratio, thus providing a potential new biomarker for the prediction and treatment of AAAs.

Structural insights into human MHC-II association with invariant chain

The loading of processed peptides on to major histocompatibility complex II (MHC-II) molecules for recognition by T cells is vital to cell-mediated adaptive immunity. As part of this process, MHC-II associates with the invariant chain (Ii) during biosynthesis in the endoplasmic reticulum to prevent premature peptide loading and to serve as a scaffold for subsequent proteolytic processing into MHC-II-CLIP. Cryo-electron microscopy structures of full-length Human Leukocyte Antigen-DR (HLA-DR) and HLA-DQ complexes associated with Ii, resolved at 3.0 to 3.1 Å, elucidate the trimeric assembly of the HLA/Ii complex and define atomic-level interactions between HLA, Ii transmembrane domains, loop domains, and class II-associated invariant chain peptides (CLIP). Together with previous structures of MHC-II peptide loading intermediates DO and DM, our findings complete the structural path governing class II antigen presentation.

Biobran/MGN-3, an Arabinoxylan Rice Bran, Exerts Anti-COVID-19 Effects and Boosts Immunity in Human Subjects.

Corona Virus Disease 19 (COVID-19) has been a major pandemic impacting a huge population worldwide, and it continues to present serious health threats, necessitating the development of novel protective nutraceuticals. Biobran/MGN-3, an arabinoxylan rice bran, is a potent immunomodulator for both humans and animals that has recently been demonstrated to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We here investigate Biobran/MGN-3's potential to enhance an antiviral immune response in humans. Peripheral blood mononuclear cells (PBMCs) derived from eight subjects taking Biobran/MGN-3 (age 55-65 years) and eight age-matched control subjects were stimulated with irradiated SARS-CoV-2 virus and then subjected to immuno-phenotyping and multiplex cytokine/chemokine assays. Results showed that PBMCs from subjects supplemented with Biobran/MGN-3 had significantly increased activation of plasmacytoid dendritic cells (pDCs) coupled with increased IFN-α secretion. We also observed higher baseline expression of HLA-DR (human leukocyte antigen-DR isotype) on dendritic cells (DCs) and increased secretion of chemokines and cytokines, as well as a substantial increase in cytotoxic T cell generation for subjects taking Biobran/MGN-3. Our results suggest that Biobran/MGN-3 primes immunity and therefore may be used for boosting immune responses against SARS-CoV-2 infections and other diseases, particularly in high-risk populations such as the elderly.

Active Tuberculosis Is Associated with Depletion of HIV-Specific CD4 and CD8 T Cells in People with HIV.

Infection with Mycobacterium tuberculosis (Mtb) in people with HIV (PWH) is associated with depletion of Mtb-specific CD4 T cell responses, increased risk of progression to active tuberculosis (TB) disease, and increased immune activation. Although higher HIV viral loads have been reported in Mtb/HIV co-infection, the extent to which Mtb infection and TB disease impact the frequency and phenotype of HIV-specific T cell responses has not been well described. We enrolled a cohort of PWH in Kenya across a spectrum of Mtb infection states, including those with no evidence of Mtb infection, latent Mtb infection (LTBI), and active pulmonary TB disease, and evaluated the frequency, immune activation, and cytotoxicity phenotype of HIV-specific CD4 and CD8 T cell responses in peripheral blood by flow cytometry. We found evidence of depletion of HIV-specific CD4 and CD8 T cells in people with TB, but not with LTBI. Expression of the immune activation markers human leukocyte antigen-DR isotype (HLA-DR) and Ki67 and of the cytotoxic molecules granzyme B and perforin were increased in total CD4 and CD8 T cell populations in individuals with TB, although expression of these markers by HIV-specific CD4 and CD8 T cells did not differ by Mtb infection status. These data suggest that TB is associated with overall increased T cell activation and cytotoxicity and with depletion of HIV-specific CD4 and CD8 T cells, which may contribute to further impairment of T cell-mediated immune control of HIV replication in the setting of TB.