Characterization of the Novel HLA-C*07:01:126 Allele by Sequencing-Based Typing.

HLA-C*07:01:126 differs from HLA-C*07:01:01:01 by one nucleotide substitution in codon 328 in exon 7.

Advances in understanding and managing celiac disease: Pathophysiology and treatment strategies.

In this editorial, we comment on an article published in the recent issue of the World Journal of Gastroenterology. Celiac disease (CeD) is a disease occurring in genetically susceptible individuals, which is mainly characterized by gluten intolerance in the small intestine and clinical symptoms such as abdominal pain, diarrhea, and malnutrition. Therefore, patients often need a lifelong gluten-free diet, which greatly affects the quality of life and expenses of patients. The gold standard for diagnosis is intestinal mucosal biopsy, combined with serological and genetic tests. At present, the lack of safe, effective, and satisfactory drugs for CeD is mainly due to the complexity of its pathogenesis, and it is difficult to find a perfect target to solve the multi-level needs of patients. In this editorial, we mainly review the pathological mechanism of CeD and describe the current experimental and improved drugs for various pathological aspects.

Variation within the non-coding genome influences genetic and epigenetic regulation of the human leukocyte antigen genes.

Variation within the non-coding genome may influence the regulation and expression of important genes involved in immune control such as the human leukocyte antigen (HLA) system. Class I and Class II HLA molecules are essential for peptide presentation which is required for T lymphocyte activation. Single nucleotide polymorphisms within non-coding regions of HLA Class I and Class II genes may influence the expression of these genes by affecting the binding of transcription factors and chromatin modeling molecules. Furthermore, an interplay between genetic and epigenetic factors may also influence HLA expression. Epigenetic factors such as DNA methylation and non-coding RNA, regulate gene expression without changing the DNA sequence. However, genetic variation may promote or allow genes to escape regulation by epigenetic factors, resulting in altered expression. The HLA system is central to most diseases, therefore, understanding the role of genetics and epigenetics on HLA regulation will tremendously impact healthcare. The knowledge gained from these studies may lead to novel and cost-effective diagnostic approaches and therapeutic interventions. This review discusses the role of non-coding variants on HLA regulation. Furthermore, we discuss the interplay between genetic and epigenetic factors on the regulation of HLA by evaluating literature based on polymorphisms within DNA methylation and miRNA regulatory sites within class I and Class II HLA genes. We also provide insight into the importance of the HLA non-coding genome on disease, discuss ethnic-specific differences across the HLA region and provide guidelines for future HLA studies.

Differences in chronic lung allograft dysfunction between deceased-donor lung transplantation and living-donor lobar lung transplantation.

OBJECTIVE: This study explored the characteristics and prognostic impact of chronic lung allograft dysfunction (CLAD) after deceased-donor lung transplantation and living-donor lobar lung transplantation, wherein the lower lobes from two donors are usually transplanted into one recipient. METHODS: The clinical data of 123 deceased-donor and 67 living-donor lung transplantations performed in adult patients at our institution between June 2008 and September 2019 were retrospectively reviewed. The cumulative incidence of CLAD was evaluated on a per-recipient and per-donor graft basis using the Kaplan-Meier method. RESULTS: The smaller number of human leukocyte antigen mismatches, shorter ischemic time, and lower incidence of grade 3 primary graft dysfunction were observed in living-donor transplantation than in deceased-donor transplantation (p<0.001). Restrictive allograft syndrome (RAS)-type CLAD occurred in 9 (20.9%) of 43 CLAD patients after deceased-donor transplantation and 9 (45.0%) of 20 CLAD patients after living-donor transplantation. CLAD occurred unilaterally in 15 patients (75.0%) after bilateral living-donor transplantation. Despite the higher incidence of RAS-type CLAD after living-donor transplantation, the overall survival rates after the transplantation and survival rates after the onset of CLAD were comparable between the deceased-donor transplant and living-donor transplant patients. The cumulative incidence of CLAD per recipient was similar between the deceased-donor and the living-donor transplant recipients (p=0.32). In the per-donor graft analysis, the cumulative incidence of CLAD was significantly lower in the living-donor grafts than in the deceased-donor grafts (p=0.003). CONCLUSIONS: The manifestation of CLAD after living-donor lobar lung transplantation is unique and differs from that after deceased-donor lung transplantation.

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.

Allogeneic mesenchymal stromal cell therapy in kidney transplantation: should repeated human leukocyte antigen mismatches be avoided?

Mesenchymal stromal cells (MSCs) have immunomodulatory properties and are therefore considered promising tools in kidney transplantation. Although most studies have been conducted with autologous MSCs, using allogeneic MSCs as an off-the-shelf product is more feasible in clinical settings. However, allogeneic MSCs could potentially induce an immune response, which might eventually be directed towards the kidney allograft because of shared human leukocyte antigen (HLA) epitope mismatches between the kidney and MSC donor. In this study, we performed in-depth analyses of two cohorts (n = 20) that received third-party MSC therapy after kidney transplantation. While the Neptune Study from Leiden University Medical Center specifically selected MSC to avoid repeated HLA antigen mismatches between kidney and MSC donors, the study from the University of Liège did not perform specific MSC selection. The comparative analyses of amino acid mismatches between these cohorts showed that MSC selection to avoid repeated HLA mismatches at the split antigen level was not sufficient to prevent repeated mismatches at the amino acid level. However, repeated amino acid mismatches were not associated with the occurrence of donor-specific antibodies (DSAs). Thus, the clinical relevance of repeated amino acid mismatches seems to be limited with regard to the risk of DSA formation. Since DSA formation was limited (3 of 20 patients) in this study, larger studies are required to investigate the relevance of preventing repeated HLA mismatches in allogeneic MSC therapy in kidney transplantation.

Association of the Genetic Diversity of Killer Cell Immunoglobulin-like Receptor Genes and HLA-C Ligand in Saudi Women With Thyroid Cancer.

INTRODUCTION: Genetic diversity in the killer immunoglobulin-like receptor (KIR) gene composition and human leukocyte antigen (HLA) class I ligands, such as HLA-C, can affect the activity of natural killer cells and determine anti-cancer immunity. Specific KIR-HLA combinations can enhance cancer predisposition by promoting immune evasion. Studying the relationship between KIR-HLA polymorphisms and thyroid cancer (TC) risk can offer insights into how natural immunity fails, leading to disease development. Therefore, we investigated the association between KIR and HLA-C genotypes and TC risk in Saudi women. METHODS: In this retrospective study, sixteen KIR genotypes and 2 HLA-C allotypes were determined using the polymerase chain reaction-sequence-specific primer (PCR-SSP) method, and the genotypes of 50 Saudi female patients with TC were compared with those of 50 Saudi female healthy controls (HC). RESULTS: We observed a highly significant decrease in the presence of the KIR2DS2 and KIR2DS4 genes (OR = 0.15, 95% CI = 0.05-0.41, P = 0.0001; OR = 0.06, 95% CI = 0.02-0.2, P = 0.000, respectively) and in the presence of the KIR2DL5A gene (OR = 0.05, 95% CI = 0.02-0.14, P = 0.0000) in the TC group compared to the HC group. The frequency of the HLA-C2C2 allotype was significantly higher in HC compared to patients with TC (P = 0.02). The KIR haplotype group A and AB genotypes revealed a protective effect against TC (P = 0.0003 and P = 0.000, respectively), while the BB genotype showed a risk effect on TC compared to HC. Our results showed significant differences in the KIR gene combinations and KIR-HLA combinations between Saudi female TC patients and HC. CONCLUSION: These results suggest that the expression of KIR genes and their HLA-C ligands may influence the risk of TC development in Saudi women.

Genetic diversity in killer immunoglobulin-like receptors (KIR) gene composition and human leukocyte antigen class I (HLA) ligands such as HLA-C can impact the activity of natural killer cells (NK cells) and determine the results of cancer immunity. Specific KIR-HLA combinations can enhance vulnerability by promoting immune evasion. Studying the relationship between KIR-HLA polymorphisms and thyroid cancer (TC) risk can offer insights into how natural immunity failing leading to disease development. Therefore, we investigated the association between KIR and HLA-C genotypes and TC risk in Saudi women.

[Traumatic injuries in ankylosing spinal diseases]. / Traumatische Verletzungen der ankylosierenden Wirbelsäule.

Ankylosing spinal diseases, such as ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH), are highly important in spinal traumatology and are therefore specifically considered in the AO Spine Classification of spinal injuries. These diseases make the spine extremely susceptible to injury and also complicate the diagnosis and treatment, leading to an increased mortality. Concomitant neurological injuries are frequent. The treatment of such injuries requires great attention and careful preparation. Early and precise diagnostics using computed tomography (CT) and magnetic resonance imaging (MRI) as well as a surgical intervention are crucial for the survival and the quality of life of patients. The treatment is carried out surgically as conservative treatment often leads to high complication rates. In postoperative care special attention must be paid to cardiopulmonary complications.

HLA diversity unveils susceptibility and organ-specific occurrence of second primary cancers: a prospective cohort study.

BACKGROUND: Up to 17% of cancer survivors have been reported to develop second primary cancers (SPC), which cause significant physical and economic distress and often complicate clinical decision-making. However, understanding of SPC remains limited and superficial. Human leukocyte antigen (HLA) is characterized by its polymorphism and has been associated with various diseases. This study aims to explore the role of HLA diversity in SPC incidence. METHODS: We analyzed a cohort of 47,550 cancer patients from the UK Biobank. SNP-derived HLA alleles were used and SPC-related HLA alleles were identified using logistic regression, followed by stepwise filtering based on the Akaike information criterion (AIC) and permutation tests. Additionally, we examined the association between extragenetic factors and the risk of SPC in patients carrying hazardous HLA alleles. RESULTS: During a median follow-up of 3.11 years, a total of 2894 (6.09%) participants developed SPC. We identified three protective HLA alleles (DRB1*04:03 and DPA1*02:02 for males and DRB5*01:01 for females) and two hazardous alleles (A*26:01 for males and DPB1*11:01 for females) about SPC. The presence of the protective alleles was associated with a reduced SPC risk (males: hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.59-0.89; females: HR 0.81, 95% CI 0.70-0.93), while the hazardous alleles were linked to an increased risk (males: HR 1.27, 95% CI 1.03-1.56; females: HR 1.35, 95% CI 1.07-1.70). The hazardous allele A*26:01 indicated skin-lung organ-specific SPC occurrence in males. Animal fat and vitamin C were associated with SPC risk in males carrying the hazardous alleles, while free sugar and vegetable fat were linked to SPC risk in females. CONCLUSIONS: These results suggest that HLA alleles may serve as biomarkers for the susceptibility and organ-specific occurrence of SPC, while dietary modulation may mitigate hazardous alleles-related SPC risk, potentially aiding in the early prediction and prevention of SPC.

Cluster of Differentiation Markers and Human Leukocyte Antigen Expression in Chronic Lymphocytic Leukemia Patients: Correlations and Clinical Relevance.

Chronic lymphocytic leukemia (CLL) is a distinct category of lymphoproliferative disorder characterized by the clonal expansion of mature B cells, followed by their accumulation in primary and secondary lymphoid organs. Cluster of differentiation (CD) markers such as CD79b, CD45, CD23, CD22 and CD81 serve as reliable prognostic indicators in CLL as well as the human leukocyte antigen (HLA) with its well-documented associations with various cancers. This study aims to investigate, for the first time, potential connections between HLA typing and CD marker expression in CLL. Although it is one of the most prevalent neoplasms, there is a need for biomarkers that can improve survival. This study included 66 CLL patients and 100 controls, with all samples analyzed using biochemical methods, flow cytometry, and cytomorphology. Next-generation sequencing was performed for HLA typing. The results indicate that several CD markers are statistically associated with different HLA alleles, specifically CD45 with HLA-C*07:01:01; CD79b with HLA-DPA1*02:01:02; CD23 with HLA-B*39:01:01; CD22 with HLA-B*49:01:01, HLA-C*07:01:01, HLA-DPB1*02:01:02, and HLA-DRB1*07:01:01; and CD81 with HLA-DPB1*04:02:01, HLA-DQA1*01:04:01, and HLA-DQB1*05:03:01. In conclusion, this research demonstrates significant statistical links between HLA genes and immunophenotypic markers in CLL patients, shedding new light on the immunological context of CLL.

HLA class II profile in patients with different stages of cystic echinococcosis according to the WHO ultrasound imaging classification.

The factors involving in the natural history and determinants of different features of human cystic echinococcosis (CE) are not adequately understood. Several host-related factors including the genetic structure of the host and human leukocyte antigens (HLAs) are believed to be involved in the natural history of CE in humans. The present study was conducted to investigate the association between HLA class II genes and active and inactive stages of hepatic cystic echinococcosis. Echinococcus granulosus cyst samples and patient information were collected from the biobank of the Iranian Hydatid Disease Registry from 2019 to 2022. HLA-DRB and HLA-DQB were characterized by PCR method. CE patients were categorized into three active (CE1 and CE2), inactive (CE4 and CE5), and transitional (CE3) stages according to the WHO ultrasound classification of CE. In total, 77 participants including 38 patients (36.8% men and 63.2% women) with different stages of CE as well as 39 healthy individuals (38.5% men and 61.5% women) were included in the study. Findings of the study showed that the frequency of HLA-DRB1*03 was significantly lower in the patients compared to the healthy individuals. The frequencies of HLA-DQB and HLA-DRB alleles were not differed significantly between active, inactive, and transitional stages of E. granulosus cysts. Findings of this study indicate the potential role of this allele in the susceptibility of human to cystic echinococcosis. Further large-scale studies in different endemic countries are required to document the significance of HLA-DQB and HLA-DRB as a host-related factor in the natural history of CE in human.

HLA-A, -B, -C and -DRB1 Association with Autism Spectrum Disorder Risk: A Sex-Related Analysis in Italian ASD Children and Their Siblings.

Autism Spectrum disorders (ASD) are diagnosed more often in males than in females, by a ratio of about 3:1; this is likely to be due to a difference in risk burden between the sexes and/or to "compensatory skills" in females, that may delay the diagnosis of ASD. Identifying specific risk factors for ASD in females may be important in facilitating early diagnosis. We investigated whether HLA- class I: -A, -B, -C and class II -DRB1 alleles, which have been suggested to play a role in the development of ASD, can be considered as sex-related risk/protective markers towards the ASD. We performed HLA allele genotyping in 178 Italian children with ASD, 94 healthy siblings, and their parents. HLA allele distribution was compared between children with ASD, sex-matched healthy siblings, and a cohort of healthy controls (HC) enrolled in the Italian bone marrow donor registry. Allele transmission from parents to children with ASD and their siblings was also assessed. Our findings suggest that HLA-A*02, B*38, and C*12 alleles are more frequently carried by females with ASD compared to both HC and healthy female siblings, indicating these alleles as potential risk factors for ASD in females. Conversely, the HLA-A*03 allele was more commonly transmitted to healthy female siblings, suggesting it might have a protective effect. Additionally, the HLA-B*44 allele was found to be more prevalent in boys with ASD, indicating it is a potential risk factor for male patients. This is the first Italian study of sex-related HLA association with ASD. If confirmed, these results could facilitate early ASD diagnosis in female patients, allowing earlier interventions, which are crucial in the management of neurodevelopmental disorders.

Correlation Between the Prevalence of Myasthenia Gravis and the Frequency of Class II Human Leucocyte Antigen Alleles in Various Geographical Locations Around the World.

Myasthenia gravis (MG) is an autoimmune condition characterised by muscle weakness due to antibodies produced against post-synaptic receptors. The impact of MG can be significant, especially with an ageing population. Human leukocyte antigens (HLA) are polymorphic genes associated with autoimmune conditions. Establishing the HLA alleles associated with MG may aid in the diagnosis, screening and early management of individuals at risk of MG. This research aims to establish the class II HLA alleles associated with the prevalence of MG in various regions of the world and identify the alleles that could predispose to the condition. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart and various databases including, Scopus and PubMed as well as other sources were used to find appropriate papers on HLA class II alleles associated with MG and the prevalence of MG in various countries. The frequency of selected HLA alleles in selected regions were obtained from the website, allelefrequencies.net. From this, a correlation coefficient and p-value were calculated to investigate whether the frequency of MG and the prevalence of HLA alleles had a significant association.  The results highlighted two HLA alleles, DRB1*04:04 and DRB1*03, to have a significant positive association with the prevalence of MG. The frequency of the alleles showed regional variation, with European countries, particularly Northern Europe, exhibiting the highest frequencies. A significant positive correlation between HLA-DRB1*04:04 and DRB1*03 showed with the prevalence of MG, highlighting these alleles as a possible cause of the disease. Screening for these alleles, particularly in Northern Europe, may help identify individuals susceptible to MG.

Diagnosis of Graves' Disease During Treatment for Subacute Thyroiditis: A Case Report.

The co-occurrence of subacute thyroiditis (SAT) and Graves' disease (GD) is rare. A 62-year-old Japanese man presented with shifting neck pain and elevated thyroid hormone level. The patient tested positive for thyroid-stimulating hormone receptor antibodies. Additionally, thyroid hormone levels did not decrease during treatment with prednisolone for SAT. Consequently, concurrent GD was suspected, and diagnostic assistance was obtained by confirming increased uptake on99mtechnetium thyroid scintigraphy. A genetic analysis of human leukocyte antigen (HLA) revealed genotypes associated with susceptibility to SAT (HLA-B*35:01) and GD (HLA-DPB1*05:01). Furthermore, the possibility of COVID-19 as a related environmental factor cannot be ruled out in this case.

Targeting Dual Immune Checkpoints PD-L1 and HLA-G by Trispecific T Cell Engager for Treating Heterogeneous Lung Cancer.

Immunotherapy targeting immune checkpoints (ICPs), such as programmed death-ligand-1 (PD-L1), is used as a treatment option for advanced or metastatic non-small cell lung cancer (NSCLC). However, overall response rate to anti-PD-L1 treatment is limited due to antigen heterogeneity and the immune-suppressive tumor microenvironment. Human leukocyte antigen-G (HLA-G), an ICP as well as a neoexpressed tumor-associated antigen, is previously demonstrated to be a beneficial target in combination with anti-PD-L1. In this study, a nanobody-based trispecific T cell engager (Nb-TriTE) is developed, capable of simultaneously binding to T cells, macrophages, and cancer cells while redirecting T cells toward tumor cells expressing PD-L1- and/or HLA-G. Nb-TriTE shows broad spectrum anti-tumor effects in vitro by augmenting cytotoxicity mediated by human peripheral blood mononuclear cells (PBMCs). In a humanized immunodeficient murine NSCLC model, Nb-TriTE exhibits superior anti-cancer potency compared to monoclonal antibodies and bispecific T cell engagers. Nb-TriTE, at the dose with pharmacoactivity, does not induce additional enhancement of circulating cytokines secretion from PMBCs. Nb-TriTE effectively prolongs the survival of mice without obvious adverse events. In conclusion, this study introduces an innovative therapeutic approach to address the challenges of immunotherapy and the tumor microenvironment in NSCLC through utilizing the dual ICP-targeting Nb-TriTE.

Human leukocyte antigen evolutionary divergence as a novel risk factor for donor selection in acute lymphoblastic leukemia patients undergoing haploidentical hematopoietic stem cell transplantation.

Introduction: The human leukocyte antigen (HLA) evolutionary divergence (HED) reflects immunopeptidome diversity and has been shown to predict the response of tumors to immunotherapy. Its impact on allogeneic hematopoietic stem cell transplantation (HSCT) is controversial in different studies. Methods: In this study, we retrospectively analyzed the clinical impact of class I and II HED in 225 acute lymphoblastic leukemia patients undergoing HSCT from related haploidentical donors. The HED for recipient, donor, and donor-recipient pair was calculated based on Grantham distance, which accounts for variations in the composition, polarity, and volume of each amino acid within the peptide-binding groove of two HLA alleles. The median value of HED scores was used as a cut-off to stratify patients with high or low HED. Results: The class I HED for recipient (R_HEDclass I) showed the strongest association with cumulative incidence of relapse (12.2 vs. 25.0%, P = 0.00814) but not with acute graft-versus-host disease. The patients with high class II HED for donor-recipient (D/R_HEDclass II) showed a significantly higher cumulative incidence of severe aGVHD than those with low D/R_HEDclass II (24.0% vs. 6.1%, P = 0.0027). Multivariate analysis indicated that a high D/R_HEDclass II was an independent risk factor for the development of severe aGVHD (P = 0.007), and a high R_HEDclass I had a more than two-fold reduced risk of relapse (P = 0.028). However, there was no discernible difference in overall survival (OS) or disease-free survival (DFS) for patients with high or low HED, which was inconsistent with the previous investigation. Discussion: While the observation are limited by the presented single center retrospective cohort, the results show that HED has poor prognostic value in OS or DFS, as well as the associations with relapse and aGVHD. In haploidentical setting, class II HED for donor-recipient pair (D/R_HEDclass II) is an independent and novel risk factor for finding the best haploidentical donor, which could potentially influence clinical practice if verified in larger cohorts.

Immunogenetic profiles of 9 human herpes virus envelope glycoproteins.

Human herpes viruses (HHV) are ubiquitous and have been implicated in numerous long-term health conditions. Since the association between viral exposure and long-term health impacts is partially influenced by variation in human leukocyte antigen (HLA) genes, we evaluated in silico the binding affinities of 9 HHV envelope glycoproteins with 127 common HLA Class I and Class II molecules. The findings show substantial variability in HHV binding affinity across viruses, HLA Class, HLA genes, and HLA alleles. Specific findings were as follows: (1) the predicted binding affinities of HHVs were characterized by four distinct groupings-[HHV1, HHV2], [HHV3, HHV4, HHV5], [HHV6A], [HHV6B, HHV7, HHV8]-with relatively lower binding affinities for HHV1, HHV2, and HHV6a compared to other HHVs; (2) significantly higher binding affinity was found for HLA Class I relative to Class II; (3) analyses within each class demonstrated that alleles of the C gene (for Class I) and DRB1 gene (for Class II) had the highest binding affinities; and (4) for each virus, predicted binding affinity to specific alleles varied, with HHV6a having the lowest affinity for HHV-HLA complexes, and HHV3, HHV4, and HHV5 having the highest. Since HLA-antigen binding is the first step in initiating an immune response to foreign antigens, these relative differences in HHV binding affinities are likely to influence long-term health impacts such that the cells infected with viruses associated with higher binding affinities across common HLA alleles may be more reduced in numbers, thereby lowering the potential for long-term sequelae of their infections.

Exploring the Connection Between HLA Class I and Class II Genotypes and Diabetic Retinopathy: A Comprehensive Review of Experimental Evidence.

Diabetic retinopathy (DR) is a microvascular complication associated with diabetes mellitus (DM). During the course of the disease, high blood glucose levels induce damage to the vasculature of the retina and promote neovascularization. Although numerous environmental risk factors have been associated with the emergence of DR, the role of genetics should not be underestimated. The human leukocyte antigen (HLA) plays a significant role in the regulation of the immune system. DR exhibits significant heterogeneity among patients, with differences in how the disease presents and progresses over time. The HLA gene, characterized by its extensive genetic variation, largely contributes to this diverse spectrum. Differences in HLA allele frequencies among healthy people, diabetic patients without retinopathy, and diabetic patients with different stages of retinopathy highlight the need for proper management of the disease. This comprehensive review outlines the current understanding of the relationship between HLA class I and class II variants and DR, shedding light on their potential significance as early onset indicators, prognostic indicators, and important risk factors for the development of this retinal condition.

HLA-I and breast cancer prognosis: A systematic review and meta-analysis.

BACKGROUND: Breast cancer (BC) is a significant global health issue, accounting for 1 in 8 cancer diagnoses worldwide. HLA class I molecules are typically expressed on the cell surface, but cancer cells can develop mechanisms to evade recognition by CTLs, including the downregulation of HLA class I expression. In this context, we aimed to conduct a systematic review and meta-analysis to clarify the role of HLA class I expression in clinical outcomes for patients with BC. METHODS: A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, and the Cochrane databases. Effect sizes, along with I2 and Tau2 statistics, were used to assess heterogeneity through a DerSimonian and Laird random-effects model. Statistical analyses were performed using R statistical software, version 4.2.3. RESULTS: Among the 8 included studies, most of the analyzed samples consisted of ductal carcinoma cases (1588, 86.39 %), from the luminal (A or B) intrinsic subtype (1865, 69.07 %), with no lymph node metastasis (2658, 57.24 %), no HER2 overexpression (2594, 67.46 %), negative Ki67 status (1721, 71.26 %), and positive hormone receptor status (4732, 64.05 %). The analysis revealed a significant reduction in disease-free survival (HR 0.57; 95 % CI 0.34 to 0.95; p = 0.034; I2 = 84 %) in the group with low HLA-I expression. However, no significant difference was found between the groups with high and low HLA-I expression regarding overall survival (HR 0.77; 95 % CI 0.28 to 2.14; p = 0.62; I2 = 86 %). CONCLUSIONS: This systematic review and meta-analysis demonstrated that HLA class I expression is associated with a significant improvement in disease-free survival, though no significant effect on overall survival was observed.

HLA-DR/DQ eplet mismatch predicts de novo donor-specific antibody development in multi-ethnic Southeast Asian kidney transplant recipients on different immunosuppression regimens.

Eplet mismatch has been recognized as a more precise strategy for determining HLA compatibility by analyzing donor-recipient HLA differences at the molecular level. However, predicting post-transplant alloimmunity using single-molecule eplet mismatch categories has not been validated in Asian cohorts. We examined a cohort of Southeast Asian kidney transplant recipients (n = 234) to evaluate HLA-DR/DQ eplet mismatch as a predictor of de novo donor-specific antibody (dnDSA) development. HLA-DR/DQ single-molecule eplet mismatch was quantified using HLA Matchmaker, and we utilized previously published HLA-DR/DQ eplet mismatch thresholds to categorize recipients into alloimmune risk groups and evaluate their association with dnDSA development. Recognizing that the predominance of cyclosporine use (71%) may alter published eplet mismatch thresholds derived from a largely tacrolimus-based (87%) cohort, we evaluated cohort-specific thresholds for HLA-DR/DQ single-molecule eplet mismatch categories. Recipient ethnicities included Chinese (65%), Malays (17%), Indians (14%), and others (4%). HLA-DR/DQ dnDSA developed in 29/234 (12%) recipients after a median follow-up of 5.4 years, including against isolated HLA-DR (n = 7), isolated HLA-DQ (n = 11), or both (n = 11). HLA-DR/DQ single-molecule eplet mismatch risk categories correlated with dnDSA-free survival (p = 0.001) with low-risk recipients having a dnDSA prevalence of 1% over 5 years. The cohort-specific alloimmune risk categories improved correlation with HLA-DR/DQ dnDSA-free survival and remained significant after adjusting for calcineurin inhibitor and anti-metabolite immunosuppression (p < 0.001). We validated the performance of single-molecule eplet mismatch categories as a prognostic biomarker for HLA-DR/DQ dnDSA development in a cohort of predominantly Asian kidney transplant recipients after adjusting for different immunosuppression regimens.