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Herein, we included 527 individuals from two Hospitals, Chemnitz and University-Hospital Leipzig. In total, 199 were negative for PCR and 328 were positive upon first admission. We used next generation sequencing for HLA-A, B, C, DRB1, DRB345, DQA1, DQB1, DPA1, and DPB1, and in some cases, HLA-E, F, G, and H. Furthermore, we molecularly defined 22 blood group systems comprising 26 genes and 5 platelet antigen genes. We observed a significant enrichment of homozygosity for DQA/DQB in the positive group. Within the negative subjects, HLA-B*57:01, HLA-B*55:01, DRB1*13:01, and DRB1*01:01 were enriched, and in the positive group, homozygosity for DQA/DQB, DRB1*09:01, and DRB1*15:01 was observed. DQA1*01:01, DQA1*02:01, and DQA1*01:03 were enriched in the negative group. HLA-DQB1*06:02 was enriched in the positive group, and HLA-DQB1*05:01 and HLA-DQB1*06:03 were enriched in the negative group. For the blood group systems MNS, RH, LE, FY, JK, YT, DO, and KN, enrichment was seen in both groups, depending on the antigen under observation. Homozygosity for D-positive RHD alleles, as well as the phenotypes M-N+ of the MNS blood group system and Yk(a-) of the KN system, were enriched in the positive group. All of these significances disappeared upon correction. Subjects who carried homozygous HPA-1a were more frequent in the negative group, contrasting with the finding that HPA-1ab was enriched in the positive group.

There is strong evidence that the host’s cellular immune response is linked to tumor progression, however its impact on patient outcome in breast cancer is poorly understood. The purpose of this study is to define tumor immune subtypes, focusing on cellular immune responses and investigate their prognostic effect in breast cancer patients. Our training ( n  = 440) and validation cohort ( n  = 382) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. Tumor tissue sections were immunohistochemically stained for CD8 (CTL) and PEN5 (NK cells). Tumor expression of classical and non-classical human leukocyte antigen class I, and tumor-infiltrating Tregs were previously determined. Tumor immune subtypes were constructed based on quantification of these markers and biological rationale. High, intermediate, and low immune susceptible tumor immune subtypes were found, respectively, in 16, 63, and 20 % of patients in the training cohort and 16, 71, and 13 % in the validation cohort. The subtypes showed to be statistically significant prognostic in multivariate analyses for relapse free period (RFP) [ p  < 0.0001, intermediate versus high: hazard ratio (HR) 1.95; low versus high HR 2.98] and relative survival (RS) ( p  = 0.006, intermediate versus high HR 3.84; low versus high: HR 4.26). Validation of these outcome analyses confirmed the independent prognostic associations: RFP ( p  = 0.025) and RS ( p  = 0.040). The tumor immune subtypes that we present represent a prognostic profile with solid underlying biological rationale and with high discriminative power confirmed in an independent validation cohort. Our results emphasize the importance of tumor immune surveillance in the control of tumor development and, therefore, in determining patient prognosis. Tumor immune subtype profiling is promising for prognosis prediction and the achievement of tailored treatment for breast cancer patients.

Malignant transformation of cells is often associated with changes in classical and non-classical HLA class I antigen, HLA class II antigen as well as NK cell activating ligand (NKCAL) expression. These changes are believed to play a role in the clinical course of the disease since these molecules are critical to the interactions between tumor cells and components of both innate and adaptive immune system. For some time, it has been assumed that alterations in the expression profile of HLA antigens and NKCAL on malignant cells represented loss of classical HLA class I antigen and induction of HLA class II antigen, non-classical HLA class I antigen and/or NKCAL expression. In contrast to these assumptions, experimental evidence suggests that in some cases dysplastic and malignant cells can acquire classical HLA class I antigen expression and/or lose the ability to express HLA class II antigens. In light of the latter findings as well as of the revival of the cancer immune surveillance theory, a reevaluation of the interpretation of changes in HLA antigen and NKCAL expression in malignant lesions is warranted. In this article, we first briefly describe the conventional types of changes in HLA antigen and NKCAL expression that have been identified in malignant cells to date. Second, we discuss the evidence indicating that, in at least some cell types, classical HLA class I antigen expression can be acquired and/or the ability to express HLA class II antigens is lost. Third, we review the available evidence for the role of immune selective pressure in the generation of malignant lesions with changes in HLA antigen expression. This information contributes to our understanding of the role of the immune system in the control of tumor development and to the optimization of the design of immunotherapeutic strategies for the treatment of cancer.

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), P bonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), P bonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).

The Human Leukocyte Antigen (HLA) system contains a set of genes involved at many levels in the innate and adaptive immune response. Among the non-classical HLA class I genes, HLA-G stands out for the numerous studies about its pivotal role in regulating/modulating immune responses. Also, its involvement in extravillous cytotrophoblast function, viral infections, autoimmunity, and cancer has been extensively documented. The present study explores for the first time the relationship between natural alleles of HLA-G, rather than STSs, SNPs, or partial gene polymorphisms, and the development of gastric adenocarcinoma, by analyzing the genetic profile of a cohort of 40 Spanish patients with this type of tumor using DNA extracted from paired biopsies of tumoral and adjacent non-tumoral gastric tissue. Our results reveal a significant statistical relationship between the presence of the HLA-G*01:01:01 allele and the development of gastric cancer, while other common alleles such as -G*01:04 or -G*01:05N did not demonstrate a significant correlation. Studying the involvement of HLA genes in the development of many diseases is relevant to understanding their pathophysiology. However, the absence of specific mechanisms underlying these associations suggests that investigating complete HLA natural alleles’ extended haplotypes or complotypes may offer a more precise and valuable approach to elucidating the association of HLA with the pathogenesis of disease.

Purpose of ReviewHyperexpression of classical HLA class I (HLA-I) molecules in insulin-containing islets has become a widely accepted hallmark of type 1 diabetes pathology. In comparison, relatively little is known about the expression, function and role of non-classical subtypes of HLA-I. This review focuses on the current understanding of the non-classical HLA-I subtypes: HLA-E, HLA-F and HLA-G, within and outside the field of type 1 diabetes, and considers the possible impacts of these molecules on disease etiology.Recent FindingsEvidence is growing to suggest that non-classical HLA-I proteins are upregulated, both at the RNA and protein levels in the pancreas of individuals with recent-onset type 1 diabetes. Moreover, associations between non-classical HLA-I genotypes and age at onset of type 1 diabetes have been reported in some studies. As with classical HLA-I, it is likely that hyperexpression of non-classical HLA-I is driven by the release of diffusible interferons by stressed β cells (potentially driven by viral infection) and exacerbated by release of cytokines from infiltrating immune cells.SummaryNon-classical HLA-I proteins predominantly (but not exclusively) transduce negative signals to immune cells infiltrating at the site of injury/inflammation. We propose a model in which the islet endocrine cells, through expression of non-classical HLA-I are fighting back against the infiltrating immune cells. By inhibiting the activity and function on NK, B and select T cells, the non-classical HLA-I, proteins will reduce the non-specific bystander effects of inflammation, while at the same time still allowing the targeted destruction of β cells by specific islet-reactive CD8+ T cells.

Human leukocyte antigens (HLAs) are essential regulators of immune responses against cancer, with classical HLAs well-documented for their role in tumor recognition and immune surveillance. In recent years, non-classical HLAs—including HLA-E, HLA-F, HLA-G, and HLA-H—have emerged as critical players in the immune landscape of cancer due to their diverse and less conventional functions in immune modulation. These molecules exhibit unique mechanisms that enable tumors to escape immune detection, promote tumor progression, and contribute to therapeutic resistance. This review provides a comprehensive examination of the current understanding of non-classical HLAs in solid cancers, focusing on their specific roles in shaping the tumor microenvironment and influencing immune responses. By analyzing how HLA-E, HLA-F, HLA-G, and HLA-H modulate interactions with immune cells, such as T cells, natural killer cells, and antigen-presenting cells, we highlight key pathways through which these molecules contribute to immune evasion and metastasis. Additionally, we review promising therapeutic strategies aimed at targeting non-classical HLAs, including emerging immunotherapies that could potentially enhance cancer treatment outcomes by reversing immune suppression within tumors. Understanding the influence of these non-classical HLAs in solid cancers may offer new insights into cancer immunology and may lead to the development of innovative and more effective immunotherapeutic approaches. This review underscores the importance of non-classical HLAs as potential therapeutic targets, providing a necessary foundation for future studies in the evolving field of cancer immunotherapy.

BackgroundTumors avoid destruction by cytotoxic T cells (CTL) and natural killer (NK) cells by downregulation of classical human leukocyte antigens (HLA) and overexpression of non-classical HLA. This is the first study to investigate HLA expression in relation to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)), clinicopathological parameters and survival in a large cervical cancer patient cohort.MethodsClassical (HLA-A and HLA-B/C)- and non-classical HLA molecules (HLA-E and HLA-G) were studied on primary tumors and paired lymph node (LN) metastases from cervical cancer patients (n = 136) by immunohistochemistry. The Chi2 test was used for the comparison of clinicopathological characteristics between SCC and AC patients. The Related-Samples Wilcoxon Signed Rank test was used to compare HLA expression between the primary tumor and metastasis in LN. Patient survival rates were analyzed by Kaplan-Meier curves and Log Rank test. The Mann-Whitney U Test was used to compare the distribution of HLA class I expression between SCC and AC.ResultsDecreased expression of HLA-A (SCC P < 0.001), HLA-B/C (SCC P < 0.01; AC P < 0.01) and total classical HLA (SCC P < 0.001; AC P = 0.02) was apparent in metastatic tumor cells compared to the primary tumor. In primary SCC, there was a clear trend towards complete loss of HLA-A (P = 0.05). SCC metastases showed more complete loss of HLA-A, while AC metastases showed more complete loss of HLA-B/C (P = 0.04). In addition, tumor size and parametrium involvement were also related to aberrant HLA class I expression. No significant associations between HLA expression and disease-specific (DSS) or disease-free survival (DFS) were found in this advanced disease cohort. However, in the SCC group, samples showing loss of HLA-A or loss of total classical HLA but positive for HLA-G were linked to poor patient survival (DSS P = 0.001 and P = 0.01; DFS P = 0.003 and P = 0.01, for HLA-A and total classical HLA, respectively).ConclusionThese results strengthen the idea of tumor immune escape variants leading to metastasis. Moreover, SCC tumors showing downregulation of HLA-A or total classical HLA in combination with HLA-G expression had poor prognosis. Our findings warrant further analysis of HLA expression as a biomarker for patient selection for CTL- and NK- cell based immunotherapeutic intervention.

The knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules. This study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD. We analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism. Our results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.

Human leukocyte antigen G (HLA-G) belongs to the family of non-classical HLA class I genes, located within the major histocompatibility complex (MHC). HLA-G has been the target of most recent research regarding the function of class I non-classical genes. The main features that distinguish HLA-G from classical class I genes are (a) limited protein variability, (b) alternative splicing generating several membrane bound and soluble isoforms, (c) short cytoplasmic tail, (d) modulation of immune response (immune tolerance), and (e) restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments [promoter, coding, and 3' untranslated region (UTR)]. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding, and 3'UTRs are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures.