CD74 supports accumulation and function of regulatory T cells in tumors.

Regulatory T cells (Tregs) are plastic cells playing a pivotal role in the maintenance of immune homeostasis. Tregs actively adapt to the microenvironment where they reside; as a consequence, their molecular and functional profiles differ among tissues and pathologies. In tumors, the features acquired by Tregs remains poorly characterized. Here, we observe that human tumor-infiltrating Tregs selectively overexpress CD74, the MHC class II invariant chain. CD74 has been previously described as a regulator of antigen-presenting cell biology, however its function in Tregs remains unknown. CD74 genetic deletion in human primary Tregs reveals that CD74KO Tregs exhibit major defects in the organization of their actin cytoskeleton and intracellular organelles. Additionally, intratumoral CD74KO Tregs show a decreased activation, a drop in Foxp3 expression, a low accumulation in the tumor, and consistently, they are associated with accelerated tumor rejection in preclinical models in female mice. These observations are unique to tumor conditions as, at steady state, CD74KO-Treg phenotype, survival, and suppressive capacity are unaffected in vitro and in vivo. CD74 therefore emerges as a specific regulator of tumor-infiltrating Tregs and as a target to interfere with Treg anti-tumor activity.

Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. METHODS: We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. RESULTS: Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQß1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. DISCUSSION: Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

Reassessing human MHC-I genetic diversity in T cell studies.

The Major Histocompatibility Complex class I (MHC-I) system plays a vital role in immune responses by presenting antigens to T cells. Allele specific technologies, including recombinant MHC-I technologies, have been extensively used in T cell analyses for COVID-19 patients and are currently used in the development of immunotherapies for cancer. However, the immense diversity of MHC-I alleles presents challenges. The genetic diversity serves as the foundation of personalized medicine, yet it also poses a potential risk of exacerbating healthcare disparities based on MHC-I alleles. To assess potential biases, we analysed (pre)clinical publications focusing on COVID-19 studies and T cell receptor (TCR)-based clinical trials. Our findings reveal an underrepresentation of MHC-I alleles associated with Asian, Australian, and African descent. Ensuring diverse representation is vital for advancing personalized medicine and global healthcare equity, transcending genetic diversity. Addressing this disparity is essential to unlock the full potential of T cells for enhancing diagnosis and treatment across all individuals.

Neoself Antigens Presented on MHC Class II Molecules in Autoimmune Diseases.

Major histocompatibility complex (MHC) class II molecules play a crucial role in immunity by presenting peptide antigens to helper T cells. Immune cells are generally tolerant to self-antigens. However, when self-tolerance is broken, immune cells attack normal tissues or cells, leading to the development of autoimmune diseases. Genome-wide association studies have shown that MHC class II is the gene most strongly associated with the risk of most autoimmune diseases. When misfolded self-antigens, called neoself antigens, are associated with MHC class II molecules in the endoplasmic reticulum, they are transported by the MHC class II molecules to the cell surface without being processed into peptides. Moreover, neoself antigens that are complexed with MHC class II molecules of autoimmune disease risk alleles exhibit distinct antigenicities compared to normal self-antigens, making them the primary targets of autoantibodies in various autoimmune diseases. Elucidation of the immunological functions of neoself antigens presented on MHC class II molecules is crucial for understanding the mechanism of autoimmune diseases.

Novel Presentation of Major Histocompatibility Complex Class II Deficiency with Hemophagocytic Lymphohistiocytosis.

PURPOSE: Major histocompatibility complex (MHC) class II deficiency is one of the combined immune deficiency disorders caused by defects in the MHC class II regulatory genes leading to abnormal T cells development and function. Therefore, patients mainly present with increased susceptibility to infections, diarrhea, and failure to thrive. In this report, we present one MHC class II deficient patient with a novel presentation with Hemophagocytic Lymphohistiocytosis (HLH). METHODS: Immunophenotyping of lymphocyte subpopulations and HLA-DR expression was assess by flow cytometry. Gene mutational analysis was performed by whole exome and Sanger sequencing. RESULTS: We reported a 7-year-old girl, who was diagnosed at age of 2 years with MHC class II deficiency by genetic testing and flow cytometry. Two years later, she developed disseminated BCGitis which was treated with proper antimicrobial agents. At the age of 7 years, she presented with clinical features fulfilling 6 diagnostic criteria of HLH including evidence of hemophagocytic activity in bone marrow aspiration. Accordingly, the diagnosis of HLH was established and the patient was started on IV Dexamethasone, Anakinra and IVIG. Eventually, patient started to improve and was discharged in good condition. Few months later, the patient was readmitted with severe pneumonia and sepsis leading to death. CONCLUSION: Patients with MHC class II deficiency might present with disseminated BCGitis especially if the patient has severe T cell lymphopenia. Additionally, this immune defect might be added to the list of inborn errors of immunity that can be complicated with HLH.

An immunogenetic basis for lung cancer risk.

Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.

Polymorphism of HLA and Susceptibility of Breast Cancer.

Breast cancer (BC) is the second most common malignancy in the world. Numerous studies have demonstrated the association between human leukocyte antigen (HLA) and cancer. The occurrence and development of BC are closely linked to genetic factors. Human leukocyte antigens G and E (HLA-G and HLA-E) are non-classical major histocompatibility complex (MHC) class I molecules. These molecules play an important role in immune surveillance by inhibiting the cytotoxic and natural killer T cells responsible for immune escape. The expression of HLA-G and HLA-E has been associated with several diseases, including tumors. The HLA system plays a key role in the escape of tumor cells from immune surveillance. This review aims to determine the correlation between BC susceptibility and HLA markers specific HLA alleles such as HLA-B07, HLA-DRB111, HLA-DRB113, and HLA-DRB115 are associated with an increased risk of developing BC. Furthermore, HLA-G mutations have been attributed to an elevated likelihood of metastasis in BC patients. Understanding the complex associations between the HLA system and BC development is critical for developing novel cancer prevention, detection, and treatment strategies. This review emphasizes the importance of analyzing HLA polymorphisms in the management of BC patients, as well as the urgent need for further research in this area.

CD74/SLC34A2-ROS1 Fusion Variants Involving the Transmembrane Region Predict Poor Response to Crizotinib in NSCLC Independent of TP53 Mutations.

INTRODUCTION: Variable partners and breakpoints have been reported in patients with ROS1-rearranged NSCLC. Here, we investigated the association of fusion partners and breakpoints with crizotinib efficacy in NSCLCs with common ROS1 fusions. METHODS: DNA and RNA next-generation sequencing (NGS) and immunohistochemistry were performed to characterize ROS1 fusions. RESULTS: Using DNA NGS, we identified ROS1 fusions in 210 cases, comprising 171 common (CD74/EZR/TPM3/SDC4/SLC34A2-ROS1) and 39 uncommon (variants identified in <5%) ROS1 fusion cases. DNA NGS detected variable ROS1 genomic breakpoints in common ROS1 fusions, whereas RNA NGS found ROS1 breakpoints mainly occurring in exons 32, 34 and 35, resulting in long (exon 32) and short (exon 34 or 35) ROS1 fusions. ROS1 immunohistochemistry revealed that membranous and cytoplasmic staining was predominant in long ROS1 fusions, whereas cytoplasmic staining was predominant in short ROS1 fusions (p = 0.006). For patients who received first-line crizotinib, median progression-free survival (mPFS) was lower in patients with long ROS1 fusions than those with short ROS1 fusions (8.0 versus 24.0 mo, p = 0.006). Moreover, mPFS for patients with and without TP53 mutations was 8.0 and 19.0 months, respectively (p = 0.159); mPFS for patients with and without BIM deletion polymorphism was 5.0 and 22.0 months, respectively (p = 0.003). When analyzing together with fusion partners, patients with long CD74/SLC34A2-ROS1 fusions were found to have shorter PFS than those with other ROS1, regardless of the presence or absence of TP53 mutations (p < 0.001 and p = 0.002, respectively). CONCLUSIONS: Long CD74/SLC34A2-ROS1 fusions, which retain transmembrane regions in ROS1 and fusion partners, are associated with poor response to crizotinib independent of TP53 mutations.

CD74-ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non-small cell lung cancer cells.

The treatment of non-small cell lung cancer (NSCLC) patients harboring a proto-oncogene tyrosine-protein kinase c-ros oncogene 1 (ROS1) fusion gene has greatly benefited from the use of crizotinib. However, drug resistance inevitably occurs after 1 year of treatment. Clinical studies have shown that patients with an L2026M mutation in the ROS1 kinase domain account for about 6% of the total number of crizotinib-resistant cases, which is an important group that cannot be ignored. To explore the mechanism involved, we constructed the HLA class II histocompatibility antigen gamma chain (CD74)-ROS1 L2026M mutant gene by fusion polymerase chain reaction (PCR) and transfected it into H460 and A549 cells. We found that the invasion and metastasis abilities of drug-resistant cells were increased. The results of monodansylcadaverine (MDC) staining, Acridine orange (AO) staining, and western blot indicated that the autophagy level of CD74-ROS1 L2026M mutant NSCLC cells was increased compared with the CD74-ROS1 group, and the inhibition of autophagy could reverse the increased invasion and metastasis abilities caused by the L2026M mutation. In addition, the L2026M mutation led to excessive activation of the MEK/ERK pathway, and MEK inhibitors could reduce the autophagy level, invasion, and metastasis abilities of cells; additionally, this process could be blocked by rapamycin, an activator of autophagy. Furthermore, crizotinib treatment activated expression of Src homology region 2 domain-containing phosphatase-2 (SHP2; also known as PTPN11) to upregulate the MEK/ERK pathway, and the combination of MEK inhibitors and crizotinib increased apoptosis compared with crizotinib alone. In conclusion, our results indicate that the MEK/ERK pathway mediates the induction of invasion, metastasis, and crizotinib resistance through autophagy caused by CD74-ROS1 L2026M mutation in NSCLC cells, and targeting MEK could reverse these processes.

Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer.

Objective: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC). Methods: We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (A, B, and C) and HLA class -II loci (DQB1, DRB1, and DPB1) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357). Results: Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant. Conclusion: Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC.

The ligand-dependent suppression of TCR signaling by the immune checkpoint receptor LAG3 depends on the cytoplasmic RRFSALE motif.

Lymphocyte activation gene 3 (LAG3) is an inhibitory immune checkpoint receptor that restrains autoimmune and antitumor responses, but its evolutionarily conserved cytoplasmic tail lacks classical inhibitory motifs. Major histocompatibility complex class II (MHC class II) is an established LAG3 ligand, and fibrinogen-like protein 1 (FGL1), lymph node sinusoidal endothelial cell C-type lectin (LSECtin), and Galectin-3 have been proposed as alternative binding partners that play important roles in LAG3 function. Here, we used a fluorescent human T cell reporter system to study the function of LAG3. We found that LAG3 reduced the response to T cell receptor stimulation in the presence of MHC class II molecules to a lesser extent compared with the receptor programmed cell death protein 1. Analysis of deletion mutants demonstrated that the RRFSALE motif in the cytoplasmic tail of LAG3 was necessary and sufficient for LAG3-mediated inhibition. In this system, FGL1, but not LSECtin or Galectin-3, acted as a LAG3 ligand that weakly induced inhibition. LAG3-blocking antibodies attenuated LAG3-mediated inhibition in our reporter cells and enhanced reporter cell activation even in the absence of LAG3 ligands, indicating that they could potentially enhance T cell responses independently of their blocking effect.

Low proviral load in the Kumamoto strain of Japanese Brown cattle infected with the bovine leukemia virus.

BACKGROUND: The Kumamoto strain of Japanese Brown (JBRK) cattle is a sub-breed of Wagyu and has a different genetic background than that of Japanese Black (JB) cattle. Bovine leukemia virus (BLV) is the pathogen causing enzootic bovine leukosis (EBL), the predominant type of bovine leukosis (BL). EBL is one of the most common bovine infectious diseases in dairy countries, including Japan. Some host genetic factors, including the bovine leukocyte antigen (BoLA)-DRB3 gene, have been associated with the proviral load (PVL) of BLV and/or onset of EBL. Here, we determined the number of BL cases by analyzing prefectural case records in detail. We measured the PVL of BLV-infected JBRK cattle and compared it with that obtained for other major breeds, JB and Holstein-Friesian (HF) cattle. Finally, the relationship between PVL levels and BoLA-DRB3 haplotypes was investigated in BLV-infected JBRK cattle. RESULTS: We determined the number of BL cases recorded over the past ten years in Kumamoto Prefecture by cattle breed. A limited number of BL cases was observed in JBRK cattle. The proportion of BL cases in the JBRK was lower than that in JB and HF. The PVL was significantly lower in BLV-infected JBRK cattle than that in the JB and HF breeds. Finally, in BLV-infected JBRK cattle, the PVL was not significantly affected by BoLA-DRB3 alleles and haplotypes. BoLA-DRB3 allelic frequency did not differ between BLV-infected JBRK cattle with low PVL and high PVL. CONCLUSIONS: To our knowledge, this is the first report showing that BL occurred less in the JBRK population of Kumamoto Prefecture. After BLV-infection, the PVL was significantly lower in JBRK cattle than that in JB and HF breeds. The genetic factors implicated in maintaining a low PVL have yet to be elucidated, but the BoLA-DRB3 haplotypes are likely not involved.

Combined imputation of HLA genotype and self-identified race leads to better donor-recipient matching.

Allogeneic Hematopoietic Cell Transplantation (HCT) is a curative therapy for hematologic disorders and often requires human leukocyte antigen (HLA)-matched donors. Donor registries have recruited donors utilizing evolving technologies of HLA genotyping methods. This necessitates in-silico ambiguity resolution and statistical imputation based on haplotype frequencies estimated from donor data stratified by self-identified race and ethnicity (SIRE). However, SIRE has limited genetic validity and presents a challenge for individuals with unknown or mixed SIRE. We present MR-GRIMM "Multi-Race Graph IMputation and Matching" that simultaneously imputes the race/ethnic category and HLA genotype using a SIRE based prior. Additionally, we propose a novel method to impute HLA typing inconsistent with current haplotype frequencies. The performance of MR-GRIMM was validated using a dataset of 170,000 donor-recipient pairs. MR-GRIMM has an average 20 % lower matching error (1-AUC) than single-race imputation. The recall metric (sensitivity) of the race/ethnic category imputation from HLA was measured by comparing the imputed donor race with the donor-provided SIRE. Accuracies of 0.74 and 0.55 were obtained for the prediction of 5 broad and 21 detailed US population groups respectively. The operational implementation of this algorithm in a registry search could help improve match predictions and access to HLA-matched donors.

Abdominal surgery induces long-lasting changes in expression and binding of CTCF with impact on Major Histocompatibility Complex II transcription in circulating human monocytes.

BACKGROUND: Postoperative immunosuppression has been recognized as an important driver of surgery-related morbidity and mortality. It is characterized by lymphocyte depression and impaired monocyte capability to present foreign antigens to T-cells via Major Histocompatibility Complex, Class II (MHC-II) molecules. In patients with postoperative abdominal sepsis, we previously detected a persisting differential binding of the CCCTC-Binding Factor (CTCF), a superordinate regulator of transcription, inside the MHC-II region with specific impact on human leucocyte antigen (HLA) gene expression. In this prospective exploratory study, we investigated to which extent major surgery affects the MHC-II region of circulating CD14+-monocytes. RESULTS: In non-immunocompromised patients undergoing elective major abdominal surgery, a postoperative loss of monocyte HLA-DR surface receptor density was accompanied by a decline in the transcription levels of the classical MHC-II genes HLA-DRA, HLA-DRB1, HLA-DPA1 and HLA-DPB1. The surgical event decreased the expression of the transcriptional MHC-II regulators CIITA and CTCF and led to a lower CTCF enrichment at an intergenic sequence within the HLA-DR subregion. During the observation period, we found a slow and only incomplete restoration of monocyte HLA-DR surface receptor density as well as a partial recovery of CIITA, HLA-DRA and HLA-DRB1 expression. In contrast, transcription of HLA-DPA1, HLA-DPB1, CTCF and binding of CTCF within the MHC-II remained altered. CONCLUSION: In circulating monocytes, major surgery does not globally affect MHC-II transcription but rather induces specific changes in the expression of selected HLA genes, followed by differential recovery patterns and accompanied by a prolonged reduction of CTCF expression and binding within the MHC-II region. Our results hint toward a long-lasting impact of a major surgical intervention on monocyte functionality, possibly mediated by epigenetic changes that endure the life span of the individual cell.

BAP31 Knockout in Macrophages Affects CD4+T Cell Activation through Upregulation of MHC Class II Molecule.

The differentiation of CD4+T cells is a crucial component of the immune response. The spleen and thymus, as immune organs, are closely associated with the differentiation and development of T cells. Previous studies have suggested that BAP31 may play a role in modulating T cell activation, but the specific impact of BAP31 on T cells through macrophages remains uncertain. In this study, we present evidence that BAP31 macrophage conditional knockout (BAP31-MCKO) mice display an enlarged spleen and thymus, accompanied by activated clustering and disrupted differentiation of CD4+T cells. In vitro co-culture studies were conducted to investigate the impact of BAP31-MCKO on the activation and differentiation of CD4+T cells. The examination of costimulatory molecule expression in BMDMs and RAW 264.7 cells, based on the endoplasmic reticulum function of BAP31, revealed an increase in the expression of antigen presenting molecules, particularly MHC-II molecule, in the absence of BAP31 in BMDMs or RAW264.7 cells. These findings suggest that BAP31 plays a role in the activation and differentiation of CD4+T cells by regulating the MHC class II molecule on macrophages. These results provide further support for the importance of BAP31 in developing interaction between macrophages and CD4+T cells.

Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors.

Disruption of antigen presentation via loss of major histocompatibility complex (MHC) expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. Here, we develop the personalized genomics algorithm Hapster and accurately call somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1,663 non-synonymous mutations that provide key insights into MHC mutagenesis. We find that MHC class I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC class II mutations are more restricted. Recurrent deleterious mutations are found within haplotype- and cancer-type-specific hotspots associated with distinct mutational processes. Functional classification of MHC residues reveals significant positive selection for mutations disruptive to the B2M, peptide, and T cell binding interfaces, as well as to MHC chaperones.

Tregs with an MHC class II peptide-specific chimeric antigen receptor prevent autoimmune diabetes in mice.

Adoptive immunotherapy with Tregs is a promising approach for preventing or treating type 1 diabetes. Islet antigen-specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B chain 10-23 peptide presented in the context of the IAg7 MHC class II allele present in NOD mice. Peptide specificity of the resulting InsB-g7 CAR was confirmed by tetramer staining and T cell proliferation in response to recombinant or islet-derived peptide. The InsB-g7 CAR redirected NOD Treg specificity such that insulin B 10-23-peptide stimulation enhanced suppressive function, measured via reduction of proliferation and IL-2 production by BDC2.5 T cells and CD80 and CD86 expression on dendritic cells. Cotransfer of InsB-g7 CAR Tregs prevented adoptive transfer diabetes by BDC2.5 T cells in immunodeficient NOD mice. In WT NOD mice, InsB-g7 CAR Tregs prevented spontaneous diabetes. These results show that engineering Treg specificity for islet antigens using a T cell receptor-like CAR is a promising therapeutic approach for the prevention of autoimmune diabetes.

Clinical, Immunological, and Genetic Findings in Iranian Patients with MHC-II Deficiency: Confirmation of c.162delG RFXANK Founder Mutation in the Iranian Population.

PURPOSE: Major histocompatibility complex class II (MHC-II) deficiency is a rare inborn error of immunity (IEI). Impaired antigen presentation to CD4 + T cells results in combined immunodeficiency (CID). Patients typically present with severe respiratory and gastrointestinal tract infections at early ages. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy. METHODS: We describe the clinical, immunologic, and genetic features of eighteen unrelated Iranian patients with MHC-II deficiency. RESULTS: Consanguinity was present in all affected families. The median age at the initial presentation was 5.5 months (range 7 days to 18 years). The main symptoms included failure to thrive, persistent diarrhea, and pneumonia. Autoimmune and neurologic features were also documented in about one-third of the patients, respectively. Thirteen patients carried RFXANK gene mutations, two carried RFX5 gene mutations, and three carried a RFXAP gene mutation. Six patients shared the same RFXANK founder mutation (c.162delG); limited to the Iranian population and dated to approximately 1296 years ago. Four of the patients underwent HSCT; three of them are alive. On the other hand, nine of the fourteen patients who did not undergo HSCT had a poor prognosis and died. CONCLUSION: MHC-II deficiency is not rare in Iran, with a high rate of consanguinity. It should be considered in the differential diagnosis of CID at any age. With the limited access to HSCT and its variable results in MHC-II deficiency, implementing genetic counseling and family planning for the affected families are mandatory. We are better determined to study the c.162delG RFXANK heterozygous mutation frequency in the Iranian population.

Possible impact of HLA class I and class II on malignancies driven by a single germ-line BRCA1 mutation.

This study provides the first immunogenetic preliminary evidence that specific human leucocyte antigen (HLA) class I and class II alleles and haplotypes may be relevant for BRCA1 c.5263_5264insC driven oncogenesis. Observed HLA associations might have practical implications for establishment of predictive markers for the response to immunotherapies in malignancies driven by this germ-line mutation.

The role of non-classical and chain-related human leukocyte antigen polymorphisms in laryngeal squamous cell carcinoma.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the major pathological subtype of laryngeal cancer. It has been shown that alterations of the expression of non-classical human leukocyte antigens (HLA) and the chain-related MIC molecules by malignant cells can lead to escape from the immune system control and certain allele variants may participate in immune editing and therefore be associated with modulation of cancer risk. The aim of the present study was to investigate the role of non-classical HLA class Ib and chain-related MIC polymorphisms, determined at the allelic level by next-generation sequencing (NGS), in patients from the Bulgarian population, diagnosed with LSCC. MATERIALS AND METHODS: In the present study DNA samples from 48 patients with LSCC were used. Data was compared to 63 healthy controls analysed in previous studies. HLA genotyping was performed by using the AlloSeq Tx17 early pooling protocol and the library preparation AlloSeq Tx17 kit (CareDx). Sequencing was performed on MiniSeq sequencing platform (Illumina) and HLA genotypes were assigned with the AlloSeq Assign analysis software v1.0.3 (CareDx) and the IPD-IMGT/HLA database 3.45.1.2. RESULTS: The HLA disease association tests revealed a statistically significant predisposing association of HLA-F*01:01:02 (Pc = 0.0103, OR = 24.0194) with LSCC, while HLA-F*01:01:01 (Pc = 8.21e-04, OR = 0.0485) has a possible protective association. Additionally we observed several haplotypes with statistically significant protective and predisposing associations. The strongest association was observed for F*01:01:01-H*01:01:01 (P = 0.0054, haplotype score=-2.7801). CONCLUSION: Our preliminary study suggests the involvement of HLA class Ib in cancer development and the possible role of the shown alleles as biomarkers of LSCC.