HLA Alleles In Patients Research Articles

HLA Association among Thai Patients with Diffuse and Limited Cutaneous Systemic Sclerosis.

This study aimed to clarify the association of HLA Class I and II with dcSSc and lcSSc in Thais. HLA typing for 11 gene loci (Class I: HLA-A, B and C, and Class II [HLA-DR, DP and DQ]) was carried out using the Next Generation DNA Sequencing method (three fields) in 92 Thai patients with systemic sclerosis (55 dcSSc, 37 lcSSc) and 135 healthy controls (HCs). The distribution of HLA alleles in patients with dcSSc and lcSSc was compared. When compared with HCs, the AF of A*24:02:01, A*24:07:01, B*27:04:01 and B*27:06 showed an increasing trend in lcSSc patients without statistical significance. DRB1*15:02:01, DRB5*01:02:01, DQA1*01:01:01, DQB1*05:01:24, DPA1*02:01:01 and DPB1*13:01:01 increased significantly in dcSSc patients. DQB1*05:01:24 and DPB1*13:01:01 also increased significantly in lcSSc patients, but less significantly than in dcSSc patients. The association of DPB1*05:01:01 with lcSSc was significantly protective. HLA-A*24:02:01, B*27:06 and C*03:04:01 formed a three-locus haplotype that also constituted an eight-locus haplotype with DRB1*15:02:01, DQA1*01:01:01, DQB1*05:01:24, DPA1*02:01:01 and DPB1*13:01:01. There was a possibility that HLA Class I would play a role in the pathogenesis of lcSSc, while Class II played more of a role in the dcSSc in Thai patients.

Changes in the Immunogenetic Landscape with the Age of Disease Onset in Acquired Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria: An Analysis of a Cohort of Adult and Pediatric Patients from the French National Reference Center for Aplastic Anemia

Over the past decade, the role of HLA molecules in the pathophysiology of immune aplastic anemia (IAA) has been highlighted by the identification of somatic clonal losses of HLA molecules on leukocytes and the enrichment of certain HLA alleles in patients with AA compared to the general population. More recently, the analysis of the HLA Evolutionary Divergence (HED) score in a large US adult cohort showed that IAA patients were carrying class II HLA molecules whose antigen-binding sites were characterized by a high degree of structural homology and that low class II HED score was associated with a higher risk of malignant progression and poorer survival (Pagliuca et al., Blood, 2021). To evaluate these findings in an independent cohort, we conducted a retrospective study of a large cohort of adult and pediatric patients diagnosed with IAA and/or PNH included in 2 different centers in Paris from the French National Center for Aplastic Anemia (RIME observatory). Patients' 2-field HLA genotyping for HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci and HLA-DQA1 genotype imputations were compared with those of a control cohort of 593 allogeneic donors in the context of hematologic malignancies. The MidasHLA R package was used to assess HLA-disease associations using logistic regression analysis with a dominant inheritance model (Benjamini-Hochberg adjusted p-values). HED metrics, used as a surrogate for the width of the immunopeptidome presented by the patient's HLA molecules (Pierini and Lenz, Mol. Biol. Evol., 2018) were calculated for the different HLA loci and for the entire HLA class I and HLA class II genes (mean of HED scores for the corresponding loci). The cohort consisted of 449 patients who were children (<15 years of age, n=130), adolescents and young adults (15-25 years of age, n= 141), and adults (> 25 years of age, n= 178) at the time of diagnosis. Fifty-five percent had IAA, 28% had AA with a PNH clone, 8% had hepatitis-associated AA and 9% had hemolytic PNH. The distribution of diagnoses differed across age groups, with a decreasing incidence of hepatitis-associated AA and an increasing incidence of both AA/PNH and PNH with age. We first confirmed a strong association between patients and the DRB1*15:01, DQB1*06:02 and DQA1*01:02 alleles (these 3 alleles being in strong linkage disequilibrium) in addition to a few additional alleles at the DPB1 and B loci (Figure 1). This finding was consistent with several published studies in populations of different ethnicities. Using stepwise conditional testing, we then showed that only DQB1*06:02 (and DPB1*01:01 to a much smaller extent) remained associated with the disease (OR=2.49, adjusted p-value = 7.55E-09). Interestingly, the DQB1*06:02 association was lost when analyzing the subset of pediatric patients. Among patients, we then demonstrated a strong correlation between the age at disease onset and the presence of the DQB1*06:02 (Figure 2, exact Fisher's test, p=0.0005), DQA1*01:02 (p= 0.006) and DRB1*15:01 alleles (p< 0.0001). Intriguingly, we additionally found an overrepresentation of the ancestral A*01:01 B*08:01 DRB1*03:01 haplotype among patients with primary PNH (14.6%) compared to both patients with AA/PNH (2.4%, p=0.009) and controls (6.3%, p=0.083). Next, we investigated the HED metrics at the different HLA loci. There was no significant decrease in HED scores in patients compared to control, either at the DQB1, DQA1 and DRB1 loci or for the overall HED Class II score (mean value of HED-DRB1, -DQB1 and -DPB1), even in the subsets of DRB1*15:01 or DQB1*06:02 non-carriers. This result differed from the aforementioned US study, likely due to differences in geographic inclusion areas between the 2 cohorts. To rule out bias due to the inclusion of pediatric patients in our cohort, we then focused on the adult-onset subgroup and observed similar results. However, considering the entire cohort and despite no differences between patients and controls, we identified a strong association between age at onset and HED-B and HED-Class I (mean value of HED-A, -B and -C), with the divergence increasing with age (Kendall correlation test, p=0.001 and p=0.007, respectively). Taken together, these results highlight different immunogenetic landscapes according to the age of disease onset. We can hypothesize that the immune-mediated pathophysiological mechanisms may differ with age with a preponderant role of DQB1*06:02 appearing at later age of disease onset.

HLA Alleles in a Behçet Disease Multiethnic Population With and Without Ophthalmic Manifestations.

The aim of this study was to analyze HLA alleles in patients with Behçet disease (BD) and their correlation with ophthalmic manifestations (OMs) in a multiethnic Brazilian population. This case-control study compared 72 BD patients with or without OM who underwent a thorough ophthalmologic evaluation, including best-corrected visual acuity, bino-ophthalmoscopy, and HLA analysis, with 144 matched healthy controls. Fluorescein angiography was also performed in the patients with BD and OM. HLA class I (A, B, and C) and II (DRB1, DQB1, and DQA1) typing were performed using PCR-SSO. Of 72 patients with BD, 42 (58%) had OM. The HLA-B*51 and -A*26 alleles were more frequent in patients with BD than in controls (23.6% vs 14.6% and 12.5% vs 4.3%, respectively), but could not differentiate OM risk. The HLA alleles of BD patients that differentiated those with and without OM were HLA-B*15 (40.5% vs 20.7%; odds ratio [OR], 2.59; p = 0.0059), HLA-C*02 (33.3% vs 13.4%; OR, 3.20; p = 0.0024), and HLA-DQB1*03 (64.3% vs 45.7%, p = 0.017), whereas HLA-A*03 (0.0% vs 13.3%, p = 0.006) and HLA-DRB1*15 (4.8% vs 19.5%; OR, 0.21; p = 0.0121) were protective against OM. In this study of a Brazilian multiethnic BD population, alleles were similar between groups of BD patients with and without OM. We described HLA-B*15, -C*02, and -DQB1*03 as risk factors and -A*03 and -DRB1*15 as protective factors for OM in BD, which could function as biomarkers for predicting disease phenotypes.

HLA-A*02:06 allele may be susceptible to myelodysplastic syndrome in Zhejiang Han population, China.

The association between HLA loci and haematological malignancy has been reported in certain populations. However, there are limited data for HLA loci at a high-resolution level with haematological malignancy in China. In this study, a total of 1115 patients with haematological malignancies (including 490 AML, 410 acute lymphoblastic leukaemia (ALL), 122 myelodysplastic syndrome [MDS] and 93 non-Hodgkin's lymphoma [NHL]) and 1836 healthy individuals as a control group in the Han population of Zhejiang Province, China, were genotyped for HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1 loci at high resolution. The possible association between HLA alleles and haplotypes and haematologic malignancy was analysed. The allele frequencies (AFs) of HLA-A*02:05, HLA-A*02:06, HLA-A*32:01, HLA-B*35:03, HLA-B*54:01, HLA-B*55:07, HLA-DRB1*04:05, HLA-DRB1*15:01, HLA-DQB1*04:01 and HLA-DQB1*06:02 in the MDS patients were much higher than those in the control group (P<0.05), while the AFs of HLA-C*07:02, HLA-DRB1*03:01, HLA-DRB1*14:54, HLA-DQB1*02:01 and HLA-DQB1*05:03 were obviously lower than those in the control group (p < .05). Interestingly, the differences in these HLA alleles in patients with MDS were not significant after applying Bonferroni correction (Pc>.05), except for HLA-A*02:06 (Pc<.01). There were 13, 6 and 10 HLA alleles with uncorrected significant differences (p < .05) among patients with AML, ALL and NHL, respectively, compared with those in the control group, but the differences in these HLA alleles were not significant after correction (Pc>.05). Compared to those of the control group, there were some haplotypes over 1.00% frequency in patients with AML, MDS and NHL patients with uncorrected significant differences (p < .05). However, none of them showed a significant difference after correction as well (Pc>.05). The study reveals that HLA-A*02:06 may lead to susceptibility to MDS, but none of the HLA alleles were associated with AML, ALL or NHL after correction. These data will help to further understand the role of HLA loci in the pathogenesis of haematological malignancy in China.

Proteogenomic identification of Hepatitis B virus (HBV) genotype-specific HLA-I restricted peptides from HBV-positive patient liver tissues.

The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8+ cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S194-202) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C141-151) from the capsid protein were validated by our discovery platform, but both were detected at very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P606-616) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.

HLA Genotypes and Type 1 Diabetes and Its Relationship to Reported Race/Skin Color in Their Relatives: A Brazilian Multicenter Study.

We aimed to investigate the relationship between HLA alleles in patients with type 1 diabetes from an admixed population and the reported race/skin color of their relatives. This cross-sectional, multicenter study was conducted in public clinics in nine Brazilian cities and included 662 patients with type 1 diabetes and their relatives. Demographic data for patients and information on the race/skin color and birthplace of their relatives were obtained. Typing of the HLA-DRB1, -DQA1, and -DQB1 genes was performed. Most studied patients reported having a White relative (95.17%), and the most frequently observed allele among them was DRB1*03:01. Increased odds of presenting this allele were found only in those patients who reported having all White relatives. Considering that most of the patients reported having a White relative and that the most frequent observed allele was DRB1*03:01 (probably a European-derived allele), regardless of the race/skin color of their relatives, we conclude that the type 1 diabetes genotype comes probably from European, Caucasian ethnicity. However, future studies with other ancestry markers are needed to fill the knowledge gap regarding the genetic origin of the type 1 diabetes genotype in admixed populations such as the Brazilian.

Identification of HLA-A/B/DRB1 alleles in Iranian patients with Fanconi anemia.

Fanconi anemia includes a number of clinically and genetically diverse disorders all of them being associated with genomic instability. Some previous studies reported higher frequencies of certain HLA alleles in patients with Fanconi anemia. In the current study, we genotyped HLA-A/B/DRB1 alleles in 40 Iranian patients with Fanconi anemia. We also genotyped these alleles in the same number of Iranian sex-matched healthy individuals. The frequency of DRB1*11 was significantly higher in patients compared with controls (OR (95% CI) = 2.143 [1.05, 4.46], P value = 0.036). On the other hand, the frequencies of DRB1*13 and B*13 were lower in patients compared with controls (OR (95% CI) = 0.134 [0.02, 0.55], P value = 0.003 and OR (95% CI) = 0.13 [0.01, 0.89], P value = 0.035, respectively). Assessment of genetic divergence using Fstat test showed complete divergence in HLA-A, -B, -DRB1 alleles and haplotypes between patients and controls. The current study provides evidences for different distribution of HLA alleles between patients with Fanconi anemia and healthy subjects.

Characteristic spectra of class I and II HLA-alleles in patients with different clinical forms of juvenile idiopathic arthritis in the Republic of Belarus

The genes of the major histocompatibility complex (HLA) play a significant role in the genetic predisposition to juvenile idiopathic arthritis (JIA) and determine up to 18 % of disease risk. This work was aimed to reveal associations of the HLA characteristic pattern with two clinically different forms of JIA in the Belarusian population. 24 patients diagnosed with systemic JIA, 24 patients with oligoarticular JIA and 24 healthy controls were included into the study. High-throughput HLA typing for 11 loci was performed using TruSight HLA v2 Sequencing Panel (Illumina) on the MiSeq system. DQB1*04:02:01 (p = 0.026; OR 5.88 [1.20–28.72]), DRB1*08:01:01 (p = 0.07; OR 3.94 [1.01–15.39]) and DR8-haplotype (p = 0.006; OR 3.95 [1.34–11.63]) frequencies were significantly higher in patients with oligoarthritis but not systemic JIA when compared with controls. While DQA1*05:01:01 and DQB1*02:01:01 alleles showed a protective effect against both systemic (p = 0.007, OR 0.08 [0.009–0.65]; p = 0.01, OR 0.09 [0.01–0.83]) and oliarticular JIA (p = 0.026, OR 0.16 [0.03–0.79]; p = 0.046, OR 0.2 [0.04–1.00], the negative association of the DRB1*03:01 allele was revealed only for systemic JIA (p = 0.03, OR 0.11 [0.01–0.88]). Thus, the obtained results suggest that different HLA-patterns are involved into the formation of various JIA subtypes.

A case-control study of HLA alleles in Brazilian patients with Melkersson-Rosenthal syndrome.

Melkersson-Rosenthal syndrome (MRS) is a neuromucocutaneous disease that manifests by the triad of recurrent orofacial edema (frequently as cheilitis granulomatosa), relapsing facial paralysis and plicated tongue. The cause of MRS remains unknown, but genetic predisposal and a relationship with inflammatory bowel disease are suspected. The objective of this research was to compare the frequency of class I and II HLA alleles in patients with a confirmed diagnosis of MRS with those of a healthy control group. We conduct a case-control study and typed of HLA A, B, C, DR, and DQ using molecular techniques. The study included 36 patients with MRS and 297 patients in the control group. There was an increase in the expression of HLA A*02 (p=0.0269; OR: 1,79 [1,045-2,973]), HLA DRB1*11 (p<0,0001; OR: 4,009 [2,214-7,277]), HLA DRB1*13 (not statistically significant) and HLA DQB1*03 (p=0,0177; OR: 1,829 [1,122-2,978]) and low levels of HLA A*01 (p=0.0046; OR: 0,097 [0,009-0,538]), HLA DRB1*04 (p=0.0274; OR: 0,228 [0,053-0,844]), HLA DRB1*07 (p=0,0091; OR: 0,183 [0,043-0,670]) and HLA DQB1*02 (p=0.0051; OR: 0,312 [0,143-0,721]) in MRS patients compared with the control group. Crohn disease (CD) patients had disparate genetic profiles versus those with MRS. This single-institution study had a small cohort, because this disease is rare. Conclusions: There is a genetic predisposition toward MRS, involving associated and protective genes.

PB1741 KIR‐LIGAND MISMATCH IS NOT PREDICTIVE FOR LEUKEMIA‐FREE SURVIVAL IN PATIENTS WITH FAVORABLE RISK AML AFTER AUTOLOGOUS STEM CELL TRANSPLANTATION.

Background:Evidence suggests that Natural Killer (NK) Cells may play a role in the prevention of relapse of Acute Myeloid Leukemia after allogeneic stem cell transplantation (alloSCT). In a specific condition being HLA mismatched transplants, NK cells may get activated because subsets of donor NK cells miss inhibitory HLA alleles on the patient's cells. This is called. KIR‐ligand mismatch, were subsets of donor NK cells get activated when the patient's HLA alleles are not fitting to one or two of the inhibitory KIRs expressed on the donor cells (Ruggeri, Science 2002). The prerequisite for effective KIR‐ligand mismatch seems to be extensive AGVHD prevention by CD34‐selection of the stem cell graft or intense immunosuppressive conditioning including ATG. In HLA‐matched sibling alloSCT the same beneficial effect of KIR‐ligand mismatch was observed when intense T cell depletion of the graft had been applied (Hsu et al., Blood 2005). It was shown that early post T‐cell depleted alloSCT normally hyporesponsive NK cells expressing KIR for non‐self HLA temporarily displayed full functional capacity (Hsu, Blood 2009).Aims:We hypothesized that a beneficial effect of KIR‐ligand mismatch effect may be present in autologous SCT (autoHCT) in AML, where GVHD obviously is impossible. This would imply that developing NK cells harboring one or two inhibitory KIR receptors (iKIRs) for which no fitting HLA‐allele is present might temporarily get activated in those patients that do not bear all three relevant groups of HLA‐alleles (Bw4, C1 and C2) for which inhibitory KIRs are almost always there (presence of KIR2DL2/3 (fitting C1), KIR2DL1 (fitting C2) and KIR3DL1 (fitting Bw4) is 100%, 92.7% and 92.1% respectively, Hsu, Blood 2005). Approximately 30% of the population bears all three ligands for these three iKIRs and are not susceptible for KIR‐ligand mismatch.Methods:We typed all autologous transplanted AML patients in our center with genetic favorable risk factors (according to ELN 2017) and in first complete remission for HLA Bw4, C1 and C2. 2‐year leukemia‐free survival (LFS) of those patients not susceptible for KIR‐ligand mismatch was compared with LFS of those being susceptible. It was expected that 33% of the auto‐transplanted patients would relapse (Vellenga, Blood 2011). Assuming a meaningful higher 2‐year LFS of 87% for patients missing at least ligand (i.e. 15% higher than observed for the whole population), 2‐year LFS in those not missing a KIR ligand would have been 32% (3x 72 = 216; 216 – (2x 87) = 216 – 174 = 32). To demonstrate this difference 9 patients per group are needed. However, because of the unequal distribution of the two groups (“missing no KIR ligand” vs. “missing at least 1i KIR ligand”) to ensure that the “not missing a KIR ligand group” contains 9 patients at least 3x9=27 patients are needed.Results:We identified 39 favorable risk auto‐transplanted AML patients. Twelve had all HLA ligands for all three iKIRs present, and 27 lacked at least one ligand. 2‐year LFS was 83% and 83% respectively. For those 11 that missed HLA C1 ligands (for which all individuals have a ligand (i.e. KIR2DL2/3) 2‐year LFS was 81%.Summary/Conclusion:2‐year LFS is very high after autoHCT in first complete remission in favorable risk AML and KIR‐ligand mismatch is not relevant.image

Abstract P1-08-13: A prospective evaluation of HLA expression in breast implant associated anaplastic large cell lymphoma to identify disease susceptibility

Abstract Background: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoma found to occur in association with breast implants. Proposed pathogenic factors for BIA-ALCL include immunologic reaction to textured implants, bacteria and biofilm, chronic inflammation, autoimmune disease, or genetic predisposition. While HLA alleles have been found to be associated with other forms of lymphoma, the frequency of HLA allele polymorphisms have not been described for BIA-ALCL. The aim of this study is to evaluate the frequency of HLA alleles in patients with BIA-ALCL. Methods: We prospectively evaluated HLA alleles in 13 patients with BIA-ALCL seen at a single institution from 2017 to 2018. HLA testing was carried out using probe based sequence specific testing and sequence based typing. The frequency of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 were evaluated in the study population. Allele frequencies in the Caucasian European general population were obtained from the National Marrow Donor Program for normative controls. We estimated the relative risk of BIA-ALCL with 95% confidence intervals for each HLA allele using a t test. All statistics were performed using SPSS. Results: Thirteen patients with BIA-ALCL and HLA testing were identified with ages ranging from 37 – 76 years. We identified 10, 11, and 9 HLA A, B, and C alleles respectively. There were 8 DRB1 alleles and 5 DQB1 alleles in the BIA-ALCL patients. The following alleles occurred more than two times more frequently in patients with BIA-ALCL as compared with the general population: A*31, A*32, A*68, B*27, B*39, B*49, B*51, and C*15. Conversely, the A*01, A*24, and B*35 alleles occurred less frequently in patients with BIA-ALCL. The A*26 allele was found to occur significantly less often in BIA-ALCL patients (0.2992 vs. 0.07692, p&amp;lt;0.001) versus normative controls. Conclusions: Our results identify differences in the frequency of specific HLA alleles in patients who develop BIA-ALCL compared with the general population. These alleles may signify genetic susceptibility factors for germline genetic variation in HLA in Caucasian patients with BIA-ALCL. Further work is needed to elucidate if these alleles confer susceptibility or resistance and are predictive for the disease in women with textured surface breast implants. Citation Format: Tevis SE, Hunt KK, Miranda RN, Butler CE, Clemens MW. A prospective evaluation of HLA expression in breast implant associated anaplastic large cell lymphoma to identify disease susceptibility [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-13.

Abstract B12: Independent comparison of the state of the art in-silico HLA typing software

Abstract To accurately characterize the neo-antigen repertoire in tumors, identifying the HLA alleles of the patient is paramount. The binding of the neo-antigens to the patient's specific HLA alleles HLA-restriction has to be determined to identify neo-antigens that might play a role in stimulating an immune response in immunotherapy. The information on the patient's HLA alleles is captured in the next-generation sequencing (NGS) data and has to be accurately teased out using in-silico HLA typing software. However, to our knowledge, until now an independent study of HLA typing software has not been carried out. In this study, five publicly available HLA typing software packages were compared using 106 whole exome sequencing samples from the 1000 Genomes Project and a published dataset of 56 Asian nasopharyngeal tumor-normal pairs with experimentally determined HLA types. Whole exome sequencing samples of varying depth and coverage were chosen to simulate real-world data and test the robustness of the HLA typing software. Citation Format: Alvin Ng, Steve Rozen. Independent comparison of the state of the art in-silico HLA typing software. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B12.

Analysis of KIR gene frequencies and HLA class I genotypes in breast cancer and control group

Breast cancer is the main cause of cancer-related death among women, with a 0.5% increase in incidence per year. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA alleles in patients with breast cancer and healthy controls. Two hundred thirty patients with breast cancer and 272 healthy controls were typed for HLA class I and KIR genes by PCR-SSO. When both groups were compared, the presence of inhibitory KIR2DL2 receptors was significantly higher in breast cancer patients than in healthy controls. No significant differences were found for HLA-C2 and HLA-Bw4. However, a higher frequency of HLA-C1 in breast cancer patients was observed. These findings suggest a potential role for the KIR gene system in breast cancer. Further studies to confirm this observation are warranted.

HLA class I and II alleles are associated with microvascular complications of type 1 diabetes.

Although HLA alleles are associated with type 1 diabetes, association with microvascular complications remains controversial. We tested HLA association with complications in multiplex type 1 diabetes families. Probands from 425 type 1 diabetes families from the Human Biological Data Interchange (HBDI) collection were analyzed. The frequencies of specific HLA alleles in patients with complications were compared with the frequencies in complications-free patients. The complications we examined were: retinopathy, neuropathy, and nephropathy. We used logistic regression models with covariates to estimate odds ratios. We found that the DRB1*03:01 allele is a protective factor for complications (OR=0.58; p=0.03), as is the DQA1*05:01-DQB1*02:01 haplotype found in linkage disequilibrium with DRB1*03:01 (OR=0.59; p=0.031). The DRB1*04:01 allele showed no evidence of association (OR=1.13; p=0.624), although DRB1*04:01 showed suggestive evidence when the carriers of the protective DRB1*03:01 were removed from the analysis. The class II DQA1*03:01-DQB1*03:02 haplotype was not associated with complications, but the class I allele B*39:06 (OR=3.27; p=0.008) suggested a strong positive association with complications. Our results show that in type 1 diabetes patients, specific HLA alleles may be involved in susceptibility to, or protection from, microvascular complications.

Analysis of KIR gene frequencies and HLA class I genotypes in prostate cancer and control group

Prostate cancer is the second most common cancer in men, with a significant increase in incidence and mortality in men over 50 years of age. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with prostate cancer and healthy controls. Two hundred patients with prostate cancer and 185 healthy controls were typed for HLA class I and KIR genes by PCR-SSP. When both groups were compared, no significant differences were found for HLA-C group 1 and group 2, HLA-Bw4, HLA-A3 and A11. No difference was seen either in KIR frequency between patients with prostate cancer and controls. In conclusion, our data suggest no potential role for the KIR gene system in prostate cancer.

Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia

AbstractIdiopathic aplastic anemia (AA) is a common cause of acquired BM failure. Although autoimmunity to hematopoietic progenitors is thought to be responsible for its pathogenesis, little is known about the molecular basis of this autoimmunity. Here we show that a substantial proportion of AA patients harbor clonal hematopoiesis characterized by the presence of acquired copy number-neutral loss of heterozygosity (CNN-LOH) of the 6p arms (6pLOH). The 6pLOH commonly involved the HLA locus, leading to loss of one HLA haplotype. Loss of HLA-A expression from multiple lineages of leukocytes was confirmed by flow cytometry in all 6pLOH(+) cases. Surprisingly, the missing HLA-alleles in 6pLOH(+) clones were conspicuously biased to particular alleles, including HLA-A*02:01, A*02:06, A*31:01, and B*40:02. A large-scale epidemiologic study on the HLA alleles of patients with various hematologic diseases revealed that the 4 HLA alleles were over-represented in the germline of AA patients. These findings indicate that the 6pLOH(+) hematopoiesis found in AA represents “escapes” hematopoiesis from the autoimmunity, which is mediated by cytotoxic T cells that target the relevant auto-antigens presented on hematopoietic progenitors through these class I HLAs. Our results provide a novel insight into the genetic basis of the pathogenesis of AA.

Could microchimerism be a source of disease associated HLA alleles in patients with scleroderma

Could microchimerism be a source of disease associated HLA alleles in patients with scleroderma

Could microchimerism be a source of disease-associated HLA alleles in patients with scleroderma?

Background and objectivesSystemic sclerosis (SSc) is an autoimmune disease divided in two subsets, diffuse cutaneous and limited cutaneous SSc (dcSSc and lcSSc), affecting mostly women. We, and others showed that...

Estudo de HLA classes I e II em trinta pacientes equatorianos com artrite reumatoide em comparação com alelos de indivíduos sadios e afetados com outras doenças reumáticas

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease that originates from a disabling disorder. To date, the etiology of RA is unknown. However, the existence of genetically susceptible individuals was considered. Many studies have been performed worldwide, for example, in Poland, Argentina, Chile, Mexico, Brazil, and Colombia, among others, regarding the influence between HLA-DR alleles and disease, but not in Ecuador. The aim of this study was to determine the involvement of Class I and II HLA alleles in patients with RA. This study was conducted in 30 adult patients with RA previously diagnosed, according to the classification criteria of the American College of Rheumatology (ACR, 1987) and 28 controls. For Class I and II HLA typing, we adopted the PCR-SSP, and statistical significances were evaluated by Chi-Square. HLA-DR4 is present in 76.7% of patients, with an allele frequency of 45%, while only 21% of control subjects presented it. The chi-square confirms that HLA-DR4 and RA variables are highly bound (X2 = 11.38, P = 0.00074). There is increased frequency of HLA-DR4 and HLA-DR14. The results are similar to those found in other studies. But it would be desirable to increase the sample size in order to find a greater number of genetic profiles and alleles involved.

Analysis of HLA class I and II alleles regarding to lymph node and distant metastasis in patients with non-small cell lung cancer

The aim of this study was to investigate the relation of HLA alleles in patients with non-small cell lung cancer (NSCLC). The incidence of class I and II HLA alleles of 63 patients with NSCLC were prospectively compared with the incidence of class I and II HLA alleles with 88 healthy controls. The number of cases with stage I and II (early stage) was 12 and there were 51 cases with stage III and IV (advanced stage). Metastasis rates of the regional lymph node in patients were as follow; N 0: n = 10; N 1: n = 13; N 2: n = 26 and N 3: n = 14. Lymph node metastasis was detected by pathological staging in 15 cases and by clinical staging in 48 cases. Lymph node metastasis was searched in all patients by a helical thorax CT. All distant metastasis were investigated by thorax CT, abdominal CT, brain CT or MRI and bone scintigraphy, and distant organ metastasis was detected in 25 cases. The patients and healthy controls were typed for HLA class I and II alleles. HLA-A2 was an independent risk factor for both critical lymph node (N 2 and 3) involvement and distant metastasis. HLA-B44, -CW6 and -CW7 frequencies appear to be significant in controls compared to patients. HLA-A2 frequency was higher in patients with advanced stage than early stage, while HLA-A26, -B35 and -CW4 frequencies were more expressed in patients with early stage than in patients with advanced stage. Compared with controls, frequency of HLA-DRB1*07, -DQ02 and -DQ07 were lower expressed in patients. Compared patients with advanced stage, HLA-DRB1*07 was higher in patients with early stage. HLA-A2 was an independent risk factor for lymph node and distant metastasis, and the allele was significantly higher in patients with critical lymph node for surgery and distant metastasis. HLA-A26 appeared to be a significance protective allele against to metastases.