Histocompatibility Leukocyte Antigen Alleles Research Articles

Broadly recognized, cross-reactive SARS-CoV-2 CD4 T cell epitopes are highly conserved across human coronaviruses and presented by common HLA alleles.

Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can affect T cell response in COVID-19. We studied T cell responses to SARS-CoV-2 and HCoVs in convalescent COVID-19 donors and identified a highly conserved SARS-CoV-2 sequence, S811-831, with overlapping epitopes presented by common MHC class II proteins HLA-DQ5 and HLA-DP4. These epitopes are recognized by low-abundance CD4 T cells from convalescent COVID-19 donors, mRNA vaccine recipients, and uninfected donors. TCR sequencing revealed a diverse repertoire with public TCRs. T cell cross-reactivity is driven by the high conservation across human and animal coronaviruses of T cell contact residues in both HLA-DQ5 and HLA-DP4 binding frames, with distinct patterns of HCoV cross-reactivity explained by MHC class II binding preferences and substitutions at secondary TCR contact sites. These data highlight S811-831 as a highly conserved CD4 T cell epitope broadly recognized across human populations.

Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8+ Tcell antiviral responses.

Persistence of HIV through integration into host DNA in CD4+ Tcells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8+ Tcells are triggered to kill infected CD4+ Tcells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial" HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A∗02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8+ Tcell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4+ Tcells prior to virus production invitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.

The prevalence of HLA alleles in a lupus nephritis population

BackgroundSystemic lupus erythematosus (SLE) is a severe autoimmune disease that involves multiple organ systems. Lupus nephritis (LN) is a complication of SLE and is associated with poor survival and high morbidity. Many genomic studies have been performed worldwide, and several histocompatibility leukocyte antigen (HLA) loci are linked to lupus susceptibility. ObjectiveThe present study evaluated the association of HLA alleles in a lupus patient population, LN group and control group. The second objective evaluated whether HLA allele match or mismatch influenced kidney graft survival in a kidney transplanted lupus population. MethodsThis study was a retrospective study of 2 major groups: general lupus patients (GSLE - n = 108) and a control group (GControl - n = 216). Both groups were also divided into subgroups. ResultsThe control group was divided into two subgroups: a healthy control group (HeCTRL) and transplant control group (TxCTRL). The GSLE group was composed of transplanted lupus patients (TxSLE) and non-transplanted lupus patients (nTxSLE). Comparison of the demographics between groups did not reveal differences between ethnicity and gender. A difference in the prevalence of three alleles, B*08, DRB1*08 and DRB1*15, was observed. These alleles were more prevalent in the lupus subgroups compared to the control groups. Five-year survival was not different between patients carrying the allele DRB1*15 in either group (overall p = 0.075; TxSLE p = 0.419; TxCTRL = 0.309). The presence of the match with this allele in the receptor was evaluated and did not demonstrate any difference in graft survival in both groups (p = 0.146) or when analyzed separately in each group (TxCTRL p = 0.739; TxSLE = 0.297). ConclusionThis study demonstrated that the presence of HLA-DRB1*15 was a strong factor that predisposed patients to the development of SLE and LN, but did not influence kidney graft survival.

Assessment of Human Leukocyte Antigen (HLA) Type on Outcomes of Allogeneic Transplant for Chronic Lymphocytic Leukemia (CLL)

BACKGROUNDAllogeneic hematopoietic cell transplant (allo-HCT) can achieve prolonged disease free survival (DFS) in patients with high risk relapsed CLL through a graft-versus-leukemia effect. This is likely mediated through alloreactive donor T-cells that recognize and eliminate residual CLL targets expressing unique and potentially tumor-specific antigens within the context of the Class I Major Histocompatibility Complex (MHC). Histocompatibility Leukocyte Antigen (HLA) alleles encoding class I MHC can be protective or predisposing to the development of a variety of hematologic malignancies. Specifically, HLA-A*02:01, which is enriched in Caucasians, increases the risk of development of CLL, while HLA A1:01 is protective against the development of CLL. Previous single center data of reduced intensity conditioning (RIC) allo-HCT with post-transplant rituximab and donor lymphocyte infusion identified an improvement in complete remission (CR) rates and DFS in patients positive for HLA-A1, negative for HLA-A2 and HLA-B44 (HLA-A1, non-A2 and non-B44) compared to patients without these HLA alleles (Khouri, et al 2011). The impact of this combination of HLA alleles (HLA-A1, non-A2 and non-B44) on outcomes of allo-HCT for CLL has not been previously explored in a multi-center study. We therefore sought to compare outcomes of CLL patients undergoing fully-matched related or unrelated donor allo-HCT in CIBMTR centers, based on recipient HLA type.METHODSCLL patients ≥ 18 years old who received a fully matched allo-HCT (from matched sibling donor or 8 out of 8 matched unrelated donors) using myeloablative (MA), non-myeloablative (NMA), or reduced intensity conditioning (RIC) between 2000 and 2013 were included. Patients with Richter’s transformation were excluded. Patient outcomes were compared based on the presence of the HLA combination HLA-A1, non-A2 and non-B44 (n=83) vs. other (n=481). Patient-related variables included age, gender, coexistent disease or organ impairment, HCT comorbidity score, Karnofsky score, donor/recipient CMV status. Disease-related variables included presence/absence of 17p-, 11q-, 13q-, and trisomy 12, IGHV mutation status, Rai stage at diagnosis, elevated LDH or bulky adenopathy at the time of HCT, type and number of treatments, response to pre-transplant chemotherapy, and disease status at transplant. Transplant-related variables included time from diagnosis to HCT, preparative regimen: MA vs. RIC vs. NMA, graft source, donor age, and donor-recipient sex match. Cox proportional hazard analysis was used to identify significant risk factors. For power calculation, it was assumed that overall survival (OS) at 1 year, 2 years and 3 years were 70%, 57%, and 50%, respectively. Median censoring time was assumed to be 70 months. There was 80% power to detect hazard ratio (HR) of 1.65 at the significance level 0.05. This HR was based on prior publication by Khoury et al.RESULTSMedian age of patients was 56 (range 22-75). 73% were male. Baseline characteristics between the groups with and without A1, non-A2, non-B44 were well matched in terms of prior therapy, remission status at time of allo-HCT, use of RIC or NMA conditioning, and baseline cytogenetics. In multivariable analysis, the HLA combination HLA-A1, non-A2, non-B44 was not associated with an improvement in GVHD, relapse rates, or OS (see Table ). Kaplan Meier estimates of the OS of the groups are shown in the accompanying Figure. There was a non-statistically significant trend towards improvement in DFS in patients without the HLA combination of interest (P = 0.06). In univariable analysis HLA-A1, A2 and B44 were not individually associated with OS.CONCLUSIONSPreviously-identified HLA alleles were not associated with any measurable outcomes of allogeneic transplant from fully matched related or unrelated donors captured in the CIBMTR registry, either alone or in combination. Future study of the impact of HLA on transplant outcomes may require assessment of killer immunoglobulin receptor (KIR) subtypes for more robust exploration of the immunologic basis for differences in allo-HCT outcomes for CLL. [Display omitted] [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Frequency of Class I and II HLA alleles in patients with lung cancer according to chemotherapy response and 5‐year survival

Lung cancer is the most common cause of cancer death in the world, and the most common type is non-small-cell lung cancer (NSCLC). At present, surgical resection, chemotherapy, and radiation therapy are the main treatments for patients with NSCLC, but unfortunately outcome remains unsatisfactory. This study aimed to determine whether Class I and II histocompatibility leukocyte antigen (HLA) alleles are related with response to chemotherapy and survival of lung cancer. A total of 65 NSCLC patients (56 men and 9 women, mean age 58.4 ± 11 years) were included in the study. Patient groups were compared with a control group of 88 unrelated healthy kidney or bone marrow donors in order to clearly identify susceptible and protective HLA alleles in lung cancer. Target lesions and tumor response were assessed using the Response Evaluation Criteria for Solid Tumors (RECIST) guidelines. Results were classified into two groups: complete-partial response and stable-progressive disease. We found that expression of HLA-A32, HLA-B41, HLA-B57, HLA-DRB1*13, and HLA-DQ5 were more frequent in the complete and partial response groups to chemotherapy than in the control group. The frequency of HLA-A11, HLA-A29, HLA-BW6, HLA-CW3, HLA-DR1*1, and HLA-DRB1*3 were determined to be higher in the stable and progressive disease groups taking chemotherapy than in the control group. Additionally, expressions of HLA-A2 and HLA-B49 were statistically related with 5-year survival. Our results suggested that expressions of HLA-BW6 and HLA-DRB1*13 alleles may be predictable markers for response to chemotherapy in lung cancer patients.

Profiling of human leukocyte antigens in Eales disease and tuberculosis

To analyze the association between Eales disease, histocompatibility leukocyte antigen alleles (HLA-A/B, HLA-DRB/DQB) and tuberculosis infection, and to explore susceptible genes and protective genes associated with Eales disease and tuberculosis infection in a population of Han nationals from Zunyi City in Guizhou Province, China. The subjects were analyzed by a case-control study consisting of three groups--Eales disease group (47 cases), pulmonary tuberculosis group (36 cases) and normal control group (100 cases). The Eales disease group was divided into four parts. Part one consisted of 12 patients who had suffered from pulmonary tuberculosis. Part two consisted of 27 patients who had not suffered from pulmonary tuberculosis. Parts three and four consisted of 27 patients with a positive purified protein derivative test and 12 patients with a negative test, respectively. DNA samples from 47 patients with Eales disease, 36 patients with pulmonary tuberculosis and 100 healthy people were detected by polymerase chain reaction with sequence-specific primers. The 59 HLA-A/B and HLA-DRB/DQB alleles from Eales disease were compared with those from tuberculosis and normal control, and a correlativity test of common susceptible genes was performed to analyze the potential relationship between Eales disease and pulmonary tuberculosis. The frequency distribution of HLA-A*02 alleles (OR 9.719, OR 95 % CI 4.377-21.580, P = 0.000) and HLA-B*07 (OR 11.605, OR 95 % CI 2.397-56.191, P = 0.001) in the Eales disease group was higher than in the normal control group, but the HLA-A*11 alleles (OR 0.495, OR 95 % CI 0.245-1.000, P = 0.048) were lower than in the normal control group, showing a significant difference. Compared with parts two and four, the frequency distribution of HLA-A*02, HLA-A*11 and HLA-B*07 alleles in parts one and three showed no significant difference (P > 0.05). HLA-A*A02, HLA-A*24, HLA-B*07 and HLA-DRB*16 alleles between the Eales disease, pulmonary tuberculosis and normal control group showed statistical significance (P < 0.05). HLA-A*24 alleles in the pulmonary tuberculosis group were lower than the Eales disease group (χ(2) 7.289, P = 0.007), but HLA-A*02 alleles showed no significant difference (P > 0.05) between the two groups. The results show that HLA-A*02 and HLA-B*07 may be genetic predisposing genes, but HLA-A*11 alleles may be protective genes of Eales disease, the HLA-A*02 allele may be a common susceptible gene of Eales disease and pulmonary tuberculosis. HLA-A*11 and HLA-A24 alleles are protective genes of Eales disease and pulmonary tuberculosis, respectively. In summary, the frequency distribution of susceptible genes of Eales disease and pulmonary tuberculosis in a population of Han nationals from Zunyi City in Guizhou Province, China showed no significant difference.

Linkage Disequilibrium Between TNF-α-308 G/A Promoter and Histocompatibility Leukocyte Antigen Alleles in Han-Nationality Lung Transplant Recipients From Eastern China

Genes encoding histocompatibility leukocyte antigen (HLA) and proinflammatory cytokines are involved in rejection after organ transplant. The authors explored the association between HLA alleles and the tumor necrosis factor (TNF)- α-308 G/A promoter region in lung transplant recipients of Han nationality from East China. They also evaluated the correlation between TNF-α-308 G/A and the onset of acute rejection after lung transplant. All lung transplant recipients of Han nationality who were admitted into our hospital between August 2004 and July 2011 were included. Patients were divided into 2 groups according to the presence or absence of acute rejection episodes. Genotypes of HLA and single nucleotide polymorphisms of TNF-α-308 G/A were determined using polymerase chain reaction-single specific primer kits. A total of 106 lung transplant recipients were investigated. HLA-A*2 allele was in linkage disequilibrium with TNF-α-308 G allele. HLA-A*33, -B*58 and -DRB1*03 alleles were in linkage disequilibrium with TNF-α-308 A allele. Notably, TNF-α-308 A allele was in complete linkage disequilibrium with HLA-B*58 allele. Furthermore, TNF-α-308 A allele was in linkage disequilibrium with the HLA-A*33-DRB1*03 and HLA-B*58-DRB1*03 haplotypes. Clinical analysis indicated that TNF-α-308 G/A was not associated with onset of acute rejection after lung transplant. TNF-α-308 G/A polymorphism was strongly associated with HLA-A*2, -A*33, -B*58, and -DRB1*03 alleles in our population. HLA genotyping can identify lung transplant recipients carrying the highly productive phenotype of TNF-α-308 A allele, which may provide information on rejection after transplant. However, the authors found that TNF-α-308 A subtype has no correlation with acute rejection after lung transplant.

Correlation Between HLA Alleles and EGFR Mutation in Japanese Patients with Adenocarcinoma of the Lung

The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene is one of the most intriguing recent discoveries in the field of lung cancer research, and they are more commonly found in adenocarcinoma occurring in females, never/light smokers, and East Asian patients. Why such certain patients are susceptible to the development of EGFR-mutant tumors is currently unknown. This study evaluated the medical records of 437 patients with adenocarcinoma of the lung who underwent a surgical resection. The genetic status of the EGFR gene was investigated by polymerase chain reaction-based analyses. The serological typing of histocompatibility leukocyte antigen (HLA) class I was performed using a microcytotoxicity test of lymphocytes or polymerase chain reaction-sequence-specific oligonucleotides, and the correlation between the EGFR mutation and HLA alleles was analyzed. An EGFR mutation was found more frequently in females and never/former smokers than their counterpart. In females, the incidences of EGFR mutation were 61.0% and 41.7% in HLA-A2 (+) and A2 (-) patients with adenocarcinoma of the lung, respectively (p = 0.008). The EGFR mutation was found more frequently in female patients with HLA-A2. However, no significant correlation was identified between the frequencies of other HLA alleles and EGFR mutations in the same patients group. EGFR: mutations are associated with HLA-A2 in female patients with adenocarcinoma of the lung. Further research was needed to elucidate the other relevant factors in the histogenesis of lung cancer with an EGFR mutation.

Lipoprotein(a) and HLA-DRB1 and -DQB1 genes in coronary artery disease

In some respects, atherosclerosis resembles autoimmune disease. Since many autoimmune diseases are associated with certain histocompatibility leukocyte antigen (HLA) class II alleles, we have looked for a similar HLA association with atherosclerosis. In the first phase, genomic typing was performed in 52 men with coronary artery disease. In the second phase, 50 men with early onset (before 50 years of age) coronary artery disease were studied. 12 DRB1 and 4 DQB1 alleles were determined by restriction fragment length polymorphism analysis. No significant difference in frequency of the examined alleles was observed in any of the patient groups compared to healthy controls. The plasma level of lipoprotein(a) (Lp(a)) is considered an important risk factor for early coronary heart disease. A linkage between inherited high levels of Lp(a) and certain HLA class II genotypes has been suggested. In the present study, Lp(a) levels were measured in men with early onset of coronary artery disease. 11 (23%) Study patients and 3 (7%) control subjects had Lp(a) levels above 450 mg/l. However, no correlation between high Lp(a) levels and certain HLA genotypes was found. Summarized, these findings indicate that atherosclerosis, especially early onset coronary atherosclerosis, is not a disease associated with particular HLA alleles.