Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.
One hundred and two Southern Thai-Muslims (STM) from Nakhon Si Thammarat province were studied for HLA class I and II by SSP ARMS-PCR and PCR-SSO, respectively. The allele frequencies, haplotype frequencies, delta value and linkage disequilibrium between alleles were expressed. The most frequent alleles for HLA-A, HLA-B and HLA-C were A*24(02,03), A*11 (01,02), A*02(01,03,05-07,11): B*15(01,04-07,12,19,20), B*07(02-05), B*51(01-05)/B*52 (011,012); and Cw*07(01-03), Cw*04(01,02), Cw*08(01-03), respectively. The HLA class II alleles frequently found were DRB1*1202, DRB1*15021, DRB1*0701; DRB3*0301; DRB5* 0101; DQA1*0101, DQA1*0103, DQA1*0601; DQB1*0301, DQB1*0501, DQB1*0201; and DPB1*1301, DPB1*2301 and DPB1*0501. Two common HLA class I and II haplotypes with significant linkage disequilibrium were A*24 (02,03)-Cw*08 (01-03)-B*15 (01,04-07,12,19,20) -DRB1*1202 and A*33 (01,02)-Cw*0302-B*5801-DQB1*0201. The absence of B*27 and DRB1 *1401, the presence of A*2301 and high frequency of A*68 were observed in STM.
Similar HLA association was found in patients with elephantiasis in Sri Lankans and Southern Indians. HLA-B15 was observed in 13/44 (30%) Sri Lankan patients with elephantiasis compared to 1/27 (4%) Sri Lankan controls (p = .0058; RR = 10.9) and in 5/8 (28%) Southern Indian elephantiasis compared to 10/101 (10%) Southern Indian controls (p = 0.04; RR = 3.5). In combining the data, the significance of the difference of the frequency of B15 between patients with elephantiasis and controls was even more marked (p = 0.00045; corrected p = 0.012; RR = 4.4).
New data are presented concerning the relationship between NPC and HLA antigens among Chinese. When attention is confined to newly diagnosed cases, it can be shown that, apart from the increased risk associated with the joint occurrence of A2 and B-Sin 2, there is also an increased risk associated with BW17 and a decrease in risk associated with A11. Among long-term survivors, however, BW17 is appreciably decreased, whereas A2 in the absence of B-Sin 2 or BW17 is increased. Among Malays, a non-Chinese group, there is an excess among NPC patients of a locus A blank, a blank which is probably associated with the AW19 complex.
Understanding the structure of the major histocompatibility complex, especially the number and frequency of alleles, loci and haplotypes, is crucial for efficient investigation of the way in which the MHC influences susceptibility to disease. Nematode infection is one of the most important diseases suffered by sheep, and the class II region has been repeatedly associated with differences in susceptibility and resistance to infection. Texel sheep are widely used in many different countries and are relatively resistant to infection. This study determined the number and frequency of MHC class II genes in a small flock of Texel sheep. There were 18 alleles at DRB1, 9 alleles at DQA1, 13 alleles at DQB1, 8 alleles at DQA2 and 16 alleles at DQB2. Several haplotypes had no detectable gene products at DQA1, DQB1 or DQB2, and these were defined as null alleles. Despite the large numbers of alleles, there were only 21 distinct haplotypes in the population. The relatively small number of observed haplotypes will simplify finding disease associations because common haplotypes provide more statistical power but complicate the discrimination of causative mutations from linked marker loci.
The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing (TAP) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers.
In this study, human leukocyte antigen (HLA) class I and II were examined through sequence-specific primer typing in 176 unrelated individuals from six Malay subethnic groups of Peninsular Malaysia: Kelantan (n = 25), Minangkabau (34), Jawa (30), Bugis (31), Banjar (33), and Rawa (23). The most common HLA alleles in all groups were A*24 (26-41%), Cw*07 (24-32%), B*15 (22-30%), DRB1*12 (15-36%), and DQB1*03 (25-51%). The Malay subethnic groups studied demonstrated a close relationship to each other and to other Asian populations, despite specific differences between them. Banjar, Bugis, and Jawa Malays demonstrated no significant difference from each other, which could be a result of their related origin from the islands around the Java Sea. These three Malay subethnic groups were then collapsed into one group, which also helped to increase the sample number and sharpen statistical results. Minangkabau and Rawa Malays exhibited high similarities in allele group and haplotype frequencies, which could be a consequence of their common origin from Sumatera. Kelantan Malays, in addition to their statistically significant differences compared with the other groups, also exhibited differences on the most frequent haplotypes, which are almost absent in the other subethnic groups studied.
One hundred and fifty-eight Kadazan, Iban and Bidayuh individuals registered with the Malaysian Marrow Donor Registry were typed for human leukocyte antigen (HLA)-A, HLA-B and HLA-DR. Six, seven and eight HLA-A alleles as well as 13, 15 and 16 HLA-B alleles were detected in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-A allele in all three groups was HLA-A*24 with a frequency of 0.456, 0.490 and 0.422 in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-B allele detected in the Kadazan was HLA-B*40 with a frequency of 0.333; for the Bidayuh and the Iban it was HLA-B*15 with a frequency of 0.460 and 0.275, respectively. The HLA-DR allele with the highest frequency in the Kadazan was HLA-DR*1502 with a frequency of 0.500. In the Iban and the Bidayuh, HLA-DRB1*1202 was the most common DR allele with frequencies of 0.235 and 0.310, respectively. The two most common haplotypes for the Kadazan are A*34-B*38-DR*1502 and A*24-B*40-DR*0405, whereas for the Bidayuh they are A*24-B*15-DR*1602 and A*24-B*35-DR*1202 and for the Iban they are A*34-*B15-DR*1502 and A*24-B*15-DR*1202.
This is the first report of high-resolution human leukocyte antigen (HLA) typing in four indigenous groups in Malaysia. A total of 99 normal, healthy participants representing the Negrito (Jehai and Kensiu), Proto-Malay (Temuan) and a native group of Borneo (Bidayuh) were typed for HLA-A, -B, -DRB1 and -DQB1 genes using sequence-based typing. Eleven HLA-A, 26 HLA-B, 16 HLA-DRB1 and 14 HLA-DQB1 alleles were detected, including a new allele, HLA-B*3589 in the Jehai. Highly frequent alleles were A*2407, B*1513, B*1801, DRB1*0901, DRB1*1202, DRB1*1502, DQB1*0303 and DQB1*0502. Principal component analysis based on high-resolution HLA-A, -B and -DRB1 allele frequencies showed close affinities among all four groups, including the Negritos, with other Southeast Asian populations. These results showed the scope of HLA diversity in these indigenous minority groups and may prove beneficial for future disease association, anthropological and forensic studies.
BACKGROUND: Studies have shown that certain genes within the major histocompatibility complex predispose to systemic lupus erythematosus (SLE) and may influence clinical and autoantibody expression. Thus, we studied the frequency of HLA-DR, -DQA, -DQB and -DPB alleles in ethnic Malays with SLE to determine the role of these genes in determining disease susceptibility and their association with clinical and immunological manifestations.
METHODS: Fifty-six Malay SLE patients were enrolled into the study. Demographic, clinical and immunological findings were obtained from medical records. HLA-DR, DQ and DP typing were done using modified PCR-RELP. Controls were from ethnically-matched healthy individuals.
RESULTS: We found a strongly significant association of the DR2 and DQB1 *0501 and DQB1*0601 (pcorr = 0.03, rr = 3.83, pcorr = 0.0036, rr = 4.56 and pcorr = 0.0048 and rr = 6.0, respectively). There was also a weak increase of DQB1*0.201 and DPB1*0.0901 with a weak decrease of DQA1*0601 and DQB1*0503 and *0301 which were not significant after corrections for multiple comparisons were made. There was a significant positive association of DR2 and DQB1*0501 with renal involvement and DR8 with alopecia. A nonsignificant increase of DQB1*0503 in patients with photosensitivity was noted. Significant autoantibody associations were also found: DQB1*0601 with anti-Sm/RNP, DR2 with antiSSA (Ro)/SSB (La), and DR2, DQB1*0501 and *0601 with antibodies to ds DNA. There was no specific DR, DQ or DP associations with age of disease onset (below 30 years or those at or above 30 years).
CONCLUSION: Our data suggests the role of the HLA class II genes in conferring SLE susceptibility and in clinical and autoantibody expression.
Study site: SLE Clinic, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
Insulin-dependent diabetes mellitus (IDDM) is inherited in a multifactorial manner with polygenes and environmental factors contributing to its emergence in a particular individual. The evidence for such a mode of inheritance is reviewed. One of the most important genetic roles is that played by the HLA genes on chromosome 6 and the different alleles which increase or decrease susceptibility in Caucasians, Japanese, Singapore Chinese and Shanghai Chinese are described. It is inferred that these alleles are different in different ethnic groups. The other genes which are important are unknown. The environmental influences are less well known although viral infections may act as triggers. Because the morbidity and mortality are still extremely serious in IDDM patients in spite of insulin therapy, it is proposed that preventive measures should be instituted in families prone to IDDM. The role of prenatal diagnosis is discussed especially in those families with multiple HLA susceptibility genes present. Great care paid to management of hyperglycemia from onset of the disease may reduce future morbidity and mortality.