Assessment of association between HLA alleles and acquired aplastic anemia in Iranian population

2021 ◽  
Vol 18 ◽  
pp. 100075
Author(s):  
Mohammad Taheri ◽  
Mohammad Taghi Akbari ◽  
Mohammadreza Ostadali ◽  
Amir Ali Hamidieh ◽  
Hamid Fallah ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Iranian Population ◽  
Hla Alleles

HLA and Aplastic Anemia: associations In Large Brazilian Cohorts

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1237-1237
Author(s):  
Marco Aurelio Salvino ◽  
Larissa A Medeiros ◽  
Alessandro Moura ◽  
Marianna Batista ◽  
Marilda Souza Goncalves ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Aplastic Anemia ◽  
Protective Factor ◽  
Conflicts Of Interest ◽  
Hla Antigens ◽  
Hla Typing ◽  
Control Group ◽  
Hla Alleles ◽  
Northeast Region

Abstract Introduction Aplastic anemia (AA) is perceived as an immune mediated disease where T-lymphocytes recognize and destroy bone marrow elements leading to varying degrees of failure of hematopoiesis. Many autoimmune diseases have been linked to certain HLA alleles and such a relationship has been also been reported in AA. Expansion of CD8+ oligoclones has been reported in AA and likely contributes to pathogenesis. However, the interaction of CD4+ and CD8+ T cells and their targets mediated by human leukocyte antigen (HLA) class I and II peptides remain elusive. Thus, it has been speculated that polymorphic loci of these genes could be implicated in the susceptibility to the disease. Various alleles and haplotypes of HLA molecules have been implicated in the predisposition of AA development. The influence of HLA has been studied in North America, European and Asian countries. Data from Latin America, where there is a large mixture of Hispanic, European, and African descendants, is still lacking. This study focuses on the association between HLA alleles in AA patients in different regions of Brazil with particular ethnic groups. Patients and methods From 2000 to 2013, all patients with a diagnosis of acquired AA in the Brazilian state of Bahia (BA) followed at the Federal University of Bahia Hospital/ Foundation Hemoba who tested the HLA typing were included, totaling 215 patients. In this northeast region there is a predominance of African descendant (25% white, 75% brown/black). The genes in the analysis included HLA A, B, DR and DQ. SPSS was used to statistical calculations. Qui-square test/Fisher test were using the p-value correction of Bonferroni (p significant <0,0016) for comparison of genetic varieties.The HLA of patients with acquired AA Bahia (n = 215) were compared to the control group (3680 healthy non-related bone marrow volunteers donors from Bahia). To address regional differences within the country we also analyzed the HLA of AA patients (n = 344) from the State of Paraná located in the southern portion of the country and is characterized by a diverse ethnic mixture (71.3% white and 27% black/brown). Thus, we compared the findings of HLA associated with acquired AA in the two states, Bahia (northeast region) and Parana( south region). Of those statistically associated with AA (p<0,0016), we considered HLA clinically relevant only those present in at least 10% of cases and/or controls. Results From the 559 AA patients analysed, 45,1% were women, and 54.9% were men.The mean age was 23.4 (± 12.3). Among the HLA antigens with OR of risk or protection only HLA DR15 and B15, were significant, respectively (in both populations: Bahia and Parana). Identified as a risk factor for development of AA, HLA DR15 was found in 41.6% of patients (Bahia) versus 24% in controls (OR: 2.23 - CI: 1.68 to 2.9) (p <0.0001). As protective factor for AA development the HLA B15 was found in only 6% of patients (Bahia) versus 21.3% of controls (OR: 0.213, CI 0.12 to 0.370) (p <0.0001). A stratified analysis was conducted to assess the presence of interaction between the antigens DR15 and B15 in AA patients. When analyzing synergistically, the effects of HLA DR15 and B15, we observed that, in the AA group, the positivity of DR15+ of 41,6% falls significantly to 14,8%, when concurrently with the presence of B15+. The AA risk factor of HLA DR15+ loses its statistical risk power in presence of B15+. The incidence of B15+ patients (6% in AA patients) falls to 4% in the presence of DR15 negativity (p=ns). Conclusion We observed in 2 large AA cohorts (totaling 559 patients) from very distinct ethnic regions of Brazil, that, in both, HLA DR15 positivity was associated with a higher risk of disease, while B15 positivity was associated with a lesser likelihood of developing AA. The synergic combination of these alleles appears to be further associated with AA development. New studies analyzing synergic effect between HLA antigens/alleles should be conducted in immuno-mediated diseases. Disclosures: No relevant conflicts of interest to declare.

Improved Outcome of Unrelated Bone Marrow Transplantation for Severe Aplastic Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3053-3053
Author(s):  
Hiroshi Yagasaki ◽  
Seiji Kojima ◽  
Hiromasa Yabe ◽  
Koji Kato ◽  
Hisato Kigasawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Age Distribution ◽  
Significant Risk ◽  
Severe Aplastic Anemia ◽  
Hla Matching ◽  
Hla Alleles ◽  
Gvhd Prophylaxis ◽  
C 32

Abstract In Japan, unrelated bone marrow transplantations (U-BMT) for severe aplastic anemia (SAA) were first performed in 1993. Transplant regimens and patient selection have changed substantially since then. We aimed to determine the effect of these changes on transplant outcome. We retrospectively analyzed the outcome in patients with SAA who received U-BMT through the Japan Marrow Donor Program between 1993 and 2005. We selected 302 recipient-donor pairs in which molecular analysis of HLA-A, -B, -C, -DRB1, and DQB1 were performed. Patient ages ranged from 1 to 64 years (median, 17 years). Various preconditioning regimens were used by individual centers. Either tacrolimus with methotrexate or cyclosporine with methotrexate was used for the prophylaxis against graft-versus-host disease (GVHD) in 137 (45%) patients and 127 patients (42%), respectively. Of the 302 pairs, 104 (34%) were found to be matched at HLA-A, -B, -C, -DRB1, and DQB1; 97 (32%) were mismatched at a single HLA allele (23 HLA-A or -B, 42 HLA-C, 32 HLA-DRB1 or HLA-DQB1); 83 (28%) were mismatched at two HLA alleles (35 HLA-A or -B and HLA-C, 8 HLA-A or -B and HLA-DRB1 or -DQB1, 40 HLA-C and HLA-DRB1 or -DQB1); and 18 (6%) were mismatched at three HLA alleles. Currently, 210 of the 302 patients are alive with the median follow-up period of 722 days after transplantation. The incidence of graft failure was 2.2%; that of grade II/IV GVHD was 29.0%; that of III/IV acute GVHD was 13.8%; and that of chronic GVHD was 25.2%. Multivariate analysis revealed the following significant risk factors for survival: patients older than 15 years (RR, 1.98; range 1.17–3.35); HLA-A or -B + HLA-C or HLA-DQB1 or -DRB1 (RR 2.18; range 1.29–3.68); three loci mismatching (RR 3.14; range 1.47–6.69); prophylaxis against GVHD with tacrolimus with methotrexate (RR 0.45; range 0.28–0.73), ABO major mismatch (RR 1.67; range 1.05–2.63), and non-ATG-containing CY+TBI regimen (RR 2.17; range 1.16–4.03). Patients were divided into two cohorts based on years of transplantation and we compared patients transplanted within two time periods: 1993–2000 and 2001–2005. Five-year survival increased 55.9+/−4.6% in the 1993–2000 cohort (n=116) and 72.7+/−3.8% in the 2001–2005 cohort (n=186) (p=0.008). Patients and transplant characteristics that differed significantly between the two periods were patients’ age distribution, GVHD prophylaxis, HLA matching, and conditioning regimens. The percentage of patients older than 15 years was significantly larger in the recent period (p<0.001). However, the use of cyclosporine and non-ATG-containing CY+TBI regimen were more frequent in the earlier period (p<0.001). HLA-mismatching between patients and donors was more frequent in 1993–2000 (p<0.001). In conclusion, U-BMT for SAA has improved significantly in the recent 5-years period. Improved HLA matching, avoiding non-ATG-containing CY+TBI regimen, and the use of tacrolimus for GVHD prophylaxis account for this improvement.

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3513-3519 ◽  
Author(s):  
Jaroslaw P. Maciejewski ◽  
Dean Follmann ◽  
Ryotaro Nakamura ◽  
Yogen Saunthararajah ◽  
Candido E. Rivera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Normal Incidence ◽  
Primary Diagnosis ◽  
Hla Alleles ◽  
Predictors Of Response ◽  
Pnh Clone

Abstract Many autoimmune diseases are associated with HLA alleles, and such a relationship also has been reported for aplastic anemia (AA). AA and paroxysmal nocturnal hemoglobinuria (PNH) are related clinically, and glycophosphoinositol (GPI)–anchored protein (AP)–deficient cells can be found in many patients with AA. The hypothesis was considered that expansion of a PNH clone may be a marker of immune-mediated disease and its association with HLA alleles was examined. The study involved patients with a primary diagnosis of AA, patients with myelodysplastic syndrome (MDS), and patients with primary PNH. Tests of proportions were used to compare allelic frequencies. For patients with a PNH clone (defined by the presence of GPI-AP–deficient granulocytes), regardless of clinical manifestations, there was a higher than normal incidence of HLA-DR2 (58% versus 28%; z = 4.05). The increased presence of HLA-DR2 was found in all frankly hemolytic PNH and in PNH associated with bone marrow failure (AA/PNH and MDS/PNH). HLA-DR2 was more frequent in AA/PNH (56%) than in AA without a PNH clone (37%;z = 3.36). Analysis of a second cohort of patients with bone marrow failure treated with immunosuppression showed that HLA-DR2 was associated with a hematologic response (50% of responders versus 34% of nonresponders; z = 2.69). Both the presence of HLA-DR2 and the PNH clone were independent predictors of response but the size of PNH clone did not correlate with improvement in blood count. The results suggest that clonal expansion of GPI-AP–deficient cells is linked to HLA and likely related to an immune mechanism.

Immunologically-Selected Hematopoiesis Caused by HLA Allelic Loss In Patients with Aplastic Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 198-198
Author(s):  
Takamasa Katagiri ◽  
Aiko Matsubara ◽  
Koichi Kashiwase ◽  
Motohiro Kato ◽  
Yasuo Morishima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Aplastic Anemia ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
Class I ◽  
Allelic Loss ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Hla Alleles

Abstract Abstract 198 Background: Idiopathic aplastic anemia (AA) is a syndrome characterized by pancytopenia and bone marrow (BM) hypoplasia, which are caused by the auto-immune destruction of hematopoietic stem cells (HSCs). However, little is known about the nature of HSCs that survive the occurrence of autoimmune insults and maintain hematopoiesis both during and after aplastic diathesis. While the severity of the autoimmunity is the major determinant of BM failure in patients with AA, some intrinsic genetic changes in HSCs could also be involved in the disease process, since the clonality of the residual, persistent hematopoiesis under the aplastic state has been well recognized. Objectives/Methods: To characterize the nature of the HSCs that support hematopoiesis in AA, peripheral blood (PB) specimens obtained from 317 patients with AA were subjected to the genome-wide analysis of genetic lesions using Affymetrix® 500K SNP arrays. For the normal controls, 1746 PB specimens from the Japan Marrow Donation Program (JMDP) were also analyzed. All specimens were genotyped for HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles. In the eligible cases, PB leukocytes and CD34+ BM cells were also examined to determine their expression of HLA-A antigens using allele-specific monoclonal antibodies by flow cytometry (FCM). To identity the common HLA types associated with AA, a total of 6,629 registries from JMDP who had received allogeneic bone marrow transplantation between 1992 and 2008 were employed, where the HLA frequencies in AA (N=406) were compared with those among other hematopoietic disorders, in acute myeloid leukemia (N=1,822), acute lymphocytic leukemia (N=1,406), chronic myeloid leukemia (N=1,014), myelodysplastic syndromes (N=824), non-Hodgkin's lymphoma (N=565), and other neoplastic disorders (N=392). Results: A number of genetic alterations were detected in our AA case series, among which the most conspicuous was acquired uniparental disomy (UPD), or the copy number-neutral loss of heterozygosity, involving the 6p arms (6pUPD). The 6pUPD was identified in 38 patients (12%) but not in any JMDP donor specimens, and it commonly affected the HLA locus, which was expected to result in the loss of one HLA haplotype. In fact, loss of HLA-A expression from the missing haplotype was confirmed by FCM in all 13 6pUPD-positive cases thus far tested, whereas the HLA-A expression from both haplotypes was preserved in the 58 samples without 6pUPD. The loss of HLA-A expression in the 6pUPD-positive cases was found in multiple lineages of leukocytes, including granulocytes, monocytes, B cells, BM CD34+ cells, and to a lesser extent in T cells. Of particular interest was the fact that the missing HLA haplotypes that were predicted from the SNP array data were extremely biased to particular class I HLA alleles, including HLA-A*02:01, HLA-A*02:06, A*31:01, B*40:02, and B*40:06. Moreover, when the frequencies of these alleles were compared among the 6,629 JMDP registries, they were shown to be strongly associated with AA in comparison to other non-significant HLA alleles, where the odds ratios for these alleles with regard to non-significant alleles as for the risk of the development of AA were 2.00 (95%CI; 1.52 – 2.62) for A*02:01, 2.37 (95%CI; 1.80 – 3.12) for A*02:06, 1.46 (95%CI; 1.06 – 2.02) for A*31:01, 2.07 (1.56 - 2.77) for B*40:02, and 2.67 (1.95 - 3.66) for B*40:06. Conclusions: AA patients frequently show permissive hematopoiesis with 6pUPD, which is thought to develop due to the occurrence of auto-immune insult based on the Darwinian principle of “survival of the fittest” (Figure). The tight association of AA with particular class I antigens that are invariably missing in permissive hematopoiesis with 6pUPD strongly supports the hypothesis that the auto-immunity responsible for AA is primarily mediated by cytotoxic T cells which target a relatively limited species of auto-antigens presented on HSCs through these relevant HLAs. Our findings therefore also provide a solid basis for isolating the target auto-antigens responsible for the development of AA in the future studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Somatic Loss of HLA Class I Alleles Is a Common Genetic Alteration in Acquired Aplastic Anemia and Reveals Aplastic Anemia Risk Alleles

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 730-730 ◽  
Author(s):  
Daria V. Babushok ◽  
Jamie Duke ◽  
Hongbo M. Xie ◽  
Deborah Ferriola ◽  
Natasha Stanley ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Somatic Mutations ◽  
Hla Class I ◽  
Median Number ◽  
Class I ◽  
Loss Of Function ◽  
Immune Selection ◽  
Hla Alleles ◽  
Hla Loss ◽  
Pediatric Onset

Abstract Acquired aplastic anemia (AA) is a rare bone marrow failure syndrome. AA is believed to be immune-mediated, supported by in vitro studies and the success of empiric immunosuppressive therapy. Recently, a chromosomal alteration-copy number-neutral loss of heterozygosity of chromosome arm 6p, the site of the Major Histocompatibility Complex and the Human Leukocyte Antigen (HLA) genes-has been identified as a recurrent somatic change in AA. Clonal hematopoiesis marked by 6p CN-LOH is hypothesized to emerge by immune escape of hematopoietic cells lacking certain HLA alleles. However, because of the large size of the genomic region involved by 6p CN-LOH and the strong linkage disequilibrium among other genes in the region, specific alleles targeted by the immune selection in AA are unknown. In a previous study, we reported two patients with somatic loss-of-function mutations in HLA class I genes, leading us to hypothesize that loss of HLA alleles in AA may be common and likely defines a subset of patients with unique characteristics and disease course. To characterize the prevalence of HLA allele loss in AA, we performed targeted next generation sequencing of HLA-A, B, and C genes, in conjunction with single nucleotide polymorphism array genotyping of bone marrow (BM) or peripheral blood DNA in 74 patients with AA. 52 patients had pediatric-onset AA, and 22 had adult-onset AA. Somatic status of mutations was confirmed by sequencing paired constitutional DNA. Eleven patients (15%) were found to have somatic loss of HLA alleles: 5 patients had 6p CN-LOH, 3 patients had loss-of-function mutations (frameshift, nonsense, or start codon loss) of the HLA class I alleles, and 3 patients were found to have both 6p CN-LOH as well as loss-of-function HLA mutations. HLA loss was more frequent in pediatric-onset AA (9 of 52 patients, 17%) as compared to adults (2 of 22 patients, 9%), although the difference did not reach statistical significance. No HLA mutations were identified in 19 patients with classical Paroxysmal Nocturnal Hemoglobinuria, nor in 20 healthy relatives (p=0.06). Among the 11 patients with somatic HLA loss, 8 patients had evidence of oligoclonal hematopoiesis with several independent clones carrying different alterations of the same HLA allele. Among the 6 patients with loss-of-of function HLA mutations, the median number of HLA mutations per patient was 1.5 (range 1-3). Of the 8 patients with acquired 6p CN-LOH, the median number of distinct 6p CN-LOH events per patient was 2 (range 1-4). In the 3 patients harboring both 6p CN-LOH as well as the loss-of-function HLA mutations, both mechanisms led to the recurrent loss of the same allele. Strikingly, only a few distinct HLA class I alleles were targeted by mutations. The most frequently affected were HLA-B*40:02:01 (5 independent mutations in 2 patients) and HLA-B*14:02:01 (3 mutations in 2 patients, and as well as loss through polyclonal 6p CN-LOH in 2 patients). Additionally, one patient each had loss of HLA-A*68:01:01 and HLA-A*33:03:01 through mutational inactivation as well as through 6p CN-LOH. To investigate whether HLA mutations are sufficient to cause clonal expansion or whether other somatic mutations are required, we performed comparative whole exome sequencing (WES) of paired BM and skin DNA in five patients carrying inactivating HLA mutations. Four of the five patients had no other mutations affecting protein sequence or untranslated regulatory regions. One patient had additional somatic mutations, which were subclonal to and co-segregated with the three independent inactivating mutations in the HLA-B*40:02:01 allele. Serial follow-up confirmed that HLA mutations persisted overtime, with a relative expansion of one of the HLA-B*40:02:01 mutant clones bearing a protein-altering mutation in the BCL9 gene. Our results show that loss of HLA class I alleles is common in AA, second only to PIGA gene mutations. The affected alleles are non-random, with immune selection most commonly targeting HLA-B* 40:02:01 and HLA-B*14:02:01 alleles, providing the first evidence of specificity of immune attack in AA. The resultant hematopoiesis caused by selection of cells with HLA allele loss is typically oligoclonal and commonly occurs in the absence of other somatic mutations. Acquisition of additional mutations can lead to clonal dominance overtime. Further studies are underway to better understand the role of HLA loss in patient outcomes and AA pathogenesis. Disclosures No relevant conflicts of interest to declare.

Evidence That HLA-B*40:02 and HLA-Α*31:01 Are Strongly Involved in the Presentation of Autoantigens to CTLs Responsible for the Development of Acquired Aplastic Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2948-2948
Author(s):  
Yoshitaka Zaimoku ◽  
Hiroyuki Maruyama ◽  
Kana Maruyama ◽  
Takamasa Katagiri ◽  
An T. T. Dao ◽  
...  
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Nk Cells ◽  
Conflicts Of Interest ◽  
Neutral Loss ◽  
The Other ◽  
Class I ◽  
Allelic Loss ◽  
Hla Alleles ◽  
Allele Specific

Abstract The presence of leukocytes lacking one haplotype of the human leukocyte antigen (HLA) gene as a result of copy-neutral loss of heterozygosity of chromosome 6p (6pLOH) is compelling evidence that cytotoxic T cells (CTLs) have a key role in the development of acquired aplastic anemia (AA). Pathogenic auto-antigens are presumed to be presented by particular HLAs, such as HLA-B*40:02, HLA-A*31:01, HLA-A*02:01 and HLA-A*02:06, all of which are frequently lost due to 6pLOH (Katarigi, Blood 2011). However, this presumption may be incorrect, because the frequency of lacking haplotypes that contain KIR-ligands (KIR-Ls), such as HLA-A*24:02 and HLA-B*52:01, the most frequent alleles of HLA-A and HLA-B, may be underestimated as a result of the killing of 6pLOH(+) leukocytes by NK cells. Indeed, all four frequently missing HLA alleles are non-KIR-Ls. To address these issues, we conducted a mass screening of 6pLOH(+) leukocytes in newly diagnosed AA patients using an assay that allows us to detect 6pLOH(+) cells within one day, and reanalyzed haplotypes that are likely to be lost. The HLA-B and –C allele-specific duplex real time PCR (2qPCR) that we established compared the copy number of heterozygous HLA alleles in a single reaction mixture using two allele-specific TaqMan probes labeled with two different fluorochromes (VIC and FAM) and one primer pair complementary to consensus sequences, which allowed us to detect as small as 5% 6pLOH(+) leukocytes in the total leukocytes. The HLA haplotypes of 6pLOH(+) patients were determined based on the HLA-A antigen expression as demonstrated by flow cytometry and the HLA-B and -C allele data from the 2qPCR, in combination with the haplotype database of the Japanese population available in the HLA laboratory website. A total of 498 patients with AA were subjected to this analysis and 60 6pLOH(+) patients, including 39 6pLOH(+) patients that had been identified by our previous study were used in this analysis. The allelic loss frequencies of HLA-B*40:02 (25%, 33/132) and HLA-A*31:01 (19%, 14/75) were markedly higher than those of the other HLA-B (2.9%, 24/814, P = 7x10-16) and HLA-A (4.9%, 36/731, P = 0.002) alleles, while the frequencies of HLA-A*02:01 (11%, 11/99) and HLA-A*02:06 (11%, 11/99) were similar to those of the other HLA-A alleles. In 41 6pLOH(+) patients possessing either HLA-B*40:02 or HLA-A*31:01, these alleles were all contained in the missing haplotype. On the other hand, four of the 15 patients with HLA-A*02:01(+) haplotypes and two of the 13 patients with HLA-A*02:06(+) haplotypes had these alleles in the retained haplotype. The 6pLOH(+) patients could be divided into three groups according to the status of KIR-Ls (HLA-Bw4 and HLA-C1/C2) of their haplotype; A, the lack of the KIR-L does not occur when either of the two haplotypes is lost; B, the lack of KIR-L occurs when one specific haplotypes is lost; C, the lack of KIR-L occurs when either haplotype is lost. These groups comprised 42%, 53% and 5% of the total. The proportion of group C was much lower than that expected in the general population (16%) and only five (16%) of the 31 group B patients lacked KIR-Ls, thus suggesting that NK cells had an effect on the appearance of 6pLOH(+) leukocytes in AA patients. However, the very high frequency of HLA-loss in the HLA-B*40:02 and HLA-A*31:01 alleles could not be explained by the absence of KIR-Ls in the missing haplotype. Of particular note, the lack of KIR-Ls occurred in eight patients as a result of 6pLOH; six of the eight lost a haplotype containing HLA-B*40:02 and one lost an A*31:01-containing haplotype, suggesting that CTLs specific for autoantigens presented by these class I alleles more dominantly inhibit HSCs than NK cells. Together, these results indicate that HLA-B*40:02 and HLA-A*31:01 have particularly important roles in the presentation of autoantigens to T cells in AA. Studies of T-cell responses to autoantigens restricted by these class I alleles are thus warranted. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6601-6609 ◽  
Author(s):  
Takamasa Katagiri ◽  
Aiko Sato-Otsubo ◽  
Koichi Kashiwase ◽  
Satoko Morishima ◽  
Yusuke Sato ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Copy Number ◽  
Large Scale ◽  
Genetic Basis ◽  
Cytotoxic T Cells ◽  
Neutral Loss ◽  
Epidemiologic Study ◽  
Hematopoietic Progenitors ◽  
Hla Alleles ◽  
Insight Into

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.

scholarly journals HLA-DR Association in Papillary Thyroid Carcinoma

2010 ◽  
Vol 28 (1) ◽  
pp. 49-53 ◽  
Author(s):  
Mahsa M. Amoli ◽  
Nasrin Yazdani ◽  
Parvin Amiri ◽  
Forogh Sayahzadeh ◽  
Vahid Haghpanah ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Human Leukocyte ◽  
Iranian Population ◽  
Papillary Thyroid ◽  
Predisposing Factor ◽  
Hla Alleles ◽  
Leukocyte Antigens ◽  
Hla Dr ◽  
Thyroid Malignancies

Objective:Papillary thyroid carcinoma (PTC) is the most frequent types of thyroid malignancies. Several genes may be involved in susceptibility of thyroid cancer including Human Leukocyte Antigens (HLA). The association of thyroid carcinoma with HLA alleles has been previously studied in other populations and certain HLA alleles were shown to be either predisposing or protective. The aim of this study was to determine the association between HLA-DR and papillary thyroid carcinoma in an Iranian population.Design:HLA-DR antigen frequencies were determined in patients with papillary thyroid carcinoma (N = 70) and non-related healthy controls (N=180) using PCR -SSP.Main Outcome:We found that HLA-DRB1*04 frequency was significantly higher in our patients compared to the controls [P= 0.02, OR; 1.9, 95% CI (1.04–3.57)].Conclusions:Our results revealed HLA-DRB1*04 as predisposing factor in papillary thyroid carcinoma in Iranian population. This confirms the previous findings for associations between HLA-DRB1 and differentiated carcinomas in other populations.

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