Association of HLA class II (-DRB1,-DQB1,-DPB1) alleles and haplotypes on susceptibility to aplastic anemia in northern Chinese Han

Qi, Jun; Wang, Tianju; Li, Hengxin; Wu, Di; Du, Dan; Wu, Junhua; Shang, L. Q.; Le, Chen; Wang, Man-Ni; Wang, Xiaofang

doi:10.1016/j.humimm.2020.07.001

Cited by 11 publications

(17 citation statements)

References 38 publications

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“…The immune pathophysiology of AA has been, in part, inferred from frequent somatic loss of HLA class I alleles. Increased frequency of some HLA alleles has been reported in AA patients of various ethnicities, [3][4][5][6][7][8][9][10][11][12][13][14] and has been confirmed in a recent genome-wide association study. 15 Somatic loss of HLA class I alleles may result from copy-neutral chromosome 6p loss of heterozygosity (6p LOH) 11,16,17 or acquired inactivating HLA gene mutations.…”

Section: Introductionmentioning

confidence: 96%

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

Zaimoku

Patel

Adams

et al. 2021

Blood

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Immune aplastic anemia (AA) features somatic loss of HLA class I allele expression on bone marrow cells, consistent with a mechanism of escape from T cell-mediated destruction of hematopoietic stem and progenitor cells. The clinical significance of HLA abnormalities has not been well characterized. We examined somatic loss of HLA class I alleles, and correlated HLA loss and mutation-associated HLA genotypes with clinical presentation and outcomes after immunosuppressive therapy in 544 AA patients. HLA class I allele loss was detected in 92 (22%) of the 412 patients tested, in whom there were 393 somatic HLA gene mutations and 40 instances of loss of heterozygosity. Most frequently affected was HLA-B*14:02, followed by HLA-A*02:01, HLA-B*40:02, HLA-B*08:01, and HLA-B*07:02. HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 were also overrepresented in AA. High-risk clonal evolution was correlated with HLA loss, HLA-B*14:02 genotype, and older age, which yielded a valid prediction model. In two patients, we traced monosomy 7 clonal evolution from preexisting clones harboring somatic mutations in HLA-A*02:01 and HLA-B*40:02. Loss of HLA-B*40:02 correlated with higher blood counts. HLA-B*07:02 and HLA-B*40:01 genotypes and their loss correlated with late onset of AA. Our results suggest the presence of specific immune mechanisms of molecular pathogenesis with clinical implications. HLA genotyping and screening for HLA loss may be of value in the management of immune AA. This study was registered at clinicaltrials.gov as NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167.

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Section: Introductionmentioning

confidence: 96%

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

Zaimoku

Patel

Adams

et al. 2021

Blood

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“…We also checked for the presence of reported AA-susceptible HLA (n = 10, encompassing Cases 1–2, 4, 6–12) ( Table 2 ) or non- HLA (n = 6) variants. Notably, AA-risky alleles of HLA-A *02, HLA-DRB1 including *15 and *15:01 , and HLA-DQB1*06:02 were present in six of the ten patients we analyzed [ 22 , 23 ] ( Table 2 ). An AA-susceptible SNP (rs1042151 A > G, encoding HLA-DPB1 Val76) reportedly associated with an increased risk of AA solely among Europeans [ 23 , 24 ] was not identified among our patient cohort.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, AA-risky alleles of HLA-A *02, HLA-DRB1 including *15 and *15:01 , and HLA-DQB1*06:02 were present in six of the ten patients we analyzed [ 22 , 23 ] ( Table 2 ). An AA-susceptible SNP (rs1042151 A > G, encoding HLA-DPB1 Val76) reportedly associated with an increased risk of AA solely among Europeans [ 23 , 24 ] was not identified among our patient cohort. However, we did identify HLA-DRB1*03:01/*13:01 (Case 11) and *14 (Case 4), which are reportedly protective against AA [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

Anti-Thymocyte Globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-Transplantation Cyclophosphamide Is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia

Chen

Shaw

et al. 2022

IJMS

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Most cases of acquired aplastic anemia (AA) arise from autoimmune destruction of hematopoietic stem and progenitor cells. Human leukocyte antigen (HLA)-haploidentical nonmyeloablative hematopoietic stem cell transplantation (HSCT) plus post-transplantation cyclophosphamide (PTCy) is increasingly applied to salvage AA using bone marrow as graft and anti-thymocyte globulin (ATG) in conditioning. Herein, we characterize a cohort of twelve AA patients clinically and molecularly, six who possessed other immunological disorders (including two also carrying germline SAMD9L mutations). Each patient with SAMD9L mutation also carried an AA-related rare BCORL1 variant or CTLA4 p.T17A GG genotype, respectively, and both presented short telomere lengths. Six of the ten patients analyzed harbored AA-risky HLA polymorphisms. All patients recovered upon non-HSCT (n = 4) or HSCT (n = 8) treatments. Six of the eight HSCT-treated patients were subjected to a modified PTCy-based regimen involving freshly prepared peripheral blood stem cells (PBSC) as graft and exclusion of ATG. All patients were engrafted between post-transplantation days +13 and +18 and quickly reverted to normal life, displaying a sustained complete hematologic response and an absence of graft-versus-host disease. These outcomes indicate most AA cases, including of the SAMD9L-inherited subtype, are immune-mediated and the modified PTCy-based regimen we present is efficient and safe for salvage.

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“…Therefore, HLA genotyping probably has a particular predictive value for the response to IST and the risk of clonal evolution. However, the polymorphisms of HLA alleles are distinct in different ethnic groups (6,(14)(15)(16)(17)(18), and there are few related studies in the Chinese population. This study aimed to investigate the association of HLAclass I and HLA-class II alleles with the response to IST and the risk of clonal evolution in Chinese patients.…”

Section: Introductionmentioning

confidence: 99%

Association between human leukocyte antigen and immunosuppressive treatment outcomes in Chinese patients with aplastic anemia

Chen

Huo

et al. 2023

Front. Immunol.

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BackgroundActivated cytotoxic T cells (CTLs) recognize the auto-antigens presented on hematopoietic stem/progenitor cells (HSPCs) through class I human leukocyte antigen (HLA) molecules and play an important role in the immune pathogenesis of aplastic anemia (AA). Previous reports demonstrated that HLA was related to the disease susceptibility and response to immunosuppressive therapy (IST) in AA patients. Recent studies have indicated that specific HLA allele deletions, which helped AA patients to evade CTL-driven autoimmune responses and escape from immune surveillance, may lead to high-risk clonal evolution. Therefore, HLA genotyping has a particular predictive value for the response to IST and the risk of clonal evolution. However, there are limited studies on this topic in the Chinese population.MethodsTo explore the value of HLA genotyping in Chinese patients with AA, 95 AA patients treated with IST were retrospectively investigated.ResultsThe alleles HLA-B*15:18 and HLA-C*04:01 were associated with a superior long-term response to IST (P = 0.025; P = 0.027, respectively), while the allele HLA-B*40:01 indicated an inferior result (P = 0.02). The allele HLA-A*01:01 and HLA-B*54:01 were associated with high-risk clonal evolution (P = 0.032; P = 0.01, respectively), and the former had a higher frequency in very severe AA (VSAA) patients than that in severe AA (SAA) patients (12.7% vs 0%, P = 0.02). The HLA-DQ*03:03 and HLA-DR*09:01 alleles were associated with high-risk clonal evolution and poor long-term survival in patients aged ≥40 years. Such patients may be recommended for early allogeneic hematopoietic stem cell transplantation rather than the routine IST treatment.ConclusionHLA genotype has crucial value in predicting the outcome of IST and long-term survival in AA patients, and thus may assist an individualized treatment strategy.

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Association of HLA class II (-DRB1,-DQB1,-DPB1) alleles and haplotypes on susceptibility to aplastic anemia in northern Chinese Han

Cited by 11 publications

References 38 publications

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia

Anti-Thymocyte Globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-Transplantation Cyclophosphamide Is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia

Association between human leukocyte antigen and immunosuppressive treatment outcomes in Chinese patients with aplastic anemia

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