ACQUIRED HLA-B*40:02 MUTATION LEADING TO FRAME SHIFT IN IDIOPATHIC APLASTIC ANEMIA
(Abstract release date: 05/19/16)
EHA Library. Huh J. 06/09/16; 134662; PB1762
Prof. Jungwon Huh
Contributions
Contributions
Abstract
Abstract: PB1762
Type: Publication Only
Background
Idiopathic aplastic anemia(AA) has been reported to be associated with autoimmunity to hematopoietic stem/progenitor cells (HSPCs). Specific human leukocyte antigen (HLA) alleles are the target antigens of autoreactive cytotoxic T cells (CTL). One study reported that Japanese patients with idiopathic AA typically inherited only those four HLA alleles such as HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. (Katagiri et al, 2011).AA acquired copy number neutral loss of heterozygosity of the 6p arms (6p CN-LOH), leading to loss of one HLA haplotype. Moreover, the missing haplotype was concentrated in the same particular alleles : HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. Therefore, 6p CN-LOH may arise from selective pressure to escape from autoreactive CTL through loss of HLA alleles.In the other hand, nonsense mutation in HLA-B*40:02 (CAG to TAG) at codon 54 in exon 2 of HLA-B*40:02 with no involvement of 6p CN-LOH in a case with AA was first reported by Osumi T et al (Br J Haematol 2013:162:706).
Aims
In this study, we report a patient with idiopathic AA who acquired a mutation in HLA-B*40:02 allele (4 nucleotide deletion, leading frame shift). Our case is the second report of HLA-B*40:02 mutation, to our best knowledge.
Methods
HLA high resolution typing was performed by sequence based typing (Biowithus HLA PCR-SBT, Korea).
Results
A 54-year-old man was diagnosed with severe acquired AA with normal karyotype. Although he received immunosuppressive therapy (cyclosporine and anti-thymocyte globulin) for 8 months, he didn’t achieve remission and regular blood transfusions and G-CSF had been required. Therefore, stem cell transplantation was scheduled. His HLA results identified by high resolution sequencing based typing in a peripheral blood sample was HLA-A*26:01, HLA-A*33:03, HLA-C*03:04, HLA-C*07:01, HLA-DRB1:07:01, HLA-DRB1:15:01, HLA-DQB1:02:02, HLA-DQB1:06:02. However, HLA-B could not be easily typed by sequencing based typing. To resolve the problem, we performed the low resolution HLA typing using SSP(sequence-specific primer) method and the result showed HLA-B*40 and HLA-B*44. Furthermore, HLA-B type of one sibling having HLA-A, HLA-C and HLA-DRB1 matching was HLA-B*40, HLA-B*44. We reanalyzed HLA-B high resolution typing using DNA from patient’s buccal epithelial cells, patient’s peripheral blood and the sibling’s peripheral blood. The HLA-B typing of patient’s buccal epithelial cells and the sibling’s blood showed the same results : HLA-B*40:02, HLA-B*44:03. By a closer examination of sequence electropherogram of patient’s peripheral blood, we identified that that 4 nucleotides (ACAC deletion) were deleted between codon 187 and 188 in exon 4 of HLA-B*40:02, leading to a frame shift. The mosaicism of wild type and mutant HLA-B*40:02 alleles was restricted to patient’s blood cells, not buccal epithelial cells.
Conclusion
Acquisition of mutation could not be an accidental event, but is caused by immunological escape and selection, because HLA-B*40:02 is a possible target antigen of T cells in idiopathic AA. Activated CTLs might kill HSPCs that expressed HLA-B:40:02, whereas HSPCs carrying the mutation might survive with a growth advantage over other HSPCs expressing HLA-B:40:02.Our case suggests that mutation (ACAC deletion) of HLA-B:40:02 could be a possible mechanism to restore hematopoiesis via immune escape with no involvement of 6pLOH.
Session topic: E-poster
Keyword(s): Aplastic anemia, HLA, Mutation
Type: Publication Only
Background
Idiopathic aplastic anemia(AA) has been reported to be associated with autoimmunity to hematopoietic stem/progenitor cells (HSPCs). Specific human leukocyte antigen (HLA) alleles are the target antigens of autoreactive cytotoxic T cells (CTL). One study reported that Japanese patients with idiopathic AA typically inherited only those four HLA alleles such as HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. (Katagiri et al, 2011).AA acquired copy number neutral loss of heterozygosity of the 6p arms (6p CN-LOH), leading to loss of one HLA haplotype. Moreover, the missing haplotype was concentrated in the same particular alleles : HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. Therefore, 6p CN-LOH may arise from selective pressure to escape from autoreactive CTL through loss of HLA alleles.In the other hand, nonsense mutation in HLA-B*40:02 (CAG to TAG) at codon 54 in exon 2 of HLA-B*40:02 with no involvement of 6p CN-LOH in a case with AA was first reported by Osumi T et al (Br J Haematol 2013:162:706).
Aims
In this study, we report a patient with idiopathic AA who acquired a mutation in HLA-B*40:02 allele (4 nucleotide deletion, leading frame shift). Our case is the second report of HLA-B*40:02 mutation, to our best knowledge.
Methods
HLA high resolution typing was performed by sequence based typing (Biowithus HLA PCR-SBT, Korea).
Results
A 54-year-old man was diagnosed with severe acquired AA with normal karyotype. Although he received immunosuppressive therapy (cyclosporine and anti-thymocyte globulin) for 8 months, he didn’t achieve remission and regular blood transfusions and G-CSF had been required. Therefore, stem cell transplantation was scheduled. His HLA results identified by high resolution sequencing based typing in a peripheral blood sample was HLA-A*26:01, HLA-A*33:03, HLA-C*03:04, HLA-C*07:01, HLA-DRB1:07:01, HLA-DRB1:15:01, HLA-DQB1:02:02, HLA-DQB1:06:02. However, HLA-B could not be easily typed by sequencing based typing. To resolve the problem, we performed the low resolution HLA typing using SSP(sequence-specific primer) method and the result showed HLA-B*40 and HLA-B*44. Furthermore, HLA-B type of one sibling having HLA-A, HLA-C and HLA-DRB1 matching was HLA-B*40, HLA-B*44. We reanalyzed HLA-B high resolution typing using DNA from patient’s buccal epithelial cells, patient’s peripheral blood and the sibling’s peripheral blood. The HLA-B typing of patient’s buccal epithelial cells and the sibling’s blood showed the same results : HLA-B*40:02, HLA-B*44:03. By a closer examination of sequence electropherogram of patient’s peripheral blood, we identified that that 4 nucleotides (ACAC deletion) were deleted between codon 187 and 188 in exon 4 of HLA-B*40:02, leading to a frame shift. The mosaicism of wild type and mutant HLA-B*40:02 alleles was restricted to patient’s blood cells, not buccal epithelial cells.
Conclusion
Acquisition of mutation could not be an accidental event, but is caused by immunological escape and selection, because HLA-B*40:02 is a possible target antigen of T cells in idiopathic AA. Activated CTLs might kill HSPCs that expressed HLA-B:40:02, whereas HSPCs carrying the mutation might survive with a growth advantage over other HSPCs expressing HLA-B:40:02.Our case suggests that mutation (ACAC deletion) of HLA-B:40:02 could be a possible mechanism to restore hematopoiesis via immune escape with no involvement of 6pLOH.
Session topic: E-poster
Keyword(s): Aplastic anemia, HLA, Mutation
Abstract: PB1762
Type: Publication Only
Background
Idiopathic aplastic anemia(AA) has been reported to be associated with autoimmunity to hematopoietic stem/progenitor cells (HSPCs). Specific human leukocyte antigen (HLA) alleles are the target antigens of autoreactive cytotoxic T cells (CTL). One study reported that Japanese patients with idiopathic AA typically inherited only those four HLA alleles such as HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. (Katagiri et al, 2011).AA acquired copy number neutral loss of heterozygosity of the 6p arms (6p CN-LOH), leading to loss of one HLA haplotype. Moreover, the missing haplotype was concentrated in the same particular alleles : HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. Therefore, 6p CN-LOH may arise from selective pressure to escape from autoreactive CTL through loss of HLA alleles.In the other hand, nonsense mutation in HLA-B*40:02 (CAG to TAG) at codon 54 in exon 2 of HLA-B*40:02 with no involvement of 6p CN-LOH in a case with AA was first reported by Osumi T et al (Br J Haematol 2013:162:706).
Aims
In this study, we report a patient with idiopathic AA who acquired a mutation in HLA-B*40:02 allele (4 nucleotide deletion, leading frame shift). Our case is the second report of HLA-B*40:02 mutation, to our best knowledge.
Methods
HLA high resolution typing was performed by sequence based typing (Biowithus HLA PCR-SBT, Korea).
Results
A 54-year-old man was diagnosed with severe acquired AA with normal karyotype. Although he received immunosuppressive therapy (cyclosporine and anti-thymocyte globulin) for 8 months, he didn’t achieve remission and regular blood transfusions and G-CSF had been required. Therefore, stem cell transplantation was scheduled. His HLA results identified by high resolution sequencing based typing in a peripheral blood sample was HLA-A*26:01, HLA-A*33:03, HLA-C*03:04, HLA-C*07:01, HLA-DRB1:07:01, HLA-DRB1:15:01, HLA-DQB1:02:02, HLA-DQB1:06:02. However, HLA-B could not be easily typed by sequencing based typing. To resolve the problem, we performed the low resolution HLA typing using SSP(sequence-specific primer) method and the result showed HLA-B*40 and HLA-B*44. Furthermore, HLA-B type of one sibling having HLA-A, HLA-C and HLA-DRB1 matching was HLA-B*40, HLA-B*44. We reanalyzed HLA-B high resolution typing using DNA from patient’s buccal epithelial cells, patient’s peripheral blood and the sibling’s peripheral blood. The HLA-B typing of patient’s buccal epithelial cells and the sibling’s blood showed the same results : HLA-B*40:02, HLA-B*44:03. By a closer examination of sequence electropherogram of patient’s peripheral blood, we identified that that 4 nucleotides (ACAC deletion) were deleted between codon 187 and 188 in exon 4 of HLA-B*40:02, leading to a frame shift. The mosaicism of wild type and mutant HLA-B*40:02 alleles was restricted to patient’s blood cells, not buccal epithelial cells.
Conclusion
Acquisition of mutation could not be an accidental event, but is caused by immunological escape and selection, because HLA-B*40:02 is a possible target antigen of T cells in idiopathic AA. Activated CTLs might kill HSPCs that expressed HLA-B:40:02, whereas HSPCs carrying the mutation might survive with a growth advantage over other HSPCs expressing HLA-B:40:02.Our case suggests that mutation (ACAC deletion) of HLA-B:40:02 could be a possible mechanism to restore hematopoiesis via immune escape with no involvement of 6pLOH.
Session topic: E-poster
Keyword(s): Aplastic anemia, HLA, Mutation
Type: Publication Only
Background
Idiopathic aplastic anemia(AA) has been reported to be associated with autoimmunity to hematopoietic stem/progenitor cells (HSPCs). Specific human leukocyte antigen (HLA) alleles are the target antigens of autoreactive cytotoxic T cells (CTL). One study reported that Japanese patients with idiopathic AA typically inherited only those four HLA alleles such as HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. (Katagiri et al, 2011).AA acquired copy number neutral loss of heterozygosity of the 6p arms (6p CN-LOH), leading to loss of one HLA haplotype. Moreover, the missing haplotype was concentrated in the same particular alleles : HLA-A*02:01, HLA-A*02:06, HLA-A*31:01 and HLA-B*40:02. Therefore, 6p CN-LOH may arise from selective pressure to escape from autoreactive CTL through loss of HLA alleles.In the other hand, nonsense mutation in HLA-B*40:02 (CAG to TAG) at codon 54 in exon 2 of HLA-B*40:02 with no involvement of 6p CN-LOH in a case with AA was first reported by Osumi T et al (Br J Haematol 2013:162:706).
Aims
In this study, we report a patient with idiopathic AA who acquired a mutation in HLA-B*40:02 allele (4 nucleotide deletion, leading frame shift). Our case is the second report of HLA-B*40:02 mutation, to our best knowledge.
Methods
HLA high resolution typing was performed by sequence based typing (Biowithus HLA PCR-SBT, Korea).
Results
A 54-year-old man was diagnosed with severe acquired AA with normal karyotype. Although he received immunosuppressive therapy (cyclosporine and anti-thymocyte globulin) for 8 months, he didn’t achieve remission and regular blood transfusions and G-CSF had been required. Therefore, stem cell transplantation was scheduled. His HLA results identified by high resolution sequencing based typing in a peripheral blood sample was HLA-A*26:01, HLA-A*33:03, HLA-C*03:04, HLA-C*07:01, HLA-DRB1:07:01, HLA-DRB1:15:01, HLA-DQB1:02:02, HLA-DQB1:06:02. However, HLA-B could not be easily typed by sequencing based typing. To resolve the problem, we performed the low resolution HLA typing using SSP(sequence-specific primer) method and the result showed HLA-B*40 and HLA-B*44. Furthermore, HLA-B type of one sibling having HLA-A, HLA-C and HLA-DRB1 matching was HLA-B*40, HLA-B*44. We reanalyzed HLA-B high resolution typing using DNA from patient’s buccal epithelial cells, patient’s peripheral blood and the sibling’s peripheral blood. The HLA-B typing of patient’s buccal epithelial cells and the sibling’s blood showed the same results : HLA-B*40:02, HLA-B*44:03. By a closer examination of sequence electropherogram of patient’s peripheral blood, we identified that that 4 nucleotides (ACAC deletion) were deleted between codon 187 and 188 in exon 4 of HLA-B*40:02, leading to a frame shift. The mosaicism of wild type and mutant HLA-B*40:02 alleles was restricted to patient’s blood cells, not buccal epithelial cells.
Conclusion
Acquisition of mutation could not be an accidental event, but is caused by immunological escape and selection, because HLA-B*40:02 is a possible target antigen of T cells in idiopathic AA. Activated CTLs might kill HSPCs that expressed HLA-B:40:02, whereas HSPCs carrying the mutation might survive with a growth advantage over other HSPCs expressing HLA-B:40:02.Our case suggests that mutation (ACAC deletion) of HLA-B:40:02 could be a possible mechanism to restore hematopoiesis via immune escape with no involvement of 6pLOH.
Session topic: E-poster
Keyword(s): Aplastic anemia, HLA, Mutation
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