PMID- 34748628
OWN - NLM
STAT- MEDLINE
DCOM- 20220114
LR  - 20240207
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 138
IP  - 26
DP  - 2021 Dec 30
TI  - The similarity of class II HLA genotypes defines patterns of autoreactivity in 
      idiopathic bone marrow failure disorders.
PG  - 2781-2798
LID - 10.1182/blood.2021012900 [doi]
AB  - Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure (BMF) 
      disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response 
      to unknown antigens. As in other autoimmune disorders, the predilection for 
      certain HLA profiles seems to represent an etiologic factor; however, the 
      structure-function patterns involved in the self-presentation in this disease 
      remain unclear. Herein, we analyzed the molecular landscape of HLA complexes of a 
      cohort of 300 IAA patients and almost 3000 healthy and disease controls by deeply 
      dissecting their genotypic configurations, functional divergence, self-antigen 
      binding capabilities, and T-cell receptor (TCR) repertoire specificities. 
      Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) 
      showed that IAA patients carried class II HLA molecules whose antigen-binding 
      sites were characterized by a high level of structural homology, only partially 
      explained by specific risk allele profiles. This pattern implies reduced HLA 
      binding capabilities, confirmed by binding analysis of hematopoietic stem cell 
      (HSC)-derived self-peptides. IAA phenotype was associated with the enrichment in 
      a few amino acids at specific positions within the peptide-binding groove of DRB1 
      molecules, affecting the interface HLA-antigen-TCR beta and potentially constituting 
      the basis of T-cell dysfunction and autoreactivity. When analyzing associations 
      with clinical outcomes, low HED was associated with risk of malignant progression 
      and worse survival, underlying reduced tumor surveillance in clearing potential 
      neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light 
      on the immunogenetic risk associated with IAA etiology and clonal evolution and 
      on general pathophysiological mechanisms potentially involved in other autoimmune 
      disorders.
CI  - (c) 2021 by The American Society of Hematology.
FAU - Pagliuca, Simona
AU  - Pagliuca S
AUID- ORCID: 0000-0003-4688-2478
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
AD  - University of Paris, Paris, France.
FAU - Gurnari, Carmelo
AU  - Gurnari C
AUID- ORCID: 0000-0001-6829-5544
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
AD  - Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 
      Italy.
FAU - Awada, Hassan
AU  - Awada H
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - Kishtagari, Ashwin
AU  - Kishtagari A
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - Kongkiatkamon, Sunisa
AU  - Kongkiatkamon S
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - Terkawi, Laila
AU  - Terkawi L
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - Zawit, Misam
AU  - Zawit M
AUID- ORCID: 0000-0003-2991-4386
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - Guan, Yihong
AU  - Guan Y
AUID- ORCID: 0000-0001-8002-5141
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - LaFramboise, Thomas
AU  - LaFramboise T
AD  - Department of Genetics and Genome Sciences, Case Western Reserve University, 
      Cleveland, OH.
FAU - Jha, Babal K
AU  - Jha BK
AUID- ORCID: 0000-0002-7660-5255
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - Patel, Bhumika J
AU  - Patel BJ
AD  - Leukemia Program, Department of Hematology and Oncology, Cleveland Clinic, 
      Cleveland, OH.
FAU - Hamilton, Betty K
AU  - Hamilton BK
AD  - Blood and Marrow Transplant Program, Department of Hematology and Oncology, 
      Cleveland Clinic, Cleveland, OH.
FAU - Majhail, Navneet S
AU  - Majhail NS
AUID- ORCID: 0000-0001-7082-891X
AD  - Blood and Marrow Transplant Program, Department of Hematology and Oncology, 
      Cleveland Clinic, Cleveland, OH.
FAU - Lundgren, Sofie
AU  - Lundgren S
AUID- ORCID: 0000-0003-3146-9816
AD  - Hematology Research Unit Helsinki, University of Helsinki-Helsinki University 
      Hospital Comprehensive Cancer Center, Helsinki, Finland.
AD  - Translational Immunology Research Program and Department of Clinical Chemistry 
      and Hematology, University of Helsinki, Helsinki, Finland.
FAU - Mustjoki, Satu
AU  - Mustjoki S
AUID- ORCID: 0000-0002-0816-8241
AD  - Hematology Research Unit Helsinki, University of Helsinki-Helsinki University 
      Hospital Comprehensive Cancer Center, Helsinki, Finland.
AD  - Translational Immunology Research Program and Department of Clinical Chemistry 
      and Hematology, University of Helsinki, Helsinki, Finland.
AD  - ICAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
FAU - Saunthararajah, Yogen
AU  - Saunthararajah Y
AUID- ORCID: 0000-0002-9757-1031
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - Visconte, Valeria
AU  - Visconte V
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
FAU - Chan, Timothy A
AU  - Chan TA
AD  - Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, 
      Cleveland, OH.
FAU - Yang, Chao-Yie
AU  - Yang CY
AUID- ORCID: 0000-0002-5445-0109
AD  - Department of Pharmaceutical Sciences, University of Tennessee Health Science 
      Center, Memphis, TN.
FAU - Lenz, Tobias L
AU  - Lenz TL
AD  - Research Group for Evolutionary Immunogenomics, Max Planck Institute for 
      Evolutionary Biology, Plon, Germany; and.
AD  - Research Unit for Evolutionary Immunogenomics, Department of Biology, University 
      of Hamburg, Hamburg, Germany.
FAU - Maciejewski, Jaroslaw P
AU  - Maciejewski JP
AD  - Translational Hematology and Oncology Research Department, Cleveland Clinic, 
      Cleveland, OH.
LA  - eng
GR  - R01 HL128425/HL/NHLBI NIH HHS/United States
GR  - R21 CA249138/CA/NCI NIH HHS/United States
GR  - R01 HL118281/HL/NHLBI NIH HHS/United States
GR  - R35 CA232097/CA/NCI NIH HHS/United States
GR  - R35 HL135795/HL/NHLBI NIH HHS/United States
GR  - R01 HL123904/HL/NHLBI NIH HHS/United States
GR  - R01 HL132071/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (HLA-D Antigens)
RN  - Aplastic anemia, idiopathic
SB  - IM
CIN - Blood. 2021 Dec 30;138(26):2744-2745. PMID: 34967871
MH  - Adult
MH  - Alleles
MH  - Anemia, Aplastic/*genetics
MH  - Cohort Studies
MH  - Female
MH  - *Genes, MHC Class II
MH  - Genotype
MH  - HLA-D Antigens/*genetics
MH  - Humans
MH  - Male
MH  - Middle Aged
PMC - PMC8718627
EDAT- 2021/11/09 06:00
MHDA- 2022/01/15 06:00
PMCR- 2022/12/30
CRDT- 2021/11/08 17:23
PHST- 2021/06/09 00:00 [received]
PHST- 2021/10/18 00:00 [accepted]
PHST- 2021/11/09 06:00 [pubmed]
PHST- 2022/01/15 06:00 [medline]
PHST- 2021/11/08 17:23 [entrez]
PHST- 2022/12/30 00:00 [pmc-release]
AID - S0006-4971(21)01842-5 [pii]
AID - 2021/BLD2021012900 [pii]
AID - 10.1182/blood.2021012900 [doi]
PST - ppublish
SO  - Blood. 2021 Dec 30;138(26):2781-2798. doi: 10.1182/blood.2021012900.