The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders

  • Simona Pagliuca
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Carmelo Gurnari
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Hassan Awada
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Ashwin Kishtagari
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Sunisa Kongkiatkamon
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Laila Terkawi
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Misam Zawit
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Yihong Guan
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Thomas LaFramboise
    Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH;
  • Babal K. Jha
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Bhumika J. Patel
    Leukemia Program, Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH;
  • Betty K. Hamilton
    Blood and Marrow Transplant Program, Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH;
  • Navneet S. Majhail
    Blood and Marrow Transplant Program, Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH;
  • Sofie Lundgren
    Hematology Research Unit Helsinki, University of Helsinki–Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland;
  • Satu Mustjoki
    Hematology Research Unit Helsinki, University of Helsinki–Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland;
  • Yogen Saunthararajah
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Valeria Visconte
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;
  • Timothy A. Chan
    Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH;
  • Chao-Yie Yang
    Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN;
  • Tobias L. Lenz
    Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön, Germany; and
  • Jaroslaw P. Maciejewski
    Translational Hematology and Oncology Research Department, Cleveland Clinic, Cleveland, OH;

抄録

<jats:title>Abstract</jats:title><jats:p>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 β 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.</jats:p>

収録刊行物

  • Blood

    Blood 138 (26), 2781-2798, 2021-12-30

    American Society of Hematology

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