Fiche publication
Date publication
décembre 2021
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr PAGLIUCA Simona
Tous les auteurs :
Pagliuca S, Gurnari C, Awada H, Kishtagari A, Kongkiatkamon S, Terkawi L, Zawit M, Guan Y, LaFramboise T, Jha BK, Patel BJ, Hamilton BK, Majhail NS, Lundgren S, Mustjoki S, Saunthararajah Y, Visconte V, Chan TA, Yang CY, Lenz TL, Maciejewski JP
Lien Pubmed
Résumé
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.
Mots clés
Adult, Alleles, Anemia, Aplastic, genetics, Cohort Studies, Female, Genes, MHC Class II, Genotype, HLA-D Antigens, genetics, Humans, Male, Middle Aged
Référence
Blood. 2021 12 30;138(26):2781-2798
