hide
Free keywords:
-
Abstract:
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 anti-
gens. 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, func-
tional 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 band 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.
