Class II human leukocyte antigen (HLA) loci in idiopathic bone marrow failure (BMF) disorders are characterized by low structural divergence
This immunogenetic pattern contributes to decreasing T-cell receptor repertoire diversity, favoring cross-reactivity and autoimmunity
Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T cell response to unknown antigens. As for 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 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 also in other autoimmune disorders.