The Immunogenetic Basis of Idiopathic Bone Marrow Failure Syndromes: A Paradox of Similarity and Self-Presentation

Abstract

AbstractIdiopathic 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. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms potentially involved in autoimmunity.Key pointsClass II human leukocyte antigen (HLA) loci in idiopathic bone marrow failure (BMF) syndromes are characterized by low functional divergence and decreased peptide binding capabilities, only partially explained by enrichment in risk alleles.A superstructure at the interface with the peptide binding site of DRB1 locus, potentially involved in the presentation of self-antigenic specificities, can be identified in BMF patients.This immunogenetic pattern may contribute to decrease T-cell receptor repertoire diversity, expand autoreactive T-cell clones and increase autoimmune propensity in BMF.