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

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. 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.