The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders

Abstract

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.

Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond

“…(F) WebLogo visualization of the variable amino acids within the peptide binding domains (corresponding to exon 2 and 3) of the HLA-A alleles in a representative population of healthy controls (N=960). ( 12 ) The height of each letter corresponds to the relative frequency of each amino acid in the population. This graphic represents an attempt to visualize the variability of the antigen binding domain of HLA-A alleles, but does not capture the whole spectrum of heterogeneity, since it represents only a limited population.…”

“…One could speculate that similar mechanisms of immune escape may be present at a certain level also in some autoimmune disorders. A prototypic example in this direction is represented by idiopathic aplastic anemia (IAA), an immune mediated bone marrow failure disease characterized by T cell mediated destruction of hematopoietic stem cells, translating in failure of hematopoiesis ( 12 , 77 , 80 , 81 , 89 , 104 , 105 ). Here, genomic loss of HLA molecules has been shown as a frequent mode of immune escape of target cells from autoimmune attack, theoretically lowering the presentation of immunogenic peptides below the activation threshold of T-cell effectors.…”

Next-generation sequencing: unraveling genetic mechanisms that shape cancer immunotherapy efficacy

“…The power in measuring HLA-I variation seems to extend to correlation of benefit with some combination therapies, e.g., combination of tyrosine kinase inhibitors with ICIs in RCC ( 95 ). HED predicts aplastic anemia outcomes, bone marrow transplant outcomes, and organ transplant outcomes ( 96 – 98 ). In a meta-analysis of factors that influence ICI efficacy, Litchfield et al also showed that HLA divergence was a significant factor influencing ICI response in melanoma ( 64 ).…”

HLA-B evolutionary divergence is associated with outcomes after SARS-CoV-2 infection

“…The more diverse are the features of paired amino acids, the higher the probability of more diverse peptides being presented to immune cells [7] , [8] . Furthermore, some authors have used HED to estimate the capacity to present different peptides as a prognostic factor in cancer and aplastic anemia [6] , [9] , [10] . We hypothesize that higher HED scores for class I HLA loci may be associated with favorable outcomes in hospitalized COVID-19 patients due to the increased probability of presenting viral peptides for recognition by adaptive immunity.…”