AUTHOR=Ren Xu , Amarajeewa A. W. Peshala , Jayasinghe M. D. Tharushika , Garstka Malgorzata A. 

TITLE=Differences in F pocket impact on HLA I genetic associations with autoimmune diabetes

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1342335

DOI=10.3389/fimmu.2024.1342335

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Human leukocyte antigen (HLA) I molecules present antigenic peptides to activate CD8<sup>+</sup> T cells. Type 1 Diabetes (T1D) is an auto-immune disease caused by aberrant activation of the CD8<sup>+</sup> T cells that destroy insulin-producing pancreatic β cells. Some <italic>HLA I</italic> alleles were shown to increase the risk of T1D (T1D-predisposing alleles), while some reduce this risk (T1D-protective alleles).</p></sec><sec><title>Methods</title><p>Here, we compared the T1D-predisposing and T1D-protective allotypes concerning peptide binding, maturation, localization and surface expression and correlated it with their sequences and energetic profiles using experimental and computational methods.</p></sec><sec><title>Results</title><p>T1D-predisposing allotypes had more peptide-bound forms and higher plasma membrane levels than T1D-protective allotypes. This was related to the fact that position 116 within the F pocket was more conserved and made more optimal contacts with the neighboring residues in T1D-predisposing allotypes than in protective allotypes.</p></sec><sec><title>Conclusion</title><p>Our work uncovers that specific polymorphisms in HLA I molecules potentially influence their susceptibility to T1D.</p></sec>