HLA-DRB1 molecules and the presentation of anchor peptides from RhD, RhCE, and KEL proteins

Antigens from the Rh and Kell systems are recognized as the most immunogenic in clinical practice. This study evaluated the possible molecular mechanisms involved in the interaction of antigenic peptides with the DRB1 molecules, which help to explain the high frequency of anti-K and association of D + C antibodies in transfusion and incompatible pregnancy.

We included 201 patients with antibodies against antigens from the Rh and Kell systems and compare them with 174,015 controls. HLA-DRB1 genotyping and in silico analysis were performed. The NetMHCIIpan software was used to identify RhD-, RhCE-, and KEL-derived anchor peptides that bind to DRB1 molecules.

HLA-DRB1*15 is associated with an increased risk of D, C, E, and K alloimmunization, while the HLA-DRB1*01 and *12 alleles are overrepresented in patients with anti-C and anti-D, respectively. In silico analysis showed that three polymorphic points (60I, 68S, and 103S) common to C and D antigens can be presented by several DRB1 molecules, including DRB1*15:01. The DRB1*09:01 molecule, although not showing statistical significance, was able to interact strongly with almost all five anchor peptides from the sequence containing the polymorphic determinants of E antigen, except 217-WMFWPSVNS-225.

The DRB1*15 molecule has specific physicochemical characteristics in residues 11P and 13R in the P4 pocket that can favor the response to various antigenic peptides. Anti-K alloimmunization is unrestricted for interaction with specific DRB1 molecules, which suggests that almost all individuals in our population have DRB1 molecules capable of binding to KEL-derived anchor peptides and produce anti-K when stimulated.