Why Is HLA-C Less Immunogenic than HLA-A and -B?

Abstract

In solid organ transplantation only scarce information is available on the role of HLA-C mismatches in unsensitized patients waiting for a first transplant. The third MHC locus is possibly a duplication of HLA-B and has all characteristics of a major histocompatibility antigen: it can present peptides to T cells and acts as a ligand for NK cells (v. Bergen et al AJT 2011). Very few alloantisera are reported to be specific for HLA-C, suggesting a lower immunogenicity compared to HLA-A and HLA-B. This may partly be explained by the lower expression of HLA-C on the cell surface. We questioned whether from the immunogenicity point of view HLA-C also differs from HLA-A and B with respect to the induction of alloantibody responses. For this purpose we selected from our local population all HLA-A,B,C,DR,DQ phenotypes which occurred at least twice and calculated the mean triplet incompatibilities (TRPI) using HLAMatchmaker of 77 HLA antigens simulating the situation in which these would have been a single mismatch in solid organ transplantation. The mean TRPI for HLA-A was 5.2 vs. 3.95 for HLA-B and 2.4 for HLA-C (p< 0.001). In a second approach we divided HLA-B in Bw4 and Bw6 and HLA-C in C1 and C2 on basis of their function as NK cell ligands. This analysis showed the following descending order in terms of TRPI: Bw4 (5.3)>A (5.2)>C2 (3.6)>Bw6 (3.1)>C1 (1.5). As our previous studies showed a direct link between the number of TRPI and alloantibody production after graft loss it is to be expected that HLA-A and HLA-B mismatches, have a higher chance to induce alloantibody production than HLA-C mismatches. Within the different subtypes of HLA-C the C2 NK ligand group of antigens seems to be of higher immunogenicity than the C1 group.