Differential Binding of Pyruvate Dehydrogenase Complex-E2 Epitopes by DRB1*08:01 and DRB1*11:01 Is Predicted by Their Structural Motifs and Correlates with Disease Risk

Abstract

DRB1*08:01 (DR0801) and DRB1*11:01 (DR1101) are highly homologous alleles that have opposing effects on susceptibility to primary biliary cirrhosis (PBC). DR0801 confers risk and shares a key feature with other HLA class II alleles that predispose to autoimmunity: a non-aspartic acid at beta57. DR1101 is associated with protection from PBC and its sequence includes an aspartic acid at beta57. To elucidate a mechanism for the opposing effects of these HLA alleles on PBC susceptibility we compared the features of epitopes presented by DR0801 and DR1101. First, we identified DR0801- and DR1101-restricted epitopes within multiple viral antigens, observing both shared and distinct epitopes. Since DR0801 is not well characterized, we deduced its motif by measuring binding affinities for a library of peptides, confirming its key features through structural modeling. DR0801 was distinct from DR1101 in its ability to accommodate charged residues within all but one of its binding pockets. In particular, DR0801 strongly preferred acidic residues in pocket 9. These findings were used to identify potentially antigenic sequences within PDC-E2 (an important hepatic auto-antigen) that contain a DR0801 motif. Four peptides bound to DR0801 with reasonable affinity, but only one of these bound to DR1101. Three peptides PDC-E2145-159, PDC-E2249-263, and PDC-E2629-643, elicited high affinity T cell responses in DR0801 subjects, implicating these as likely auto-reactive specificities. Therefore, the unique molecular features of DR0801 may lead to the selection of a distinct T cell repertoire that contributes to breakdown of self-tolerance in primary biliary cirrhosis while those of DR1101 promote tolerance.

A role for HLA‐DRB1*1101 and DRB1*0801 in cognitive ability and its decline with age

“…The opposing effects of DRB1*0801 and DRB1*1101 in our study show the same direction of effect as those reported in a study of PBC, which is a condition associated with cognitive impairment [Newton et al, ; Hollingsworth et al, ; Chow et al, ]. PBC is an autoimmune liver disease where 53% of patients have moderate to severe problems with concentration and memory that are not correlated with histological and biochemical markers of disease severity [Newton et al, ].…”

“…DRB1*0801 and DRB1*1101 have previously been associated with a number of conditions including juvenile idiopathic arthritis (JIA) [Massa et al, ], multiple sclerosis (MS) [Qiu et al, ], systemic lupus erythematosus [Graham et al, ; Castaño‐Rodríguez et al, ], type 1 diabetes [Petrone et al, ; Erlich et al, ; Muixí et al, ], and PBC [Donaldson et al, ; Chow et al, ]. In the latter three conditions, DRB1*1101 has been reported to be a protective allele and DRB1*0801 has been the susceptibility allele.…”

Broad-Based CD4+ T Cell Responses to Influenza A Virus in a Healthy Individual Who Lacks Typical Immunodominance Hierarchy

“…However, we found a portion of the epitopes restricted to more than one HLA allele. For example, M1 232–244 and M1 240–252 , although reported to be restricted to DRB5 and DQ1, respectively (29), were found in our study to be presented by DPB1*0501 (Figures 4C,D); NP 409–421 restricted to DRB1*12:02 (Figure 5B) was once reported to be restricted to DRB1*15:01 (IEDB) and DRB1*08:01 (26), etc. These results further confirmed that many CD4 + T cell epitopes may be presented by multiple HLA molecules (Table 1).…”

“…A few previously reported epitopes were among the ones we identified in this study, such as M1 105–117 , NP 102–114 , and NP 463–475 . However, some of these such as M1 33–52 , M1 228–244 , NP 102–114 , and NP 409–421 were reported to be restricted to different HLA-II molecules; for example NP 409–421 peptide restricted to DRB1*0801 rather than here DRB1*1202 (26). Moreover, M1 240–252 restricted to DPB1*0501, was identified as a highly conserved epitope among strains of H1N1, H3N2, and even H5N1 (Table 2).…”

The immunogenetics of primary biliary cirrhosis: A comprehensive review

“…Although these possibilities require further investigation, recent exciting work has shown that T cells with the risk-conferring HLA DRB1*08:01 genotype shown high-affinity responses to specific pyruvate dehydrogenase E2 subunit peptides, response that did not develop in the presence of the protective DRB1*11:01 allele [56].…”