Dual, HLA B27 subtype dependent conformation of a self peptide

The products of the human leukocyte antigen subtypes HLA B 2705 and HLA B 2709 differ only in residue 116 Asp vs. His within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis AS ; HLA B 2705 occurs in AS patients, whereas HLA B 2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self peptide pVIPR RRKWRRWHL . The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA B 2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp 116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B 2709. These subtype dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA B 2705 or HLA B 2709 to the buried Asp116 His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigen

Two distinctive HLA haplotypes harbor the B27 alleles negatively or positively associated with ankylosing spondylitis in Sardinia : Implications for disease pathogensis

Objective. To compare haplotype distribution in HILA-B27-positive patients with ankylosing spondylitis (AS) and healthy control subjects possessing either AS-associated HLA-B27 alleles or the non-AS-associated HLA-B*2709 allele. Methods. DNA samples from 47 HLA-B27-positive patients with AS and 76 HLA-B27-positive healthy controls (19 positive and 57 negative for B*2709) living in different areas of Sardinia were collected and typed for HLA class I and class 11 alleles. The third exon of the B27 gene was analyzed for the presence of Asp 116 or His(116), which differentiates B*2709 from the other two B27 subtypes (B*2705 and B*2702) that are mostly found in Sardinia. The parents of 6 subjects positive for B*2709 were also typed for HLA class I and class 11 alleles. Statistical analysis was performed by Fisher's exact test. Results. In Sardinia, the B27 alleles conferring susceptibility to AS appear to be more frequently carried by a haplotype (A2;B27;Cw2;DR16) that reaches its highest frequency in patients with AS (A2 80.8%, B27 100%, Cw2 and DR16 74.5%). Conversely, the non-AS-associated B*2709 allele is more frequently found together with other HLA alleles whose frequencies are inversely correlated with the disease (A32 or A30, Cw1 and DR12). Familial analysis of 6 subjects positive for HLA-B*2709 confirmed the existence of a "Sardinian" haplotype that is not associated with AS (A32;B*2709;Cw1;DR12). Conclusion. In Sardinia, 2 distinct haplotypes harbor the non-AS-associated HLA-B*2709 allele or the AS-associated B27 alleles. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA-B27 may play some role in conferring susceptibility to AS

The Ankylosing Spondylitis-Associated HLA-B*2705 Presents a B*0702-Restricted EBV Epitope and Sustains the Clonal Amplification of Cytotoxic T Cells in Patients

Abstract HLA-B*27 is strongly associated with an inflammatory autoimmune disorder, the Ankylosing Spondylitis (AS) and plays a protective role in viral infections. The two aspects might be linked. In this work, we compared in B*2705/B*07 positive patients with AS, the CD8+ T cell responses to two immunodominant EBV-derived epitopes restricted for either the HLA-B*27 (pEBNA3C) or the HLA-B*07 (pEBNA3A). We have unexpectedly found that the HLA-B*07-restricted EBNA3A peptide is presented by both the B*0702 and the B*2705 but not by the non AS-associated B*2709, that differs from the AS-associated B*2705 for a single amino acid in the peptide-binding groove (His116Asp). We then analyzed 38 B*2705-positive/B*07-negative (31 AS-patients and 7 healthy donors) and 8 B*2709-positive/B*07-negative subjects. EBNA3A-specific CD8+ T lymphocytes were present in 55.3% of the HLA-B*2705 but in none of the B*2709 donors (p = 0.0049). TCR β-chain analysis identified common TCRBV and TCRBJ gene segments and shared CDR3β sequences in pEBNA3A-responsive CTLs of B*2705 carriers, suggesting the existence of a shared TCR repertoire for recognition of the uncanonical B*2705/pEBNA3A complex. These data highlight the plasticity of the AS-associated HLA-B*2705, which presents peptides with suboptimal binding motifs, possibly contributing both to its enhanced capacity to protect against pathogens and to predispose to autoimmunity