Fabian H, Huser H, Loll B, Ziegler A, Naumann D, Uchanska-Ziegler B (2010): HLA-B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility
Arthritis Rheum. 62 (4): 978-987. Epub Jan 13.

Objective. Although the products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within their peptide binding grooves, they are differentially associated with inflammatory rheumatic diseases like ankylosing spondylitis (AS): HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 is only rarely encountered. The reasons for this distinct association are still unclear but could include subtype-specific conformational and dynamic properties of these antigens.

Methods. The membrane-distal segments of the HLA-B*2705 and the HLA-B*2709 heavy chains were expressed in vitro and reconstituted together with ₂-microglobulin and a peptide. HLA-B27 complexes loaded with two self-peptides (TIS, RRLPIFSRL, and pVIPR, RRKWRRWHL) and a sequence-related viral peptide (pLMP2, RRRWRRLTV) were studied by isotope-edited infrared spectroscopy to detect differences in their structure and flexibility at physiological temperature.

Results. Our analyses reveal the existence of subtype-specific conformational differences of the two HLA-B27 heavy chains at physiological temperature that are undetectable using X-ray crystallography. Irrespective of the bound peptide, the heavy chain of the HLA-B*2705 complex exhibits a higher conformational flexibility than the HLA-B*2709 heavy chain.

Conclusion. The present study demonstrates the existence of hitherto undetected, systematic conformational and dynamic differences between the heavy chains of the two HLA-B27 subtypes. As the recognition of cells expressing HLA antigens by effector cells is also dependent on the dynamic properties of the interacting cell surface molecules, our finding of HLA-B27 subtype-specific heavy chain flexibility could influence the distinct association of the HLA-B27 subtypes with spondyloarthropathies.