HLA-B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility.
OBJECTIVE
Although the products of the HLA subtypes B*2705 and B*2709 differ only in residue 116 (Asp versus His) within their peptide-binding grooves, they are differentially associated with inflammatory rheumatic diseases such as ankylosing spondylitis (AS): B*2705 occurs in AS patients, whereas 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. The present study was undertaken to investigate structural and dynamic differences between B*2705 and B*2709 and their possible relationship to subtype-specific disease association.


METHODS
The membrane-distal segments of the B*2705 and B*2709 heavy chains were expressed in vitro and reconstituted together with beta(2)-microglobulin and a peptide. HLA-B27 complexes loaded with 2 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 physiologic temperature.


RESULTS
Our analyses revealed the existence of subtype-specific conformational differences between the 2 HLA-B27 heavy chains at physiologic temperature, which are undetectable using x-ray crystallography. Irrespective of the bound peptide, the heavy chain of the B*2705 complex exhibited higher conformational flexibility than the B*2709 heavy chain.


CONCLUSIONS
The present study demonstrates the existence of previously undetected systematic conformational and dynamic differences between the heavy chains of the 2 HLA-B27 subtypes. Since effector cell recognition of cells expressing HLA antigens is dependent on the dynamic properties of the interacting cell surface molecules, this HLA-B27 subtype-specific heavy chain flexibility could have a role in the distinct association of HLA-B27 subtypes with spondylarthritides.
Fabian
Heinz
H
Robert Koch Institute, 13353Berlin, Germany. fabianh@rki.de
Huser
Hans
H
Loll
Bernhard
B
Ziegler
Andreas
A
Naumann
Dieter
D
Uchanska-Ziegler
Barbara
B
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D004926:Escherichia coli / Q000276:immunology; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D013055:Spectrophotometry, Infrared; D025241:Spondylarthritis / Q000235:genetics* / Q000276:immunology*
D015796:HLA-B27 Antigen; D010446:Peptide Fragments