Immunogenetics of spondyloarthropathies.
The association of HLA-B27 with ankylosing spondylitis and related spondyloarthropathies has been known for two decades and has provided a great impetus to the epidemiologic studies and also helped broaden the clinical spectrum of these diseases. The etiology of these diseases is likely to be multifactorial and include genetic, immunologic, and environmental mechanisms. The detailed three-dimensional x-ray crystallographic structure of B27 has now been reported. It has revealed electron density compatible with oligopeptides that are nine amino acid-long (nonamers) bound in the antigen-binding cleft of the molecule. Microsequence analysis of 11 peptides eluted from the antigen-binding cleft has confirmed that all are nonamers. The most restricted position in the bound peptide is the second position, where all the 11 peptides contain arginine. The side chain of arginine extends into the B pocket ("45 pocket"), which seems to act as a specificity side pocket in the antigen-binding cleft of the B27 molecule. It is very likely that an understanding of the detailed structure of B27, including the peptide-binding motif and the structural domains recognized by cytotoxic T cells, along with the recent development of the B27 transgenic rat model for spondyloarthropathies, will further enhance our understanding of the immunogenetics of these diseases. It is hoped that this will lead to the source of the arthritogenic triggers and possibly disease prevention by antigen-specific immunomodulation. Because T-cell activation is initiated by the formation of antigen-MHC complexes that are the ligands that are recognized by the antigen-specific T-cell receptor (TCR), it might be possible to inhibit this activation by blocking the antigen-binding cleft of MHC molecules by using high-affinity MHC-binding peptides (MHC blockade) or by a novel, new, and more efficient method of TCR antagonism.
Khan
M A
MA
Case Western Reserve University, Cleveland, Ohio.
Kellner
H
H
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000502:physiology; D018407:Bacterial Physiological Phenomena; D005796:Genes; D008040:Genetic Linkage; D006680:HLA Antigens / Q000235:genetics; D015796:HLA-B27 Antigen / Q000235:genetics; D006801:Humans; D007125:Immunogenetics; D008969:Molecular Sequence Data; D013122:Spinal Diseases / Q000209:etiology / Q000235:genetics* / Q000276:immunology*
D000942:Antigens, Bacterial; D006680:HLA Antigens; D015796:HLA-B27 Antigen