Multi-modal Binding of a 'Self' Peptide by HLA-B*27:04 and B*27:05 Allelic Variants, but not B*27:09 or B*27:06 Variants: Fresh Support for Some Theories Explaining Differential Disease Association.
A self-derived-peptide with the same amino acid sequence (N-RRYLENGKETLQR-C) as residues 169-181 of the human leukocyte antigen (HLA) B27 heavy chain is known to bind to MHC Class I complexes containing the HLA-B27 heavy chain. This observation has been invoked previously in at least two different (but related) molecular explanations for the disease-association of the HLA-B27 allele. Here, we use a combination of fluorescence polarization, competitive inhibition and gel filtration chromatographic studies to show that a fluorescently-labeled peptide of the above sequence binds to two disease-associated subtypes of HLA-B27 (namely HLA-B*27:04 and HLA-B*27:05) but not to non-disease-associated subtypes (HLA-B*27:06 or HLA-B*27:09). This differential binding behavior is seen both in (a) peptide binding to complexes of heavy chain (HLA-B27) and light chain (β2microglobulin), and in (b) peptide binding to β2microglobulin-free heavy chains in the aggregated state. Such subtype-specific differences are not seen with two other control peptides known to bind to HLA-B27. Our results support the likelihood of differential peptide binding holding at least one of the keys to HLA-B27's disease association.
Department of Immunopathology, Research Block A, Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh, 160012, India.
Manish Kumar
MK
Rana
Department of Immunopathology, Research Block A, Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh, 160012, India. mguptasarma@yahoo.com.
Manni
M
Luthra-Guptasarma
D000483:Alleles; D000595:Amino Acid Sequence; D015551:Autoimmunity; D005450:Fluorescamine / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D015870:Gene Expression; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D018448:Models, Immunological; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013194:Staining and Labeling / Q000379:methods
D005456:Fluorescent Dyes; C510610:HLA-B*27:04 antigen; C464936:HLA-B*27:05 antigen; C510629:HLA-B*27:06 antigen; C464937:HLA-B*27:09 antigen; D015796:HLA-B27 Antigen; D010455:Peptides; D011994:Recombinant Proteins; D005450:Fluorescamine
Disease association; Fluorescence polarization; Gel filtration; Human leukocyte antigen; Peptide binding