Beta 2-microglobulin-free HLA class I heavy chain epitope mimicry by monoclonal antibody HC-10-specific peptide.
mAb HC-10 loses its reactivity with HLA class I (HLA-I) H chain (HC) following its association with beta(2)-microglobulin (beta(2)m). Furthermore, the HC-10 defined epitope appears to be involved in the pathogenesis of spondyloarthropathies, because HC-10 reduced their incidence in HLA-B27(+)beta(2)m degrees /MHC class II knockout mice. This study has characterized the determinant recognized by HC-10. Panning of a phage display peptide library with HC-10 resulted in isolation of the motif PxxWDR, which could be aligned with P57, W60, D61, and R62 of the first domain of the HLA-I HC allospecificities reactive with HC-10. The (55)EGPEYWDR(N/E)T(64) (p-1) is the shortest motif-bearing peptide that reacts with HC-10 and inhibits its binding to soluble HLA-B7 HC, irrespective of whether N (p-1a) or E (p-1b) is present at position 63. By contrast, HC-10 did not react with six additional peptides, each bearing motif amino acid substitutions present in HC-10-not-reactive HLA-I allospecificities. The p-1-derived Qp-1, synthesized with the additional conserved Q54, which displays the highest in vitro reactivity with HC-10, was the only one to induce in mice IgG resembling HC-10 in their fine specificity. Mapping of the HC-10-defined determinant suggests that the lack of mAb reactivity with beta(2)m-associated HLA-I HC is caused by blocking by the peptide in the groove of beta(2)m-associated HLA-I HC, though a role of HC conformational changes following its association with beta(2)m cannot be excluded. This information contributes to our understanding of the molecular basis of the antigenic profiles of beta(2)m-free and beta(2)m-associated HLA-I HC and may serve to develop active specific immunotherapy of spondyloarthropathies.
Perosa
Federico
F
Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
Luccarelli
Grazia
G
Prete
Marcella
M
Favoino
Elvira
E
Ferrone
Soldano
S
Dammacco
Franco
F
D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry*; D000918:Antibody Specificity; D017104:Bacteriophage M13 / Q000737:chemistry; D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D003198:Computer Simulation; D018604:Epitope Mapping / Q000379:methods; D005260:Female; D006680:HLA Antigens / Q000737:chemistry* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018716:Molecular Mimicry / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D021122:Protein Subunits / Q000737:chemistry / Q000276:immunology; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000276:immunology
D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D021122:Protein Subunits; D001613:beta 2-Microglobulin