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₂-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide¹

Federico Perosa^*, Grazia Luccarelli^*, Marcella Prete^*, Elvira Favoino^*, Soldano Ferrone and Franco Dammacco^2,*

^* Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy; and Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263

mAb HC-10 loses its reactivity with HLA class I (HLA-I) H chain (HC) following its association with ₂-microglobulin (₂m). Furthermore, the HC-10 defined epitope appears to be involved in the pathogenesis of spondyloarthropathies, because HC-10 reduced their incidence in HLA-B27⁺₂m°/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 ⁵⁵EGPEYWDR(N/E)T⁶⁴ (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 ₂m-associated HLA-I HC is caused by blocking by the peptide in the groove of ₂m-associated HLA-I HC, though a role of HC conformational changes following its association with ₂m cannot be excluded. This information contributes to our understanding of the molecular basis of the antigenic profiles of ₂m-free and ₂m-associated HLA-I HC and may serve to develop active specific immunotherapy of spondyloarthropathies.

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