High affinity cross-reacting mAb generated by minimal mimicry: implications for the pathogenesis of anti-nuclear autoantibodies and immunosuppression.
The antigen recognition of a profoundly immunosuppressive mAb, mAb 2E1, in vivo was investigated. In addition to the 62-kDa effector cell protease receptor 1, mAb 2E1 bound the 32-kDa T cell adhesion receptor E2 (CD99) and the 86-kDa p80 subunit of the nuclear antigen complex Ku. These molecules share no overall sequence similarity. Peptide mapping experiments identified the mAb 2E1 cross-reacting epitopes as the sequences 66GSFSDADLAD75 in E2 and 571GGAHFSVSSLAEG583 in p80 of Ku, sharing a minimal homology motif FSXXXLA, in which X is a nonconserved amino acid. Each of these peptides separately inhibited the binding of mAb 2E1 to E2, effector cell protease receptor 1, and p80 of Ku in a dose-dependent manner. Scatchard plot analysis of 125I-labeled mAb 2E1 binding to peripheral blood mononuclear cells revealed a high-affinity interaction with a dissociation constant of 7 x 10(-10) M. An anti-E2 mAb bound the same epitope 66GSFSDADLAD75 recognized by mAb 2E1 but failed to react with p80 of Ku and was not immunosuppressive. These findings demonstrate that high-affinity cross-reacting mAbs can be generated by mimicry of a minimal surface on unrelated molecules. This model of minimal mimicry may determine the nuclear reactivity of certain autoantibodies to Ku and contribute to aberrant immunosuppression in vivo.
Rothermel
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AL
Department of Pathology, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
Altieri
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DC
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000302:isolation & purification; D000915:Antibody Affinity; D000918:Antibody Specificity; D015551:Autoimmunity / Q000276:immunology; D003429:Cross Reactions; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000276:immunology
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000939:Epitopes; D010455:Peptides