HIGH AFFINITY CROSSREACTING MAB GENERATED BY MINIMAL MIMICRY - IMPLICATIONS FOR THE PATHOGENESIS OF ANTINUCLEAR AUTOANTIBODIES AND IMMUNOSUPPRESSION

The antigen recognition of a profoundly immunosuppressive mAb, mAb 2E1 . in live tvas investigated. In addition to the 62-kDa effector cell p rotease receptor I, mAb 2E1 bound the 32-kDa T cell adhesion receptor E2 (CD99) and the 86-kDa p80 subunit of tile nuclear antigen complex K u. These molecules share no overall sequence similarity, Peptide mappi ng experiments identified the mAb 2E1 cross-reacting epitopes as the s equences (66)GSFSDADLAD(75) in E2 and (571)GGAHFSVSSLAEG(583) in p80 o f Ku, sharing a minimal homology motif FSXXXLA, in which X is a noncon served amino acid, Each of these peptides separately inhibited the bin ding of mAb, 2E1 to E2, effector cell protease receptor 1, and p80 of Ku in a dose dependent manner. Scatchard plot analysis of I-125-labele d mAb 2E1 binding to peripheral blood mononuclear cells revealed a hig h-affinity interaction with a dissociation constant of 7 x 10(-10) M. An anti-E2 mAb bound the same epitope (66)GSFSDADLAD(75) recognized by mAb 2E1 but failed to react with p80 of Ku and was not immunosuppress ive. These findings demonstrate that high-affinity cross-reacting mAbs ran be generated by mimicry of a minimal surface on unrelated molecul es, This model of minimal mimicry may determine the nuclear reactivity of certain autoantibodies to Ku and contribute to aberrant immunosupp ression in vivo.