Molecular evolution of catalytic antibodies in autoimmune mice

Catalytic Abs (catAbs) preferentially evolved in autoimmune MRL/MPJ-lpr/lpr (MRL/lpr) mice upon immunization with the phosphonate transition-state ana logue (TSA), but this did not happen in normal BALB/c mice. The majority of the catAbs from MRL/lpr mice were from several independent clones of the s ame family. Most of them had a lysine at position 95 in the heavy chain (H9 5), which is at the junctional region. This residue, which interacts with t he phosphonate moiety of the TSA and presumably is involved in the catalyti c activity, was not changed even after expansive evolution following multip le mutations. By contrast, the majority that arose from BALB/c mice were th e non-catAbs, which were quite different in the sequence from the catAbs fr om MRL/lpr mice, but they were clonally related to one another, so most of them were originated from a single clone. In the MRL/lpr mice, the catalyti c subsets that existed in the initial repertoire were effectively captured by the phosphonyl oxygens in the TSA by interacting with the lysine at H95. In the BALB/c mice, however, another noncatalytic subset with only the bin ding capability directed to a moiety other than the phosphonate moiety was alternatively evolved, because of the lowest abundance or elimination of th e catalytic subsets.