Delineation of the human systemic lupus erythematosus anti-Smith antibody response using phage-display combinatorial libraries

The anti-Smith (Sm) autoantibody response is highly specific for systemic l upus erythematosus and is predominantly targeted to the Sm-B/B' and -D1 pol ypeptides, In all animal species thus Far studied, anti-Sm Abs initially re cognize proline-rich epitopes in the carboxyl terminus of the Sm-B/B' prote in and subsequently to multiple other epitopes in B/B' and D. The absence o f appropriate mAbs has limited our understanding of the genetic and structu ral basis of this autoimmune response. Using phage-display technology and l ymphocytes from a systemic lupus erythematosus patient we have generated th e first and only panel of human IgG anti-Sm mAbs thus far available, These Abs reproduced to a remarkable extent the serological reactivity of the pat ient. Epitope mapping and genetic studies revealed that the anti-Sm respons e is produced by distinct B cell clones with restricted epitope reactivity, All of the Abs in our study were exclusively encoded by different members of the V(H)4 gene family, On the aggregate, our results demonstrate that co mbinatorial libraries can recapitulate the immune repertoire of peripheral blood B memory cells and that epitope spreading appears to occur through th e sequential recruitment of nonclonally related autoreactive B cell clones.