The molecular evolution of the immune response: idiotope‐specific suppression indicates that B cells express germ‐line‐encoded V genes prior to antigenic stimulation

Abstract

Antibodies expressed by the immune B cell population are characterized by variable region amino acid substitutions resulting from somatic nucleotide replacement (somatic mutation). This is not true of antibodies expressed by the “naive” B cell population. It is at present unclear whether this discrepancy is due to the preferential clonal selection of a pre‐existing subpopulation of naive B cells that express variable regions altered via nucleotide replacement, or whether the process of nucleotide replacement occurs only during the antigen‐dependent stages of B cell differentiation. To address this question we have used anti‐idiotypic suppression to functionally delete B cells that express particular variable‐region structures from the antigen‐responsive repertoire. Suppression of the major cross‐reactive idiotype (Id^CR) expressed in strain A mice in response to p‐azophenylarsonate (Ars) was induced using the monoclonal anti‐Id^CR antibody AD8. The idiotope recognized by AD8 is easily destroyed by alteration of Id^CR variable‐region structure via nucleotide replacement. The Id^CR anti‐Ars immune repertoire is characterized by antibodies that lack the AD8‐cognate idiotope due to nucleotide replacement. However, complete suppression of the Id^CR could reproducibly be achieved by administration of AD8 prior to Ars immunization. This result indicates that all Id^CR‐expressing B cells also express the AD8‐cognate idiotope prior to immunization. Thus, somatic nucleotide replacement must occur exclusively during the antigen‐dependent stages of B cell differentiation in this system.