Molecular and cellular basis of the altered immune response against arsonate in irradiated A/J mice autologously reconstituted

The humoral immune response to arsonate (Ars) in normal A/J mice is dominat ed in the late primary and particularly in the secondary response by a recu rrent and dominant idiotype (CRIA) which is encoded by a single canonical c ombination of the variable gene segments: V(H)idcr11-DFL16.1-J(H)2 and V(ka ppa)10-J(kappa)1, Accumulation of somatic mutations within cells expressing this canonical combination or some less frequent Ig rearrangements results in the generation of high-affinity antibodies. By contrast, in partially s hielded and irradiated A/J mice (autologous reconstitution) immunized with Ars-keyhole limpet hemocyanin (KLH), both the dominance of the CRIA idiotyp e and the affinity maturation are lost, whereas the anti-Ars antibody titer is not affected. To understand these alterations, we have analyzed a colle ction of 27 different anti-Ars hybridomas from nine partially shielded and irradiated A/J mice that had been immunized twice with Ars-KLH, Sequence an alysis of the productively rearranged heavy chain variable region genes fro m those hybridomas revealed that (i) the canonical V(D)J combination was ra re, (ii) the pattern of V(D)J gene usage rather corresponded to a primary r epertoire with multiple gene combinations and (iii) the frequency of somati c mutations was low when compared to a normal secondary response to Ars, In addition, immunohistological analysis has shown a delay of 2 weeks in the appearance of full blown splenic germinal centers in autoreconstituting mic e, as compared to controls, Such a model could be useful to understand the immunological defects found in patients transplanted with bone marrow.