GENETIC-CONTROL OF NATURAL ANTIBODY REPERTOIRES - I - IGH, MHC AND TCR-BETA LOCI

Global analysis of natural antibody repertoires has revealed a marked conservation of reactivity patterns within inbred mouse strains, and c haracteristic strain-specific differences. We have now analyzed the ge netic control of reactivity repertoires, aiming at identifying the res pective selection mechanisms. Multiparametric statistics of a large nu mber of serum antibody reactivities scored by quantitative Western blo t analyses using extracts from homologous tissues and bacteria readily distinguish the reactivity patterns of C57BL/6 and BALB/c, revealing homogeneity among genetically identical individuals. Antibody repertoi res in the prototype strains can also be segregated from those express ed by the respective IgH congenics, BC.8 and CB.20, demonstrating that IgH-linked genes contribute to determining natural antibody repertoir es. Conversely, strains sharing IgH haplotype also express distinct re activity patterns, indicating that other genes participate in the sele ction of serum IgM repertoires. Two such non-IgH loci were now identif ied. Thus, analysis of four MHC-congenic strains demonstrated that MHC -linked control of natural antibody repertoires is likely to operate t hrough differential selection of T cell repertoires, since (1) mice th at are congenic at the TCR beta locus, and (2) BALB/c nude mice grafte d at birth with pure thymic epithelium from either C57BL/6 or BALB/c a lso differ in their natural antibody repertoires.