Molecular basis of a mouse strain-specific anti-hapten response

The response of C57BL/6 and BALB/c mice to immunization with proteins coupled to (4-hydroxy-3-nitrophenyl)acetyl (NP) is dominated by distinctly different sets of antibodies. The V_H gene family previously shown to be involved in the C57BL/6 response has now been shown to have highly homologous counterparts in BALB/c but of five sequenced BALB/c V_H regions, none appeared likely to be able to encode an NP-binding protein. The active V_H region from a BALB/c hybridoma making a characteristic anti-NP antibody was recovered and sequenced and shown to be quite different from the V_H gene family involved in the C57BL/6 response. Comparison of the variation of the closely related V_H regions between the two mouse strains showed that there are separate types of evolutionary pressures on the framework and complementarity-determining regions. The molecular basis for strain-specific immune responses appears to be that the structural divergence of V_H regions between mouse strains is great enough that different strains use different V_H regions for making the predominant class of antibodies to a specific hapten.