Genetic control of early antibody responses

By using a pair of strains that have similar VK haplotypes but different VH haplotypes (e.g. BALB/c and C57BL) it is possible to demonstrate VH-controlled genetic differences in antibodies. By using a pair that have similar VH haplotypes but different VK haplotypes (RF and BALB/c) it is possible to demonstrate VK-controlled genetic differences in antibodies. A plausible explanation for the high frequency of certain V-gene combinations in the primary response is a high affinity of the product without somatic mutations. The products of two such major primary response combinations (VHOx1/VKOX1(H3) and VH186.2/V lambda 1) have an affinity for the immunogen well above 10(6). One combination of V genes, VHOx1/VKOx1(H3) has a major role in the primary anti-phOx response of several mouse strains - the product is idiotype 260. C57BL/10 mice lack the VHOx1 and RF mice the VKOx1(H3) gene. They use the remaining partner of the pair for the response in combination with other genes, but the affinity of the product is lower than the affinity of id. 260. Concordantly, the frequency of these "half-idiotypes" is lower in the primary response than the frequency of the full combination (23% and 16% instead of 50%). When the product of a V-gene combination is very frequent in the primary response, the affinity for the immunogen must be high, but the reverse is not always true. The product of a combination can have an unusually high affinity but the frequency is low. The simplest explanation then is that the frequency of available virgin B cells is low. It can be low because of a low rearrangement frequency of one of the V genes, VH or VK. Another possibility is that only a small proportion of B cells that have the particular combination rearranged can be recruited to the response. We have discussed an example where strict heavy chain CDR3 requirements must strongly limit available B cells.