Biomedical subjects
Publications and source records attributed to A Gilman-Sachs.
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In contrast to normal IgG, some of the IgG molecules, which appear in compensation as a result of allotype suppression of IgG molecules of the major VH subgroup (a locus), were found to have an easily identifiable idiotypic specificity. For each of three donors' IgG, a different idiotypic specificity was present, and each idiotypic specificity was found on the Fab, as expected, but not on the Fc fragments. Further analysis of the IgG of one donor revealed that the idiotypic specificity was present on 15% of the Fab gamma fragments. The idiotypic specificity was expressed on IgG which also bor an allotypic specificity of the y locus VH subgroup of IgG which comprised most (72%) of the total compensatory IgG. This suggests that suppression of clones synthesizing the a locus major VH subgroup results in compensation by minor VH subgroup clones more limited in variability. These clones may then proliferate to synthesize larger amounts of IgG bearing the same idiotypic specificity which thereby becomes more easily detectable by immunization of rabbits.
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Two additional allotypes of rabbit IgM, n83 and n84, have been identified and characterized with antisera obtained by cross immunization of rabbits with IgM. These allotypic specificities were not detected on IgG or IgA by double diffusion in agar gel and by quantitative radioprecipitin analyses. This finding implies that the specificities reside in the CH region of the mu-chain. Most of the IgM (88%) from an n83 homozygote reacted with anti-n83 Ab and most of the IgM (79%) from the net n84 homozygote reacted with anti-n84 Ab. The IgG or IgA from n83 or n84 rabbits did not precipitate to a significant extent (less than 6%) with the anti-n83 or anti-n84 Ab, respectively. That the n83 and n84 specificities are controlled at the n locus was verified by genetic analysis. Thus, four alleles are now known at the n locus, n81, n82, n83 and n84. The n locus is closely linked to the other six defined loci in the heavy chain chromosomal region and the allelic alternatives for each of the seven loci are coinherited by gene combinations called allogroups. Ten such allogroups are now defined with respect to the allele at the n locus.
Two a1a2 heterozygous sibling rabbits were first suppressed for the paternally inherited a1 VH region allotype and then immunized with a1 IgG. Anti-a1 antibody was detected in the serum of one of the rabbits. The anti-a1 auto-antibody reacted with the same amount of a1 IgG as did a conventional anti-a1 allo-antibody. Most of the IgG and IgM of this rabbit was of the a2 allotype and no significant amount of the a1 allotype was detected as would be expected for an a1 suppressed a1a2 heterozygous rabbit. However, allotype suppression in this rabbit is maintained by endogenous anti-allotype antibody. Rabbits with anti-allotype auto-antibody may be exploited to produce litters of heterozygous and homozygous rabbits efficiently suppressed for selected allotypes.
Doubly heterozygous offspring, malen83alpha1/femalen82alpha2 or malen81alpha1/femalen82alpha2, of doubly homozygous dams, n82alpha2/n82alpha2, were injected neonatally with anti-n83 or anti-n81 antibody directed to the paternal n locus allotype. In each injected rabbit, the paternal n83 or n81 allotypes were suppressed and increased amounts of the maternal n82 allotype accounted for almost all of the serum IgM. This is the first report of allotype suppression in the rabbit mediated by antibody directed toward the CH region of any Ig class. A concomitant decrease in the paternal a1 Ig allotype and a compensatory increase in the maternal a2 allotype were also found. This finding supports the concept that IgM-bearing cells are the precursors of IgG-secreting cells.
Injection of a1x-y-n81/a2x32y33n82 heterozygous rabbit at birth with anti-a2 allotype antiserum suppresses the production of the VHa2 gene product a2 Ig as well as the expression of the closely linked Cmun gene product n82 but not of the closely linked VHx and VHy gene products x32 and x33. This effect is related to the appearance of a2 and n82 on the same IgM molecules whereas a2, x32, and y33 appear on different Ig molecules.
Heterozygous rabbits of genotype a1n81f73g74/a2n82f71g75 were suppressed at birth for the VH region a1 allotype. At 8 weeks of age, quantitative analysis of serum IgG, IgM, and IgA molecules showed that the VHa1 specificity was effectively suppressed in the three classes of Ig and that the suppression was extended to the CH region n81 specificity on mu-chains as well as to the CH region f73 and g74 specificities on alphaf and alphag chains. At 26 weeks of age, analysis of serum IgG and IgM molecules showed that a1 was still suppressed to approximately the same extent in both Ig classes and the suppression was still extended to the CH region n81 specificity. However, at 26 weeks, the percentage of molecules with a1 specificity had doubled among serum and colostral IgA molecules and this increase was extended to the CH region f73 and g74 specificities. Thus, the suppressed allotypes reappeared first among IgA molecules. Our data are consistent with a regulatory mechanism which controls and synchronizes the expression of the VHa and the CH allotypes expressed on the same heavy chain. The order of the re-expression of the suppressed allotypes with respect to Ig class may allow further definition of selective regulatory mechanisms for the synthesis of Ig classes.
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