Inheritance of Human Antibody Structures Defined By Cross-Reactivity and Idiotypes.

The inheritance patterns of human antibody structure were investigated. Two humoral immune response parameters, defining restricted clonal products, were evaluated in genetically related individuals: (1) the relative proportion of a heterogeneous antibody population that remains following absorption with several cross-reacting antigens, and (2) the presence of an idiotype marker on functionally related anitbodies. The heterogeneous anti-B blood group antibody population of each member of 61 pairs of monozygous and 61 pairs of dizygous twins was fractionated by absorption with three cross-reacting antigens: rabbit red blood cells, dog red blood cells, and sheep red blood cells. Elimination of cross-reactive populations by absorption increases the relative homogeneity of the residual anti-B antibodies and the probability that these antibodies represent a limited number of committed clonal precursors. Quantitation of the anti-B titers, before and after absorption with each of the xenogeneic red cell types, provided phenotype measurements for statistical evaluation. It was possible to show, by variance analyses, that monozygous twin pairs were consistently more concordant in anti-B titer, before and after the red cell absorptions, than were the dizygous twins. Genetic theory predicts this outcome for a gene-determined trait. The proportion of the measured phenotype which is genetically controlled was estimated using Fisher's "components of variance" model. The heritabilities estimated for each of the anti-B antibody populations increase with the increase in structural homogeneity of the observed antibody population. The implications of these findings are discussed in relation to theories of antibody diversity. The second immune response phenotype measured was the presence of individual antigenic markers (idiotypes) on the anti-B antibodies of identical cotriplets. These antigenic structures represent three-dimensional immunoglobulin conformations whose distinctiveness may be uniquely predetermined by germ-line DNA sequences. Antibodies sharing idiotypes are thought to mark the homogeneous products of a single (or related) clones. Thus, the presence of the same idiotype in genetically identical individuals would imply that (1) the idiotype is inherited, and (2) these markers represent germ-line genes contributing to the generation of antibody diversity. Three of eight guinea pigs, immunized with blood group anti-B antibodies from the serum of one member of a monozygous triplet trio, produced antisera specific for the gamma globulins of the immunizing individual, when tested in a radioimmunoassay. The first antiserum failed to react with the gamma globulins of the genetically identical monozygous siblings. Absorption of the immunogen (anti-B) from the donor serum resulted in a decreased reactivity of the guinea pig antiserum demonstrating that the guinea pig antiserum contained an anti-idiotype. The two remaining antisera could not be shown to be specific for anti-B antibodies (absorption of the anti-B from the donor serum did not affect reactivity), although one reacted only with the immunizing individual while the second antiserum reacted equally well with all three of the triplets. A theory of antibody diversity, which integrates the three sets of results by combining germinal inheritance with somatic alterations, is discussed.Ph.D.GeneticsUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/157742/1/8017266.pd