Biomedical subjects
Publications and source records attributed to M MANNIK.
Isolated L-chains with either the A4 or the A5 allotypic markers from rabbit antibodies to 2,4-dinitrophenyl determinant recombine at random with antibody H-chains in the presence or absence of the hapten to produce hybrid precipitating antibody molecules.
The specific antigenic structure of individual myeloma proteins was investigated for the presence of similar antigenic determinants in pooled gamma-globulin and for the localization of these determinants on the gamma-globulin molecules. Quantitative precipitin analyses demonstrated that in most instances absorption of antisera specific for an individual myeloma protein with large amounts of gamma-globulin markedly reduced or completely removed the reactivity of the antiserum for the homologous myeloma protein. In only one instance did strong specificity remain after absorption with 100 mg of Fr II per cc of antiserum. The antigenic determinants responsible for the individual specificity were localized in all cases studied solely to the Fab fragment produced by papain digestion. After reductive cleavage, three patterns of localization were observed. Individual specificity could be localized either to; (a) isolated heavy chains, (b) isolated light chains, (c) antigenic determinants present only when light and heavy chains were recombined. After immunization with whole myeloma proteins, individual specificity was localized in part at least to the isolated heavy chain in four of six proteins studied. It was localized to the light chains in three of five type L proteins but in none of six type K proteins. In the instances where individual specificity of the myeloma protein was present on the light chains, it was shown that the Bence Jones protein from the same patient also contained the individual specificity. Immunization with isolated heavy or light chains furnished further evidence for the individual specificity of both types of chains. These studies on myeloma proteins furnished evidence concerning the portions of the gamma-globulin molecule subject to individual antigenic variation. The light chains, particularly the L type and the Fd portion of the heavy chains were primarily involved. Evidence for the importance of the quaternary structure was also obtained from the necessity in some instances for light and heavy chains to be associated in order for individual specificity to be observed. The Fc fragment of the heavy chains on the other hand showed very limited variation which was related to subgroup specificity.
Conditions were developed by which the separated H and L chains of gamma(2) globulins recombined to form four-chained molecules in good yields. In the absence of antigen, anti-2,4-dinitrophenyl (anti-DNP) H chains randomly reassociated with a mixture of antibody and non-specific gamma(2) globulin L chains. In the presence of a specific hapten, however, the antibody H chains preferentially interacted with the anti-DNP L chains. Antibody H chain-antibody L chain recombinants formed in the presence of hapten were more active than the corresponding recombinants formed in the absence of hapten. Speculations are made regarding the possible mechanisms and biological significance of these effects.
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A wide assortment of antibodies has been analysed by qualitative and quantitative techniques for their content of group I- and group II-type gamma-globulin molecules. These included Rh antibodies, isoagglutinins, thyroglobulin antibodies, dextran antibodies, and teichoic acid antibodies. All the antibodies studied showed the presence of both groups. However, the ratio of the two varied widely in different individuals and diverged markedly from the ratio in the total gamma-globulin of the individual. Two antibodies isolated from the serum of the same individual showed different ratios for the two groups.
The genetic factors Gm(a), Gm(b), Gm(x), and Inv(a), Inv(b) described for normal human gamma-globulin were all found in different myeloma proteins. A single myeloma protein never contained more than one product of alternate alleles even in heterozygous individuals. However, factors determined by the two different loci were often found in the same myeloma protein. The Gm(a) character of the myeloma protein parallelled that of the normal gamma-globulin of the same serum in most cases. In contrast, the Gm(b) character was usually absent in the myeloma protein when it was directly demonstrable in the normal gamma-globulin. The myeloma proteins from six Negroes were Gm(a+b-), whereas the normal gamma-globulin was Gm(a+b+). This indicates that the effect of gene Gm(b) is similar in Negroes and whites, even though its relation to gene Gm(a) is different in the two races. Gm factors were found only in the 7S gamma-globulin type myelomas and not in other products of plasma cell tumors. Inv characters were, however, present in all four types of proteins studied, namely 7S and 19S gamma-globulins, beta(2A)-globulins, and Bence Jones proteins. In two instances, genetic heterogeneity of the protein products was demonstrated suggesting the proliferation of more than one clone of plasma cells in some multiple myeloma patients. The accumulated evidence obtained in this study strongly suggested that the presence and absence of genetic characters was compatible with the concept that myeloma proteins were closely analogous to individual moieties in the spectrum of normal gamma-globulins rather than truly abnormal proteins. Their study offered evidence of a heterogeneity of genetic characters among the normal gamma-globulins in a given individual. It also appears probable that in normal individuals single plasma cells have a restricted capacity to express genetic information in their protein product.
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