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Genetische Mechanismen der Antikörperbildung

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Zusammenfassung

Mutation und Selektion sind die Faktoren, die der Entwicklung spezifischer Strukturen in Antikörpermolekülen zugrunde liegen. Sie wirken ständig modifizierend auf die im genetischen Code der kompetenten Zelle des Immunsystems weitergegebene Information ein. Durch den Vergleich der Primärstruktur homologer Polypeptide sind Hypothesen über den genetischen Mechanismus möglich, der zur Entstehung der Antikörpervariabilität führt.

Die wichtigsten dieser Hypothesen werden dargestellt.

Summary

Mutation and selection are the factors on which the development of the specific structures in antibody molecules are based. They act continuously and modify the genetic information which is transmitted by the immune competent cell. Hypotheses on the genetic mechanisms leading to antibody variability are possible by a comparison of amino acid sequences of immunoglobulin polypeptides. Appropriate for investigations of this kind are the Bence-Jones proteins, which are excreted in the urine of men, mouse and rabbit in myelomatosis. These proteins resemble immunoglobulin light chains and are sufficiently homogeneous for chemical analysis (monoclonal proteins). They exist in two different types, designated ϰ and λ. Since the amino acid sequence of four Bence-Jones proteins is known completely and stretches of the sequence of about 30 other light chain proteins are known comparisons between homologous proteins are possible. It appeared that all ϰ- and λ-polypeptides consist of a variable half (v) and a constant half (c). The v-region comprises the N-terminal residues 1–117, whereas the c-region comprises the C-terminal residues 108–214. Within a given light chain type all c-halves are identical in their amino acid sequence with exception of the residue No. 191 in ϰ-chains and No. 190 in λ-chains. These positions correspond to the allotypic specifities Inv and Oz.

The variability of individual light chains is confined to that part of the molecule which carries the antibody combining site. It follows that amino acid sequence studies of the v-region of the immunoglobulin molecule provide us with information about the structural basis of antibody specifity and — at the same time — enables us to test hypotheses on the genetic mechanisms of the antibody variability. Two categories of hypotheses are distinguishable: 1. the multiple gene hypotheses and 2. the somatic mutation hypotheses.

The multiple gene hypotheses postulate as many genes as specific antibodies exist. Somatic mutation hypotheses on the other hand are based on the assumption that recombinations between homologous genes occur during the individual development of the immune system. Advantages and disadvantages of some of the somatic mutation hypotheses are discussed. The conclusions to be drawn from the observed mutations in immunoglobulin light chain proteins were considered with respect to the coding problem.

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Literatur

  • Fleischman, I. B., R. R. Porter, andE. M. Press: The arangement of the peptide chains in γ-globulin. Biochem. J.88, 220–228 (1963).

    Google Scholar 

  • Wetter, O., W. Braun u.Ch. Hertenstein: Zur Struktur des Bence-Jones-Proteins. Acta haemat. (Basel)38, 147–162 (1967).

    Google Scholar 

  • Migita, Sh.: Ann. Report of the Inst. for virus research. Kyoto University6, 86–118 (1963).

    Google Scholar 

  • Leonard, W. J., andJ. F. Foster: Changes in optical rotation in the acid transformation of plasma albumin. Evidence for the contribution of tertiary structure to rotatory behavior. J. biol. Chem.236, 2662–2669 (1961).

    Google Scholar 

  • Scholtan, W.: Die Bindung der Sulfonamide an Eiweißkörper. Arzneimittel-Forsch.14, 1234–1238 (1964).

    Google Scholar 

  • Wetter, O.: Die Spezifität von Immunglobulinen als Kombinationsspezifität ihrer leichten (L) und schweren (H) Polypeptidketten. Hoppe-Seylers Z. physiol. Chem.348, 1248 (1967).

    Google Scholar 

  • Hilschmann, N., andL. C. Craig: Amino acid sequence studies with Bence-Jones-Proteins. Proc. nat. Acad. Sci. (Wash.)53, 1403–1409 (1965).

    Google Scholar 

  • Wikler, M., K. Titani, T. Shinoda, andF. W. Putnam: The complete amino acid sequence of a λ type Bence-Jones protein. J. biol. Chem.242, 1668–1670 (1967).

    Google Scholar 

  • Ein, D., andJ. L. Fahey: Two types of lambda polypeptide chains in human immunglobulins. Science156, 947–948 (1967).

    Google Scholar 

  • Appella, E., andD. Ein: Two types of lambda polypeptide chains in human immunoglobulins based on an amino acid substitution at position 190. Proc. nat. Acad. Sci. (Wash.)57, 1449–1454 (1967).

    Google Scholar 

  • Edelman, G. M., andJ. A. Gally: Somatic recombination of dublicated genes: An hypothesis on the origin of antibody diversity. Proc. nat. Acad. Sci. (Wash.)57, 353–358 (1967).

    Google Scholar 

  • Titani, K., E. Whitley jr.,L. Avogardo, andF. W. Putnam: Immunoglobulin structure: Partial amino acid sequence of a Bence-Jones protein. Science149, 1090–1092 (1965).

    Google Scholar 

  • Titani, K., E. Whitley jr., andF. W. Putnam: Immunoglobulin structure Variation in the sequence of Bence-Jones proteins. Science152, 1513–1516 (1966).

    Google Scholar 

  • Hill, R. L., R. Delaney, R. E. Fellows jr., andH. E. Lebovitz: The evolutionary origins of the immunoglobulins. Proc. nat. Acad. Sci. (Wash.)56, 1762–1769 (1966).

    Google Scholar 

  • Press, E. M., P. J. Piggot, andR. R. Porter: The N- and C-terminal amino acid sequence of the heavy chains a pathological human immunoglobulin Ig G. Biochem. J.99, 356–366 (1966).

    Google Scholar 

  • Titani, K., M. Wikler, andF. W. Putnam: Evolution of immunoglobulins: Structural homology of kappa and lambda Bence-Jones proteins. Science155, 828–835 (1967).

    Google Scholar 

  • Gray, W. R., W. J. Dreyer, andL. Hood: Mechanism of antibody synthesis: Size differences between mouse kappa chains. Science155, 465–467 (1967).

    Google Scholar 

  • Milstein, C.: Variations in amino acid sequence near the disulphide bridges of Bence-Jones proteins. Nature (Lond.)209, 370–373 (1966).

    Google Scholar 

  • Milstein, C.: Chemical structure of light chains. Proc. roy. Soc. B166, 138–146 (1966).

    Google Scholar 

  • Milstein, C.: The disulphide bridges of immunoglobulin ϰ-chains. Biochem. J.101, 338–351 (1966).

    Google Scholar 

  • Cohen, S., andC. Milstein: Structure of antibody molecules. Nature (Lond.)214, 449–452, 540–541 (1967).

    Google Scholar 

  • Milstein, C., I. B. Clegg, andJ. M. Jarvis: C-terminal half of immunoglobulin λ chains. Nature (Lond.)214, 270–272 (1967).

    Google Scholar 

  • Smithies, O.: Antibody variability. Science157, 267–273 (1967).

    Google Scholar 

  • Milstein, C.: Linked groups of residues in immunoglobulin ϰ-chains. Nature (Lond.)216, 330–332 (1967).

    Google Scholar 

  • Lennox, E. S., andM. Cohen: Immunoglobulins. Ann. Rev. Biochem.36, 365–406 (1967).

    Google Scholar 

  • Sengbusch, P. v.: Mutation und Proteinstruktur. Naturwissenschaften54, 267–276 (1967).

    Google Scholar 

  • Goldberg, A. L., andR. E. Wittes: Genetic code: Aspect of organization. Science153, 420–424 (1966).

    Google Scholar 

  • Mackay, A. L.: Optimation of the genetic code. Nature (Lond.)216, 159–160 (1967).

    Google Scholar 

  • Hilschmann, N.: Zum Mechanismus der Antikörperbildung. Hoppe-Seylers Z. physiol. Chem.348, 1291–1300 (1967).

    Google Scholar 

Berücksichtigt wurden außerdem die nachstehenden Publikationen

  • Abel, C. A., andH. M. Grey: Carboxy-terminal amino acids of γA and γM heavy chains. Science156, 1609–1610 (1967).

    Google Scholar 

  • Callan, H. G.: The organization of genetic units in chromosomes. J. Cell Sci.2, 1–7 (1967).

    Google Scholar 

  • Doolitle, R. F., andK. H. Astrin: Light chains of rabbit immunoglobulin: Assignment to the kappa class. Science156, 1755–1757 (1967).

    Google Scholar 

  • Fitch, W. M.: The relation between frequencies of amino acids and ordered trinucleotides. J. Biol.16, 1–8 (1966).

    Google Scholar 

  • Frangione, B., andC. Milstein: Disulphide bridges of immunoglobulin G1 heavy chains. Nature (Lond.)216, 939–941 (1967).

    Google Scholar 

  • Haurowitz, F.: Antibody formation and the coding problem. Nature (Lond.)205, 847–851 (1965).

    Google Scholar 

  • Hilschmann, N.: Die chemische Struktur an zwei Bence-Jones-Proteinen (Roy und Cum) vom ϰ-Typ. Hoppe-Seylers Z. physiol. Chem.348, 1077–1080 (1967).

    Google Scholar 

  • Hilschmann, N., andL. C. Craig: Countercurrent-distribution studies with Bence-Jones protein in a dissociating system. Biochemistry4, 5–11 (1965).

    Google Scholar 

  • Hood, L., W. R. Gray, andW. J. Dreyer: On the evolution of antibody light chains. J. molec. Biol.22, 179–182 (1966).

    Google Scholar 

  • Kabat, E. A.: The paucity of species-specific amino acid residues in the variable regions of human and mouse Bence-Jones proteins and its evolutionary and genetic implications. Proc. nat. Acad. Sci. (Wash.)57, 1345–1349 (1967);

    Google Scholar 

  • A comparison of invariant residues in the variable and constant regions of human ϰ, human L, and mouse ϰ Bence-Jones proteins. Proc. nat. Acad. Sci. (Wash.)58, 229–233 (1967).

    Google Scholar 

  • Milstein, C.: Disulphide bridges and dimers of Bence-Jones proteins. J. molec. Biol.9, 836–838 (1964);

    Google Scholar 

  • Interchain disulphide bridge in Bence-Jones proteins and in γ-globulin B chains. Nature (Lond.)205, 1171–1173 (1965);

    Google Scholar 

  • Immunoglobulin ϰ-chains. Comparative sequences in selected stretches of Bence-Jones proteins. Biochem. J.101, 352–368 (1966);

    Google Scholar 

  • Variations in the c-terminal half of immunoglobulin λ-chains. Biochem. J.104, 28c-30c (1967).

    Google Scholar 

  • Niall, H. D., andP. Edman: Two structurally distinct classes of kappa-chains in human immunoglobulins. Nature (Lond.)216, 262–263 (1967).

    Google Scholar 

  • Pink, J. R. L., andC. Milstein: Disulphide bridges of a human immunoglobulin G protein. Nature (Lond.)216, 941–942 (1967);

    Google Scholar 

  • Inter heavy-light chain disulphide bridge in immunoglobulins. Nature (Lond.)214, 92–94 (1967).

    Google Scholar 

  • Ponstingl, H., M. Hess, B. Langer, M. Steinmetz-Kayne u.N. Hilschmann: Über einen Aminosäure-Austausch im konstanten Teil eines Bence-Jones Proteins vom λ-Typ. Hoppe-Seylers Z. physiol. Chem.348, 1213–1214 (1967).

    Google Scholar 

  • Prahl, J. W.: N- and C-terminal sequences of a heavy chain disease protein and its genetic implications. Nature (Lond.)215, 1386–1387 (1967).

    Google Scholar 

  • Press, E. M.: The amino acid sequence of the N-terminal 84 residues of a human heavy chain of immunoglobulin G (Daw). Biochem. J.104, 30c-33c (1967).

    Google Scholar 

  • Putnam, F. W., T. Shinoda, K. Titani, andM. Wilker: Immunoglobulin structure: Variation in amino acid sequence and length of human lambda light chains. Science157, 1050–1053 (1967).

    Google Scholar 

  • Quattrocchi, B., D. Cioli, andC. Baglioni: Distribution of an arginine-lysine interchange in the invariable half of human L-type Bence-Jones proteins. Nature (Lond.)216, 56–57 (1967).

    Google Scholar 

  • Smithies, O.: Gamma globulin variability: A genetic hypothesis. Nature (Lond.)199, 1231–1236 (1963).

    Google Scholar 

  • Smyth, G., andS. Utsumi: Structure at the hinge region in rabbit immunoglobulin G. Nature (Lond.)216, 332–335 (1967).

    Google Scholar 

  • Suran, A. A., andB. W. Papermaster: N-terminal sequences of heavy and light chains of leopard shark immunoglobulins: Evolutionary implications. Proc. nat. Acad. Sci. (Wash.)58, 1619–1623 (1967).

    Google Scholar 

  • Terry, W. D., andJ. L. Fahey: Subclasses of human γ2-globulin based on differences in the heavy polypeptide chains. Science146, 400–401 (1964).

    Google Scholar 

  • Voo, T. J., O. A. Roholt, andD. Pressman: Specific binding activity of isolated light chains of antibodies. Science157, 707–709 (1967).

    Google Scholar 

  • Weir, P. C., andR. R. Porter: Comparison of the structure of the immunoglobulins from horse serum. Biochem. J.100, 63–68 (1966).

    Google Scholar 

  • Whitehouse, H. L. K.: Crossover Model at antibody variability. Nature (Lond.)215, 371–374 (1967);

    Google Scholar 

  • A cycloid model for the chromosome. J. Cell Sci.2, 9–22 (1967).

    Google Scholar 

  • Wikler, M., K. Titani, T. Shinoda, andF. W. Putnam: The complete amino acid sequence of a λ type Bence-Jones protein. J. biol. Chem.242, 1668–1670 (1967).

    Google Scholar 

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Authors and Affiliations

  1. Klinik und Lehrstuhl für Innere Medizin Klinikum, Essen der Ruhr-Universität Bochum, Germany

    O. Wetter & C. G. Schmidt

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  1. O. Wetter
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  2. C. G. Schmidt
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Wetter, O., Schmidt, C.G. Genetische Mechanismen der Antikörperbildung. Klin Wochenschr 46, 401–407 (1968). https://doi.org/10.1007/BF01736928

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