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At least 19 recordsLinked to original sources
PubMed1976

The biological origin of antibody diversity.

Antibody diversity has a compelling fascination for many scientists and over the years speculations have sometimes seemed more numerous than facts. Now the structural basis of antibody specificity is well defined. Amino acid sequences and recently three-dimensional structures of various immunoglobulins provide the most solid basis for discussing the origin of diversity. The novel pattern of variable (V) and Constant (C) regions of amino acid sequence has been resolved further to show the functional pattern of variability. Inheritance of separate V and C genes is accepted, but attempts to define more than one gene coding for each V region are considered here to be unnecessary. The pattern of variability is still best understood in terms of mutation and the presence or absence of various selective pressures. The major area of debate still hinges around the extent to which mutation and selection operate during evolution or somatically. Sequence data have now been generally interpreted to require multiple V genes carried in the germ line. A few individual VH genes have been mapped in close linkage to CH genes in the mouse. The apparent existence of three VH alleles in rabbits was a strong argument against multiple V genes. Now the three phenotypes have been shown to be due to alleles controlling the expression of three sets of VH genes all present on the same chromosome. That V-gene expression requires rejoining of V and C genes at the DNA level is now almost certain. Models for the joining process can draw on the precedents of transposable genetic elements, which are widespread in Nature. The total extent of antibody diversity remains a philosophical point. Estimates of the number of antibody molecules required for observed diversity are reduced by two recently documented proposals. Each antibody combining site apparently has many (estimated at 100) different specificities and most combinations of VH and VL regions probably form a viable site. A given combining site can be defined by its pattern of shared specificities. Several specific antibody repertoires have been measured and the size in each case is consistent with the stringency with which the specificity is selected. Repertoire size appears to be under genetic control, but there are problems in viewing the genotype through the veil of clonal selection. Molecular hybridization has been used recently in an attempt to count V and C genes directly. C genes are seen in DNA having nonreiterated sequences, as formal genetics predicts. Each V-region probe hybridizes at a similar rate to C-region probes. Interpretation of this result depends on the extent to which one V-region probe will reveal nonhomologous V genes. Previous estimates that many cross-hybridizing genes should have been seen if present are possibly exaggerated. It is argued here that the data are compatible with a germ-line gene for each probe studied. Maximum estimates for the number of germ-line genes are sufficient to account for antibody diversity...

Amino Acid Sequence↗
PubMed1975

Germ line basis for antibody diversity.

Each antibody polypeptide chain is the product of a gene pair comprising one constant (C) gene coding for that portion of the chain common to all chains of the same type and one variable (V) gene coding for the sequence unique to each chain. Previous evidence indicates that the haploid genome has a single copy of each distinct C gene and that for expression a gene pair is formed with any one of a family of V genes present in the same haploid genome. Hybridization of purified mRNA coding for immunoglobulin heavy chain (mRNA-H) with a vast excess of DNA confirms the existence of a single C gene of each type and multiple V genes. A large number (of the order of 104) of V genes would be consistent with the hybridization results. This suggests considerable V gene redundancy which is a predictable property of a multiple V gene family maintained by expansion and contraction mechanisms. The mRNA-H used in these hybridization studies was isolated by a specific interaction with immunoglobulin. The same method has also been used to isolate a nuclear precursor of mRNA-H. Identification of this precursor strengthens the evidence for the direct joining of the V and C gene pair at the DNA level prior to transcription.

Amino Acid Sequence↗
PubMed1978

Antibody diversity in amphibians: inheritance of isoelectric focusing antibody patterns in isogenic frogs.

Anti-sheep red cell, anti-dinitrophenyl, anti-phosphorylcholine antibody responses have been followed in isogenic frogs of the genus Xenopus. Isoelectric focusing antibody patterns show a high degree of overlap for all antigens studied, and a heterogeneity that is lower than in mammals for the same antigens. Inheritance of antibody isoelectric focusing spectrotypes was demonstrated for sheep red cells and dinitrophenyl in two clones of isogenic animals. Outbred frogs show a higher frequency of spectrotype sharing than outbred mammals. It is therefore suggested that antibody diversity is lower in frogs than in mammals.

Animals↗
PubMedDate not supplied

The role of viruses in the evolution of antibody diversity.

We propose an alternate concept for the creation of antibody diversity involving the role of viruses as mediators of genetic exchange. We suggest that both species specificity and the diversity of the immune response arose as a consequence of virus co-evolution with host organisms. Processes such as viral transformation, transduction, and integration provide mechanisms of nucleotide exchange with the host leading to antibody diversity. In this model the genes coding for antibodies are stabilized through a process of antigenic and natural selection. Stabilization of genes ensures vertical transmission of appropriate nucleotide sequences.

Antibody Specificity↗
PubMed1975

Generation of antibody diversity. IV. Variation within single clones of antibody-forming cells developing in vivo.

Previous experimental work demonstrated that clonal variation occurs in vitro. The present experiments were designed to test for clonal variation in vivo. B cells were transferred at limiting dilution, with antigen, into irradiated recipients. Seven days later spleens were assayed for plaque-forming cell (PFC) colonies. Control experiments showed that these PFC colonies were clones, that is, they were derived from a single B cell precursor. When the clones were analyzed for heterogeneity of the PFC population, using cross-reactivity on various mixtures of red blood cells as a method of detecting differences in antibody specificity, from 23-83% of the clones contained variants. By adjusting the amounts of helper activity and antigen available to a developing clone, we have been able to influence this variation; high levels of help and/or antigen favor pure clones, while low levels of either produce mainly mixed clones.

Adjuvants, Immunologic↗
PubMedDate not supplied

[The acquisition of antibody diversity studied in anuran amphibians (author's transl)].

For T and B lymphocytes, the capacity of recognizing diverse antigens is acquired early in ontogeny. This is shown for T cells by graft rejection and mixed leucocyte reaction experiments and for B cells by the heterogeneity of antibody response in young larvae which only possess a small number of lymphocytes. Thus any proposed mechanism for the generation of antibody diversity in frogs has to take into account: (a) that such diversity is acquired within about 21-30 days after fertilization in larvae whose lymphocyte generation time is 36-40 h; (b) that genetically identical animals have similar immune responses as revealed by mixed leucocyte reaction for T cell responses and by isoelectric focussing patterns for anti-dinitrophenyl and anti-sheep red blood cells antibodies for B cells.

Animals↗
PubMed1976

Reiteration frequency of immunoglobulin light chain genes: further evidence for somatic generation of antibody diversity.

Methods have been developed for preparing mouse immunoglobulin light chain mRNA of better than 90% purity. Hybridization of both lambda and kappa mRNAs to excess liver DNA yielded results compatible with gene reiteration frequencies of two to three. There was no evidence of hybridization of these highly purified mRNAs to reiterated DNA, and, in fact, the kinetics of hybridization were very similar to that of purified globin mRNA. Purified lambda mRNA from tumors producing structurally different lambda chains were used in competition hybridization experiments. An unlabeled lambda mRNA competed with another, labeled lambda mRNA to the same extent as homologous unlabeled lambda mRNA. That is, base sequence homology among lambda mRNAs is so high that any lambda mRNA should cross-hybridize with all germ line variable (Vlambda) genes at least for those V-regions which are represented among myelomas. From amino-acid sequence data, it is argued that there are probably more than 25 different lambda V regions. Hence it is concluded that the number of germ line genes is too small to account for the diversity of lambda chains. A similar conclusion is drawn for kappa chains.

Antibody Formation↗
PubMedDate not supplied

Somatic generation of antibody diversity.

Hybridization of lambda-mRNAs to excess liver DNA yielded results compatible with gene reiteration frequencies of three or less. Purified mRNA from tumors producing structurally different lambda chains were used in competition hybridization experiments. An unlabeled lambda-mRNA competed with another, labelled mRNA to the same extent as homologous unlabelled lambda-mRNA. Mouse DNA was digested with Eco R-I restriction endonuclease and fractionated by gel electrophoresis. A DNA fragment carrying the V lambda-gene(s) was indentified in this digest. This fragment hybridized with lambda-mRNAs coding for two different lambdaV regions equally well. These results indicate that base sequence homology among lambda-mRNAs is so high that any lambda-mRNA should cross-hybridize with all or most of germ line V lambda genes. From amino acid sequence data, it is argued that there are probably more than 25 different lambdaV regions. Hence it is concluded that the number of germ line genes is too small to account for the diversity of lambda chains.

Amino Acid Sequence↗
PubMed1978

Antibody diversity.

Three important aspects of immunoglobulin gene organization and structure have emerged from studies of cloned immunoglobulin kappa chain genes. (i) Multiple variable genes are encoded separately in the genome of both immunoglobulin-producing and uncommitted (embryonic) cells, thereby establishing the evolutionary base for generating immunoglobulin diversity. (ii) These genes exist as many small, closely related families (subgroups) that share close sequence homology largely within their own subgroup. (iii) Comparison of two cloned variable gene segments derived from a single subgroup reveals a feature of their structure that distinguishes them from fixed genes (that is, globin genes) and provides, through extensive surrounding sequence homology, a large target for intergenic recombination. This last observation suggests that a simple recombination mechanism may account for their genetic instability in both germ line and somatic cells.

Animals↗
PubMed1978

Mechanisms of antibody diversity: multiple genes encode structurally related mouse kappa variable regions.

The complete amino acid sequences of the variable regions of three mouse Vkappa-21 kappa chains (A22, T111, and CB101) and one partial sequence (B32) have been determined and are compared to four previously reported Vkappa-21 variable regions. These eight kappa variable region sequences have, with the exception of an amide difference at residue 1, identical amino-terminal 23-residue sequences, all are of the same length, and all have extensive amino acid sequence homology throughout the variable region. When these eight variable regions are grouped by sequence homology, five different groups (Vkappa-21A, B, C, D, and E) are present whose members share common sets of amino acids within a group. Three groups of similar homology each contains at least two members (M63 and AB22 in Vkappa-21B; M321 and T124 in Vkappa-21C; and M70 and B32 in Vkappa-21A). The repetition of these five characteristic subgroup sequences in this relatively small sample indicates that these subgroups are isotypes which are controlled by separate germline genes. It is unlikely that these sequences could have been randomly somatically generated in different animals from a single germ-line gene (parallel mutation). Although a limited number of comparisons are available, the sequence differences within the Vkappa-21A, B, and C isotypes are limited to complementarity-determining regions and may have resulted from somatic mutations. The kappa chains comprising the Vkappa-21 isotypes offer a unique opportunity to compare the genetic interpretations of the primary amino acid sequence data with the nucleic acid hybridization data.

Amino Acid Sequence↗
PubMed1976

A mathematical approach to the analysis of diversity in antibody gene families.

In this article, we develop a mathematical approach for the analysis of diversity in antibody gene families. This approach is arrived at by examing two general questions about protein populations: (1) What is a relative measure of the diversity exhibited by one protein family when compared with a second? (2) What is the probability that two protein populations were derived from a single common population? These quantitative approaches permit a variety of precise evolutionary, genetic, and developmental questions to be asked of antibody gene families. Using this methodology, we demonstrate that the diversity in mouse K-immunoglobulin chains is considerably greater than in their human K counterparts. We also show that the variable (Vl) regions of light chains associated with IgG and IgA immunoglobulins in the mouse appear to have been derived from a common population of Vl genes. This approach also can be used to analyse sequence data from other informational multigene families.

Amino Acid Sequence↗