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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↗
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 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↗
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↗
PubMed1979

Patterned acquisition of the antibody repertoire: diversity of the hemagglutinin-specific B-cell repertoire in neonatal BALB/c mice.

The B-cell response of 12- to 14-day old BALB/c mice to the hemagglutinin molecule of influenzae virus A/PR/8/34(H0N1) has been examined with monoclonal antibodies obtained by the splenic focus technique. An analysis of the specificity of these antibodies with a panel of heterologous viruses indicates that the antibody repertoire is highly restricted at an intermediate stage in postnatal development of the immune system. In toto, only 10 distinct reactivity patterns have been observed in an analysis of 72 antibodies derived from 28 donors. This contrasts with a substantially more diverse repertoire present in nonimmune and immune adult populations. The neonatal antibody specificities do not appear to be a random sampling of adult specificities, because several clonotypes (as defined by reactivity pattern) frequently found in neonates are rare or absent in adults. Most importantly, the vast majority of adult clonotypes are absent from the neonatal repertoire. These findings indicate that, at a developmental stage when the B-cell repertoire contains at least 10(6) clonotypes, the repertoire of genetically identical individuals is shared. This is consistent with a diversification process that is highly patterned and genetically determined. Furthermore, because 12- to 14-day-old neonates exhibit a diversified but definable hemagglutinin-specific B-cell repertoire, this experimental system should enable precise analyses of genetic and environmental influences on repertoire expression.

Age Factors↗
PubMed1978

Ontogeny of murine-B-lymphocytes. Avidity of antigen binding cells in neonatal and adult mice.

The heterogeneity of avidity of DNP-binding (rosetting) cells has been studied in mice of various ages, in an attempt to learn more about the development of antibody diversity. The results indicate that during the neonatal period murine B cells show a limited heterogeneity of avidity with no "high" avidity ABC being detectable. This implies that the full repertoire of anti-DNP antibodies is only gradually acquired during ontogeny. The results are interpreted as favouring the hypothesis that somatic events are important in the generation of antibody diversity.

Aging↗
PubMed1979

Analysis of the diversity of murine antibodies to dextran B1355: N-terminal amino acid sequences of heavy chains from serum antibody.

The N-terminal amino acid sequences of two gamma and two mu chains from normally induced serum antibodies to dextran in BALB/c mice are presented. These heavy chains are derived from antibodies with three distinguishable idiotypes. These variable region (VH) sequences are all identical as far as they have been analyzed (27 to 53 residues). The light chains from these antibodies are all of the lambda type and are identical by isoelectric focusing analysis. Accordingly, the diversity of dextran antibodies appears to reside primarily in the heavy chains. The implications of these observations for antibody diversity are discussed.

Amino Acid Sequence↗
PubMed1979

Some sequence similarities among cloned mouse DNA segments that code for lambda and kappa light chains of immunoglobulins.

A comparison between the cloned mouse DNA segments that were found to code for the lambda and kappa light chains of immunoglobulins established that there were seven short nucleotide sequences, two of which matched 6 out of 7, two 7 out of 8, two 8 out of 9, and one 9 out of 10 bases; these sequences were located either at homologous amino acid positions or at positions displaced by four amino acids or less. They all occurred in the framework regions (FRs), five next to the complementarity-determining regions (CDRs). Three of these were unique and did not occur elsewhere in the immunoglobulin nucleotides sequenced thus far or in DNA's of phage phi X174, phage G4, or simian virus 40. Five could serve as sites of joining by recombination or insertion of CDR to FR segments, and the invariant tryptophan that is the first residue of the second FR might serve as a sixth. These sites are consistent with the mini-gene or insertional hypotheses for the generation of antibody diversity but could also serve as points of recognition for a mutator enzyme or could serve to limit somatic mutation to the CDRs.

Amino Acid Sequence↗
PubMed1979

Gene activation during immune reaction.

In cell-free systems the addition of antigen stimulates the synthesis of informational RNA (i-RNA) which exhibits the following properties: It codes for the entire antibody molecule, it codes for the synthesis of regulator protein which initiates transcription of i-RNA with the correspondent informational content from DNA, it is a template for an an i-RNA dependent RNA polymerase, it is a template for an i-RNA dependent reverse transcriptase. The i-RNA may exist in a state of latency in cells. The product of reverse transcription of i-RNA is i-DNA which can be used to transcribe further i-RNA of the same specificity. Similar to i-DNA is an extracellular DNA which codes also for antibody and from which i-RNA can be transcribed. The data presented are summarized in a scheme of the flow of information during immunological reactions. It could be shown that there exist three different types of extrachromosomally synthesized molecules--i-RNA, i-DNA and extracellular DNA--which bear immunological specific information. These extrachromosomal states of information may be relevant for the generation of antibody diversity.

Animals↗
PubMed2026

Antibody diversification in cartilaginous fishes: Mechanistic insights from the nurse shark and comparative perspectives across jawed vertebrates.

Antibody diversity in vertebrates arises through the coordinated actions of V(D)J recombination and somatic hypermutation (SHM). Cartilaginous fishes occupy a key phylogenetic position as the sister lineage to bony vertebrates and therefore provide important comparative insights into the evolution of adaptive immunity. This review focuses on the nurse shark (Ginglymostoma cirratum) as a representative model for examining antibody-diversification mechanisms in cartilaginous fishes. Shark immunoglobulin genes exhibit a multicluster organization, while immunoglobulin new antigen receptor (IgNAR), a heavy-chain-only isotype, contains a single variable domain with an extended complementarity-determining region 3 (CDR3) that can be stabilized by non-canonical disulfide bonds. These structural features, together with intracluster multi-D V(D)J recombination and distinctive SHM characterized by single and tandem substitutions and insertions/deletions, contribute to antibody diversification in sharks. By comparing cartilaginous fishes, ray-finned fishes, and mammals, this review highlights lineage-specific combinations of immunoglobulin gene organization, recombination, mutational processing, and affinity maturation. Within the heuristic framework proposed here, shark and mammalian systems are described as emphasizing "breadth-first" repertoire generation and "precision-first" affinity optimization, respectively. These terms indicate relative mechanistic emphases rather than mutually exclusive categories or sequential evolutionary stages, while ray-finned fishes exhibit a distinct combination of genomic organization and mutational features. Investigating antibody diversification in cartilaginous fishes not only advances our understanding of vertebrate immune evolution but also provides structural and mechanistic insights that may inform the development of engineered antibodies based on the IgNAR scaffold.

Antibody diversity↗
PubMed2025

Structures of respiratory syncytial virus G bound to broadly reactive antibodies provide insights into vaccine design.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease in infants and older adults. The attachment glycoprotein (RSV G) binds to the chemokine receptor CX3CR1 to promote viral entry and modulate host immunity. Antibodies against RSV G are a known correlate of protection. Previously, several broadly reactive, high-affinity anti-RSV G human monoclonal antibodies were isolated from RSV-exposed individuals and were shown to be protective in vitro and in vivo. Here, we determined the structures of three of these antibodies in complex with RSV G and defined distinct conformational epitopes comprised of highly conserved RSV G residues. Binding competition and structural studies demonstrated that this highly conserved region displays two non-overlapping antigenic sites. Analyses of anti-RSV G antibody sequences reveal that antigenic site flexibility may promote the elicitation of diverse antibody germlines. Together, these findings provide a foundation for next-generation RSV prophylactics, and they expand concepts in vaccine design for the elicitation of germline lineage-diverse, broadly reactive, high-affinity antibodies.

Humans↗
PubMed1977

The specific antigen-binding cell populations of individual fetal mouse spleens: repertoire composition, size, and genetic control.

In order to analyze the genetic and physiological basis of controls affecting the generation of the repertoire of antigen-binding cells in fetal mice, we have measured the numbers of spleen cells specific for each of four antigens as a function of the total numbers of nucleated and Ig-bearing cells in inbred, hybrid, and random bred fetuses. For each of the two inbred strains BALB/c and CBA/J, the proportion of nucleated cells specific for a given antigen was the same for all individuals of the strain at the 18th day of gestation. The proportion did vary from antigen to antigen, however, and for each antigen the proportion of specific cells observed in CBA/J fetuses was approximately four times that observed in BALB/c fetuses. This difference appeared to be due to a difference between the two strains in the relative size of the repertoire of antigen-binding spleen cells at this stage of development, inasmuch as the frequency of Ig-bearing spleen cells in CBA/J fetuses was likewise approximately four times that observed in BALB/c fetuses. In random bred Swiss-L fetal mice at the 18th day of gestation, the proportion of cells specific for a given antigen varied significantly from one individual to the next. The ratio of proportions of the two antigens observed was constant from individual to individual, however, and this constant ratio differed significantly from the ratio observed for the same two antigens in fetal BALB/c and CBA/J inbred mice. These data suggest that the ontogeny of the repertoire of antigen-binding cells in fetal mice is subject to at least two independent sets of controls, one affecting the relative size of the repertoire in the spleen, and the other affecting the distribution of antigen-binding specificities within that repertoire. Analysis of repertoire size and composition in the spleens of hybrid fetuses confirmed the observation that the two parameters are controlled independently, and suggested further that the control of repertoire size in these fetuses is due to the action of one or a few closely-linked autosomal Mendelian genes. These data are consistent with models for the origin of antibody diversity in which the genes coding for the full repertoire of antibodies are generated somatically from a small number of germ-line genes early in development and in the absence of any strong positive or negative selection with respect to antigenic specificity.

Animals↗