The molecular and cellular basis of affinity maturation in the antibody response

Nossal, G. J. V.

doi:10.1016/0092-8674(92)90198-l

Cited by 201 publications

(95 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(20,21,34). Thus, during the second week there is extensive somatic V gene hypermutation and selection for raised affinity to NP, and the chief site for these events is the germinal center (6)(7)(8). The present study shows that soluble, freshly deaggregated antigen can reduce primary anti-NP IgGl antibody formation ( Fig.…”

Section: Resultsmentioning

confidence: 68%

“…This process depends on somatic hypermutation of immunoglobulin variable region (V) genes (1)(2)(3)(4), occurring mainly in lymphoid germinal centers (5)(6)(7)(8). As tolerance can readily be induced within the primary B-cell repertoire (9-12), we have addressed the question (13) of whether mechanisms exist to prevent fortuitous mutations toward anti-self-reactivity within the secondary B-lymphocyte repertoire-i.e., the memory B-cell compartment.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Soluble antigen profoundly reduces memory B-cell numbers even when given after challenge immunization.

Nossal

Karvelas

Pulendran

1993

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The splenic B-cell repertoire of unimmunized C57BL/6 mice can be examined for anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) B cells of relatively high affinity by using a dual strategy. (14,15) and showed that it could prevent the generation of anti-HSA memory B cells in a dose-dependent manner. Adoptive transfer studies showed that the toleragen affected donor T and B cells, the former effect being more profound. Another way of studying the relative contributions of Tand B-lymphocyte populations to an antibody response is to make use of various hapten-carrier combinations (16-18). T-dependent anti-hapten antibody formation requires that anti-hapten B cells be "helped" by carrier-specific T cells. The anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) response of C57BL/6 mice has been extensively investigated (19-21) because of the preferential appearance of B-cell clones utilizing the VH 186.2 V gene and the Al light chain gene, facilitating the study of V gene hypermutation. It is also a system in which clones making relatively high-versus relatively low-affinity antibody can be discriminated by the use of, respectively, relatively lowly versus relatively highly haptenated protein conjugates in an ELISA (22,23). In the present study, we immunized mice with highly haptenated NP-HSA, and attempted tolerance induction with lowly haptenated, freshly deaggregated, NP-HSA, with HSA carrier alone, or with NP attached to irrelevant carriers. The key findings were that NP-HSA .Jways worked better than carrier alone or NP attached i other carriers in preventing memory cell appearance and that tolerance could still be induced after immunogenic challenge, up to the time of the first appearance of V gene mutations. Apparently, the functional silencing of T and B cells is necessary for the full tolerance effect, and T-ceil help is still required for continued B-memory cell generation after the germinal center reaction is well under way.

show abstract

Section: Resultsmentioning

confidence: 68%

mentioning

confidence: 99%

Soluble antigen profoundly reduces memory B-cell numbers even when given after challenge immunization.

Nossal

Karvelas

Pulendran

1993

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…[22][23][24], has shown that the molecular and cellular mechanisms involved in self-tolerance are several. For the T-lymphocyte population, negative selection or clonal abortion of high-avidity anti-self cells within the thymus is important, but the capacity for silencing repertoire elements in the periphery by means of the induction of clonal anergy is also present (23 (30)(31)(32)(33), only develop with appropriate T-cell help. We had previously demonstrated (7) that soluble antigen can abrogate the appearance of such memory cells, and here we have explored the cellular basis of this effect.…”

Section: Discussionmentioning

confidence: 99%

Memory cell generation ablated by soluble protein antigen by means of effects on T- and B-lymphocyte compartments.

Karvelas

Nossal

1992

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Adult C57BL/6 mice were injected with 100 ,ug of soluble, freshly deaggregated human serum albumin (HSA) to produce partial immunologic tolerance. UnhEjected normal control (N) mice contain only 100 B cells in their spleens with the capacity to (i) be activated in vitro into clonal proliferation by Escherichia coli lipopolysaccharide plus interleukins 2, 4, and 5, (ii) form IgG1 as well as IgM antibody, and (iii) display specificity for HSA when only IgG1 is allowed to score in an enzyme-linked immunosorbent assay (ELISA). Such N mice generate ==50,000 clonable anti-HSA IgG1 antibody-forming cell precursors in their spleens after T-dependent immunization with HSA adsorbed onto alum and given with BordeteUa pertussis adjuvant. Mice prei'jected with soluble HSA (TOL)-generate far fewer anti-HSA IgG1 antibodyforming cell precursors, termed anti-HSA memory cells. Splenocytes were transferred from N or TOL mice into lethally irradiated syngeneic recipients together with syngeneic bone marrow. Whereas N splenocytes generated plentiful memory cells within 2 weeks in antigenically challenged recipients, TOL splenocytes did not. Work with Ly-5 congenic mice ruled out memory cell generation from either the host or the bone marrow inoculum within this limited time. N T cells plus TOL B cells showed consistently lowered memory cell generation. TOL T cells plus N B cells showed an even greater lowering of adoptive memory cell generation. Thus the lowered response capacity of TOL mice resided in the T-and B-cell compartments. Attempts to show a suppressor component within the T-cell population were inconclusive, but a profound defect in capacity to respond to HSA in vitro was exhibited by the CD4' T cells of TOL mice. B lymphocytes were harvested from T-dependently immunized mice 5 days after challenge, incubated with soluble HSA for 18 hr, and then adoptively transferred together with N T cells. The recently activated B cells were not rendered tolerant by this manipulation. The results argue for a major T-cell component in the process whereby soluble protein antigens ablate affinity maturation and memory cell generation.

show abstract

“…More likely, the initial interaction with a new ligand may be weak; there would then be selection for progressively tighter binding, if this results in more effective resistance. This is similar conceptually to somatic antibody maturation that occurs in T cells of vertebrates (Nossal 1992;Mueller and Jemmerson 1996). Variation in ligand binding is consistent with the variability of dominance observed for R-gene action and the variation in resistance phenotypes in different interactions (although there are several alternative explanations).…”

Section: Resistance Specificities May Mature Through Repeated Cycles mentioning

confidence: 99%

Clusters of Resistance Genes in Plants Evolve by Divergent Selection and a Birth-and-Death Process

1998

View full text Add to dashboard Cite

Classical genetic and molecular data show that genes determining disease resistance in plants are frequently clustered in the genome. Genes for resistance (R genes) to diverse pathogens cloned from several species encode proteins that have motifs in common. These motifs indicate that R genes are part of signal-transduction systems. Most of these R genes encode a leucine-rich repeat (LRR) region. Sequences encoding putative solvent-exposed residues in this region are hypervariable and have elevated ratios of nonsynonymous to synonymous substitutions; this suggests that they have evolved to detect variation in pathogen-derived ligands. Generation of new resistance specificities previously had been thought to involve frequent unequal crossing-over and gene conversions. However, comparisons between resistance haplotypes reveal that orthologs are more similar than paralogs implying a low rate of sequence homogenization from unequal crossing-over and gene conversion. We propose a new model adapted and expanded from one proposed for the evolution of vertebrate major histocompatibility complex and immunoglobulin gene families. Our model emphasizes divergent selection acting on arrays of solvent-exposed residues in the LRR resulting in evolution of individual R genes within a haplotype. Intergenic unequal crossing-over and gene conversions are important but are not the primary mechanisms generating variation.Plants, like animals, are continually challenged by a myriad of potential pathogens. There is increasing evidence that defense systems of plants are at least as complex as vertebrate defense systems. Unlike animals, however, plants do not have a circulatory system and therefore cannot rely on a specialized, proliferative immune system. Each plant cell has to be capable of defense, even though this defense is coordinated locally and systemically between cells. There are a variety of types of resistance genes and mechanisms, some induced and some constitutive (for review, see Godiard et al. 1994;Michelmore 1995;Hammond-Kosack and Jones 1997). Often, although not always, disease resistance in plants is determined by single, usually dominant, genes. The recent cloning of several such resistance genes (R genes) is providing insight into their function and evolution. The defense system of plants may be ancient and predate the evolution of the immune system; genes similar to plant R genes have been identified in mammals van der Biezen and Jones 1998).In this review we consider what is known about the genomic organization and evolution of disease resistance genes in plants. The picture that is emerging for the organization and evolution of plant R genes is similar to that of the vertebrate major histocompatibility complex (MHC), T-cell receptor (TCR), and immunoglobulin genes. Therefore, although the specific types of genes involved are different, the evolutionary forces shaping the plant and vertebrate defense systems may be similar. We propose a model for the evolution of plant R genes that is adapted and expanded from a m...

show abstract

The molecular and cellular basis of affinity maturation in the antibody response

Cited by 201 publications

References 9 publications

Soluble antigen profoundly reduces memory B-cell numbers even when given after challenge immunization.

Soluble antigen profoundly reduces memory B-cell numbers even when given after challenge immunization.

Memory cell generation ablated by soluble protein antigen by means of effects on T- and B-lymphocyte compartments.

Clusters of Resistance Genes in Plants Evolve by Divergent Selection and a Birth-and-Death Process

Contact Info

Product

Resources

About