Somatic mutation leads to efficient affinity maturation when centrocytes recycle back to centroblasts

Oprea, Mihaela; Perelson, Alan S.

doi:10.1016/s0165-2478(97)87000-9

Cited by 108 publications

(150 citation statements)

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“…Intraclonal diversification was not evident in the majority of samples from infants < 6 months old, but this probably reflects the paucity of mutations. Since clonal diversification is believed to result from mutated/selected cells reentering the mutation process in the germinal centre [21,24], this evidence supports the conclusion that germinal centres may operate normally from a young age, although the frequency of such events is low before 6 months old.…”

Section: Discussionsupporting

confidence: 59%

Somatic mutation of immunoglobulin VH6 genes in human infants

Ridings

Dinan

Williams

et al. 1998

Clinical and Experimental Immunology

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SUMMARYInfants respond to antigen by making antibody that is generally of low affinity for antigen. Somatic hypermutation of immunoglobulin genes, and selection of cells expressing mutations with improved affinity for antigen, are the molecular and cellular processes underlying the maturation of antibody affinity. We have reported previously that neonates and infants up to 2 months of age, including individuals undergoing strong immunological challenge, show very few mutated V H 6 sequences, with low mutation frequencies in mutated sequences, and little evidence of selection. We have now examined immunoglobulin genes from healthy infants between 2 and 10 months old for mutation and evidence of selection. In this age group, the proportion of V H 6 sequences which are mutated and the mutation frequency in mutated sequences increase with age. There is evidence of selection from 6 months old. These results indicate that the process of affinity maturation, which depends on cognate T-B cell interaction and functional germinal centres, is approaching maturity from 6 months old.Keywords somatic hypermutation antibody response paediatric immunology affinity maturation immunoglobulin genes V H 6

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Section: Discussionsupporting

confidence: 59%

Somatic mutation of immunoglobulin VH6 genes in human infants

Ridings

Dinan

Williams

et al. 1998

Clinical and Experimental Immunology

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“…Bell (6)(7)(8) led to the first computer simulations of affinity maturation and demonstrated the theoretical basis for clonal selection in the Ab immune response. Subsequent work by Oprea, Perelson, and Kepler (9)(10)(11) developed simulation approaches to study somatic hypermutation and GC dynamics. Contributions by later modeling and simulation efforts included the elucidation of the role of key immune system properties, such as repertoire size, diversity, and somatic mutation rates (12,13), and the development of detailed kinetic models of B cell GC dynamics and morphologies (9,14,15).…”

mentioning

confidence: 99%

“…Subsequent work by Oprea, Perelson, and Kepler (9)(10)(11) developed simulation approaches to study somatic hypermutation and GC dynamics. Contributions by later modeling and simulation efforts included the elucidation of the role of key immune system properties, such as repertoire size, diversity, and somatic mutation rates (12,13), and the development of detailed kinetic models of B cell GC dynamics and morphologies (9,14,15). Pioneering research by Perelson and other investigators (12,16,17) helped to develop an immunological "shape space" model for representing complex shape-based Ab-Ag interactions.…”

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confidence: 99%

Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

Chaudhury

Reifman

Wallqvist

2014

The Journal of Immunology

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Polyvalent vaccines use a mixture of Ags representing distinct pathogen strains to induce an immune response that is cross-reactive and protective. However, such approaches often have mixed results, and it is unclear how polyvalency alters the fine specificity of the Ab response and what those consequences might be for protection. In this article, we present a coarse-grain theoretical model of B cell affinity maturation during monovalent and polyvalent vaccinations that predicts the fine specificity and cross-reactivity of the Ab response. We stochastically simulate affinity maturation using a population dynamics approach in which the host B cell repertoire is represented explicitly, and individual B cell subpopulations undergo rounds of stimulation, mutation, and differentiation. Ags contain multiple epitopes and are present in subpopulations of distinct pathogen strains, each with varying degrees of cross-reactivity at the epitope level. This epitope- and strain-specific model of affinity maturation enables us to study the composition of the polyclonal response in granular detail and identify the mechanisms driving serum specificity and cross-reactivity. We applied this approach to predict the Ab response to a polyvalent vaccine based on the highly polymorphic malaria Ag apical membrane antigen-1. Our simulations show how polyvalent apical membrane Ag-1 vaccination alters the selection pressure during affinity maturation to favor cross-reactive B cells to both conserved and strain-specific epitopes and demonstrate how a polyvalent vaccine with a small number of strains and only moderate allelic coverage may be broadly neutralizing. Our findings suggest that altered fine specificity and enhanced cross-reactivity may be a universal feature of polyvalent vaccines.

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“…It is particularly not clear how the processes of SHM and selection interact dynamically and temporally to shape the memory B-cell repertoire, on which the system depends for fast antigen elimination in subsequent encounters [30][31][32][33], although several models have been suggested based on imaging studies [34][35][36]. Bioinformatical approaches utilized so far in the study of affinity maturation include the analysis of the frequencies of specific types of mutation [37][38][39][40][41][42][43][44][45] and mathematical models exploring the dynamical interactions between SHM and clonal selection [46][47][48][49][50][51] and their spatial segregation [52][53][54][55].Previous histological and molecular studies of autoimmune diseases have found that autoimmune B-cell clones undergo SHM and antigen-mediated selection [55][56][57][58]. A major contribution to the understanding of the pathogenesis of IBD and particularly UC can be achieved by analysis of the B-cell clones participating in immune responses in the gut, in particular their Ig variable region gene diversity.…”

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confidence: 99%

B‐cell clonal diversification and gut‐lymph node trafficking in ulcerative colitis revealed using lineage tree analysis

et al. 2008

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In studies of inflammatory bowel diseases (IBD), research has so far focused mainly on the role of T cells. Despite evidence suggesting that B cells and the production of autoantibodies may play a significant role in IBD pathogenesis, the role of B cells in gut inflammation has not yet been thoroughly investigated. In the present study we used the new approach of lineage tree analysis for studying immunoglobulin variable region gene diversification in B cells found in the inflamed intestinal tissue of two ulcerative colitis patients as well as B cells from mucosa-associated lymph nodes (LN) in the same patients. Healthy intestinal tissue of three patients with carcinoma of the colon was used as normal control. Lineage tree shapes revealed active immune clonal diversification processes occurring in ulcerative colitis patients, which were quantitatively similar to those in healthy controls. B cells from intestinal tissues and the associated LN are shown here to be clonally related, thus supplying the first direct evidence supporting B-cell trafficking between gut and associated LN in IBD and control tissues. IntroductionUlcerative colitis (UC), one of the idiopathic inflammatory bowel diseases (IBD), is a chronic relapsing inflammatory disorder that may lead to significant impairment of gastrointestinal structure and function. UC usually involves the large intestine and extends proximally from the rectum upwards in a continuous fashion. Histologically, inflammation is usually limited to the mucosal layer and may involve ulceration and crypt abscess formation. UC has also been linked to an increased risk of gastrointestinal malignancy [1].Despite recent progress in IBD research, in human subjects as well as a wide variety of experimental animal models, many questions concerning the immunological and genetic basis of the disease remain unanswered. The mucosa-associated lymphoid 2600tissue of the gastrointestinal tract has the important tasks of, on the one hand, recognizing harmful pathogens and antigens within the gut and mounting an appropriate immune response against them and, on the other hand, knowing when and how to dampen or suppress that response once the assault has been cleared or when commensal flora or self-antigens are encountered [2]. The pathogenesis of IBD appears to be related to a disruption of that finely tuned and regulated balance which exists within the mucosa-associated lymphoid tissue, resulting in deregulated and exaggerated local immune responses. This imbalance is most probably a result of complex genetic, environmental, and immunological susceptibility factors [3].Experimental models of intestinal inflammation indicate that mucosal inflammation is probably mediated either by excessive effector T-cell function or deficient regulatory T-cell function. Exaggerated T helper 1 cell response associated with increased secretion of IL-12, IFN-g and/or TNF results in a Crohn's Disease (CD)-like colitis in these experimental models, and exaggerated T helper 2 cell response associated with increas...

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Somatic mutation leads to efficient affinity maturation when centrocytes recycle back to centroblasts

Cited by 108 publications

References 0 publications

Somatic mutation of immunoglobulin VH6 genes in human infants

Somatic mutation of immunoglobulin VH6 genes in human infants

Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

B‐cell clonal diversification and gut‐lymph node trafficking in ulcerative colitis revealed using lineage tree analysis

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