Maturation of the immune response in germinal centers

Berek, Claudia; Berger, Abi; Apel, M.

doi:10.1016/0092-8674(91)90289-b

Cited by 818 publications

(557 citation statements)

References 34 publications

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“…The finding of heterogeneous, somatically mutated IgG sequences as early as 14 days after premature birth suggests that already early in the third trimester of gestation the immune system of the neonate is sufficiently developed to respond to an external antigenic stimulus. The findings of somatic mutations with evidence of Ag selection and of clonally related sequences are hallmarks of the germinal center reaction (33,34). The knowledge of the development of the IgG memory B cell population in infancy is still incomplete.…”

Section: Evolution Of Class-switched Igg Rearrangements During Ag Expmentioning

confidence: 99%

Diversification of Ig Heavy Chain Genes in Human Preterm Neonates Prematurely Exposed to Environmental Antigens

Bauer

Zemlin

Hummel

et al. 2002

The Journal of Immunology

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Preterm neonates are exposed to extrauterine environmental Ags during the time period that corresponds to the last trimester of normal intrauterine development. To study whether this precocious exposure to Ags accelerates the Ig repertoire diversification, we compared IgH chain genes of preterm neonates (gestational age, 25–29 wk) during their first postnatal months with those of term neonates. Preterm infants approaching their expected date of delivery after 8–13 wk of extrauterine life used a similar VH, DH, and JH gene segment repertoire as term neonates born after intrauterine development. Furthermore, the length increase of the NDN region between VH and JH by 0.25 nt per gestational week (r = 0.556, p < 0.0001) was not accelerated. Thus, the generation of the VH region gene repertoire is developmentally controlled and independent of environmental influences. However, exposure to extrauterine Ags induced class switch and somatic mutations in IgH chain genes within 2 wk after premature birth and IgG transcript diversity and mutational frequency increased with the duration of extrauterine life. Three-month-old preterm infants expressed a heterogeneous IgG repertoire at their expected date of delivery with VH region genes carrying significant numbers of somatic mutations with evidence for Ag selection. Term neonates, however, had no such IgG repertoire. We conclude that restrictions in the neonatal Ig VH region gene repertoire persist until term despite exposure to environmental Ags. Yet, many weeks before term the immune system of the preterm neonate can already support germinal center reactions in response to environmental Ags.

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Section: Evolution Of Class-switched Igg Rearrangements During Ag Expmentioning

confidence: 99%

Diversification of Ig Heavy Chain Genes in Human Preterm Neonates Prematurely Exposed to Environmental Antigens

Bauer

Zemlin

Hummel

et al. 2002

The Journal of Immunology

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“…The GC reaction is initiated by rapid proliferation of few antigen-stimulated B cells called centroblasts. The vigorous proliferation is associated with somatic hypermutation of Ig V region genes leading to diversification of antigen receptor repertoire [1]. Because the somatic hypermutation is a random process, only rare mutations increase the affinity of the antigen receptor.…”

Section: Introductionmentioning

confidence: 99%

Kinetics and signaling requirements of CD40‐mediated protection from B cell receptor‐induced apoptosis

et al. 2003

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In the present study we used a human follicular lymphoma cell line, HF1A3, as an in vitro model for the antigen-driven selection process in germinal centers. Apoptosis can be induced in HF1A3 cells by B cell receptor (BCR) stimulation, but the molecular mechanisms and kinetics of this process are largely unknown. We demonstrate here that there is over 12 h delay between receptor activation and the execution phase of apoptosis, i.e. disruption of mitochondrial membrane potential, release of cytochrome c from mitochondria, caspase-3 activation and DNA fragmentation. New protein synthesis is required for mitochondrial alterations and subsequent apoptosis to occur, as these processes are completely blocked by the protein synthesis inhibitor cycloheximide. All the apoptotic events induced by BCR triggering are completely reversed by CD40 ligation with anti-CD40 antibody. CD40 ligation can reverse the apoptotic process in HF1A3 cells almost until the first mitochondrial events take place demonstrating that CD40-mediated protection operates very fast and at or before mitochondrial phase of apoptosis. Using specific inhibitors of cell signaling we could demonstrate that Raf-extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, p38 or protein kinase C activation pathways are not involved in CD40-mediated protection from BCR-induced apoptosis in HF1A3 cells.

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“…It is known that GC reaction is primarily responsible for generation of memory B cells as well as the long-lived plasma cells (Berek et al, 1991;Gray, 1993;Jacob et al, 1991). Therefore, it is interesting that IgM-deficient mice exhibit vigorous GC formation during the primary response.…”

Section: Discussionmentioning

confidence: 99%

IgM-mediated signaling is required for the development of a normal B cell memory response

Guo

Zhang

Zheng

et al. 2008

Molecular Immunology

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Mature B cells co-express both IgM and IgD types of antigen receptors before activation. Our earlier work has shown that the co-expression of IgD and IgM plays an important role in regulating the composition of antibody repertoire during a primary immune response. However, the roles of these two B cell receptors in the development of B cell memory responses remain unclear. The present study shows that during the secondary immune response to (4-hydroxy-3-nitrophenyl)acetyl (NP), IgM -/-mice secreted significant amount of NP-specific IgD antibodies. The kinetics of antigenspecific IgD antibodies produced in IgM -/-mice was similar to that of IgM antibodies in wild type mice during the secondary response. However, the production of antigen specific class-switched antibodies in IgM -/-mice was significantly reduced compared to that in wild type mice, particularly at the early phase of the memory response. In addition, germinal center (GC) reaction was significantly diminished in IgM -/-mice after secondary challenge with soluble antigen. Nevertheless, affinity maturation of antibodies appears largely intact in IgM -/-mice during memory response. Thus, our studies demonstrate that IgM-mediated signaling plays an important role in the development of efficient B cell memory responses.

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Maturation of the immune response in germinal centers

Cited by 818 publications

References 34 publications

Diversification of Ig Heavy Chain Genes in Human Preterm Neonates Prematurely Exposed to Environmental Antigens

Diversification of Ig Heavy Chain Genes in Human Preterm Neonates Prematurely Exposed to Environmental Antigens

Kinetics and signaling requirements of CD40‐mediated protection from B cell receptor‐induced apoptosis

IgM-mediated signaling is required for the development of a normal B cell memory response

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