Decision criteria for resolving isotype switching conflicts by B cells

Deenick, Elissa K.; Hasbold, Jhagvaral; Hodgkin, Philip D.

doi:10.1002/eji.200425719

Cited by 71 publications

(46 citation statements)

References 37 publications

(56 reference statements)

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“…TGFβ was also shown to have no effect on IL-4-mediated class switch to IgG1 [47]. Therefore, while mediators such as TGFβ may inhibit IgE production, other cytokines such as IFNγ may drive IgG1 production [47]. Our data also demonstrated a significant reduction in total IgE in immunized-only LPS-tolerant mice, as well as those receiving both allergen challenges.…”

Section: Discussionsupporting

confidence: 70%

“…Previous studies have reported that TGFβ and IL-10 can inhibit IL-4-mediated class switch recombination to IgE, a role for TGFβ in mediating endotoxin tolerance has been confirmed [44,45,46]. TGFβ was also shown to have no effect on IL-4-mediated class switch to IgG1 [47]. Therefore, while mediators such as TGFβ may inhibit IgE production, other cytokines such as IFNγ may drive IgG1 production [47].…”

Section: Discussionmentioning

confidence: 99%

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Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

Natarajan

Kim²,

Bouchard³

et al. 2012

Int Arch Allergy Immunol

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Background: Compounds which activate the innate immune system, such as lipopolysaccharide, are significant components of ambient air, and extremely difficult to remove from the environment. It is currently unclear how prior inhalation of endotoxin affects allergen sensitization. We examined whether lung-specific endotoxin tolerance induction prior to sensitization can modulate the response to allergen. Methods: Endotoxin tolerance was induced by repeated intratracheal exposure to endotoxin. All mice were then sensitized and challenged by direct intratracheal instillation of cockroach allergen. Results: After allergen sensitization and challenge, endotoxin tolerant mice had significantly decreased airways hyperresponsiveness to methacholine challenge, which was confirmed by invasive lung function tests. Decreased goblet cell hyperplasia and mucus production were also found by histological assessment. Tolerant mice were protected from airway eosinophilia through the mechanism of reduced CCL11 and CCL24. Interestingly, endotoxin tolerant mice had only a modest reduction in cockroach-specific IgE; however, total IgE was significantly reduced. Conclusions: These data show that induction of endotoxin tolerance prior to sensitization protects against the hallmark features of asthma-like inflammation, and that transient modulation of innate immunity can have long-lasting effects on adaptive responses.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

Natarajan

Kim²,

Bouchard³

et al. 2012

Int Arch Allergy Immunol

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“…Single-cell suspensions were prepared from spleens and lymph nodes of mice, and red cells were lysed and run on discontinuous Percoll density gradients as described (41). Small dense cells were harvested from the 65%/80% interface, and B cells were purified by means of negative selection by using magnetic beads (Miltenyi Biotec, Bergisch Gladbach, Germany).…”

Section: Methodsmentioning

confidence: 99%

A model of immune regulation as a consequence of randomized lymphocyte division and death times

Hawkins

Turner²,

Dowling³

et al. 2007

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

160

394

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The magnitude of an adaptive immune response is controlled by the interplay of lymphocyte quiescence, proliferation, and apoptosis. How lymphocytes integrate receptor-mediated signals influencing these cell fates is a fundamental question for understanding this complex system. We examined how lymphocytes interleave times to divide and die to develop a mathematical model of lymphocyte growth regulation. This model provides a powerful method for fitting and analyzing fluorescent division tracking data and reveals how summing receptor-mediated kinetic changes can modify the immune response progressively from rapid tolerance induction to strong immunity. An important consequence of our results is that intrinsic variability in otherwise identical cells, usually dismissed as noise, may have evolved to be an essential feature of immune regulation.

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“…Importantly, the percentage of switched cells in a given division remained constant over three consecutive days of culture, suggesting that switching was cell division-linked and was largely independent of time. Further work indicated that a division-linked mechanism regulated CSR to all murine Ig isotypes (15,16).Although the cellular regulation of division-linked CSR is well understood, the molecular mechanism underlying the divisiondependence is not. Using a well characterized ex vivo model, we examined several different key molecular events associated with CSR by using cell division as a reference point.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination

Rush

Liu

Odegard

et al. 2005

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

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Class switch recombination (CSR) is the process by which B cells alter the effector function properties of their Ig molecules. The decision to switch to a particular Ig isotype is determined primarily by the mode of B cell activation and cytokine exposure. More recent work indicates that the likelihood or probability of switching increases with successive cell divisions and is largely independent of time. We have analyzed different molecular features of CSR using cell division as a reference point in an attempt to gain insight into the mechanism of division-linked switching. Our results indicated that the accessibility of Ig heavy chain constant regions targeted for CSR was established after the cells had undergone a single cell division and did not vary significantly with subsequent cell divisions. In contrast, expression of activation-induced cytidine deaminase (AID) mRNA was found to increase with successive divisions, exhibiting a striking correlation with the frequency of CSR. Levels of AID in a given division remained constant at different time points, strongly suggesting that the regulation of AID expression was division-linked and independent of time. In addition, constitutive AID expression from a transgene accelerated division-linked CSR. Thus, we propose that the division-linked increase in AID expression provides an underlying molecular explanation for division-linked CSR.B lymphocyte ͉ cell division C lass switch recombination (CSR) is a region-specific DNA recombination mechanism that occurs by exchanging the currently expressed Ig heavy chain constant region (C H ) for another downstream C H region. CSR enables B cells to alter the effector properties of their Ig molecules without altering their antigen specificity. Conceptually, class switching can be divided into three stages of targeting, cleavage, and DNA repair͞rejoining, with specific molecular events associated with each stage. For example, cytokine-induced C H region accessibility is marked by acetylation of histone proteins and germ-line transcription across targeted switch (S) regions (1, 2), highly repetitive sequences upstream of each C H gene except C␦. S region cleavage involves the introduction of DNA lesions in S regions targeted for recombination (3-5), and finally, the rejoining of the cleaved ends requires a number of ubiquitously expressed DNA repair factors. In addition, CSR absolutely requires the activity of the activation-induced cytidine deaminase (AID) (6). Although originally speculated to be an RNA-editing enzyme, recent data strongly suggest that AID functions as a DNA deaminase (7,8), acting in the context of transcription to deaminate cytosines on single-stranded DNA templates within S regions before the introduction of double-stranded lesions (9-11).Class switching to particular Ig isotypes in vivo is determined by a combination of exposure to pathogenic stimuli, T cell help, and particular cytokines (reviewed in ref. 12). Induction of switching to all of the different Ig isotypes can be recapitulated ex vivo, which...

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Decision criteria for resolving isotype switching conflicts by B cells

Cited by 71 publications

References 37 publications

Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

A model of immune regulation as a consequence of randomized lymphocyte division and death times

Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination

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