Plasma Cells and Nonplasma B Cells Express Differing IgE Repertoires in Allergic Sensitization

Rogosch, Tobias; Kerzel, Sebastian; Sikula, L; Gentil, Katrin; Liebetruth, Michael; Schlingmann, Karl‐Peter; Maier, Rolf F.; Zemlin, Michael

doi:10.4049/jimmunol.0900859

Cited by 13 publications

(17 citation statements)

References 52 publications

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“…The lower average somatic mutation rate of IgE transcripts could also be explained by the fact that IgE-expressing cells that evolve from IgM (direct route) might at least initially contain fewer somatic mutations (56). This fact might be the reason that a higher and a lower mutated subpopulation of IgE transcripts in humans (35), and even more pronounced in mice (47), can be distinguished that are not easily accessible for separate transcriptome analyses. We hypothesize that the fraction of IgE-expressing cells with fewer somatic mutations predominantly represents those cells that were recruited from naive IgM-expressing B cells ("direct route," IgM→IgE) and that the cells expressing highly mutated IgE transcripts originate from the "indirect route" (IgM→IgG4→IgE).…”

Section: Discussionmentioning

confidence: 99%

“…The CDRH3 was defined to include those residues between the conserved cysteine (C104) of FRH3and the conserved tryptophan (W118) of FR-H4. Somatic mutation rates and Ag selection were studied in the VH genes, using the algorithms of Dahlke et al (44), Lossos et al (45), and Chang and Casali (46), as described previously (47). Sequence analyses were performed using IMGT/V-QUEST (42) and the Ig analysis tool (IgAT) (48).…”

Section: Sequence Analysismentioning

confidence: 99%

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IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection

Rogosch

Kerzel

Dey

et al. 2014

The Journal of Immunology

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The physiologic function of the “odd” Ab IgG4 remains enigmatic. IgG4 mediates immunotolerance, as, for example, during specific immunotherapy of allergies, but it mediates tissue damage in autoimmune pemphigus vulgaris and “IgG4-related disease.” Approximately half of the circulating IgG4 molecules are bispecific owing to their unique ability to exchange half-molecules. Better understanding of the interrelation between IgG4 and IgE repertoires may yield insight into the pathogenesis of allergies and into potential novel therapies that modulate IgG4 responses. We aimed to compare the selective forces that forge the IgG4 and IgE repertoires in allergic asthma. Using an IgG4-specific RT-PCR, we amplified, cloned, and sequenced IgG4 H chain transcripts of PBMCs from 10 children with allergic asthma. We obtained 558 functional IgG4 sequences, of which 286 were unique. Compared with previously published unique IgE transcripts from the same blood samples, the somatic mutation rate was significantly enhanced in IgG4 transcripts (62 versus 83%; p < 0.001), whereas fewer IgG4 sequences displayed statistical evidence of Ag-driven selection (p < 0.001). On average, the hypervariable CDRH3 region was four nucleotides shorter in IgG4 than in IgE transcripts (p < 0.001). IgG4 transcripts in the circulation of children with allergic asthma reflect some characteristics of classical Ag-driven B2 immune responses but display less indication of Ag selection than do IgE transcripts. Although allergen-specific IgG4 can block IgE-mediated allergen presentation and degranulation of mast cells, key factors that influence the Ag-binding properties of the Ab differ between the overall repertoires of circulating IgG4- and IgE-expressing cells.

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Section: Discussionmentioning

confidence: 99%

Section: Sequence Analysismentioning

confidence: 99%

IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection

Rogosch

Kerzel

Dey

et al. 2014

The Journal of Immunology

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“…Therefore, most such studies chose patients with atopic dermatitis with extremely high IgE titers (3,9). We have recently found indication that the IgE response might differ between allergic sensitization and helminth infection (15), but it is still unknown if the IgE response also differs between different allergic disease entities (e.g., allergic asthma, allergic rhinitis, atopic dermatitis). Systematic analyses of IgE transcripts in patients with moderately elevated IgE levels, especially in children, have not yet been published.…”

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confidence: 99%

IgE Transcripts in the Circulation of Allergic Children Reflect a Classical Antigen-Driven B Cell Response and Not a Superantigen-Like Activation

Kerzel

Rogosch

Struecker

et al. 2010

The Journal of Immunology

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Allergic asthma is the most frequent chronic disorder in childhood. Although IgE is a central effector molecule in allergic diseases, the nature of the IgE response is still under debate. The objective of our study was to clarify whether the IgE repertoire in the circulation of allergic children represents a classical Ag-driven and oligoclonal B cell response, a superantigen-like activation of a subset of B cells, or a polyclonal B-1 cell expansion. Using a highly sensitive RT-PCR method, we amplified, cloned, and sequenced IgE H chain transcripts from 13 children with allergic asthma. We gained 1366 functional IgE sequences, which currently represent the most extensive collection of human IgE transcripts. Compared to IgM transcripts from the same children, the somatic mutation rate was significantly enhanced in IgE transcripts (21‰ versus 72‰; p < 0.001), which renders a polyclonal B-1 response unlikely. Moreover, IgE sequences displayed significantly enhanced Ag selection and hence were indicative of a classical Ag-driven immune response with affinity maturation (p < 0.001). In contrast to several recent studies, the usage pattern of variable gene segment of the H Ig chain in IgE transcripts followed the germline complexity, arguing against a superantigen-like interaction. We conclude that IgE transcripts in the circulation of children with allergic asthma reflect a classical adaptive B-2 cell response. This study provides reference data for a better characterization of the IgE response under immunomodulating therapies, such as anti-IgE therapy or allergen-specific immunotherapy.

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“…It is plausible that the same ligand that is responsible for binding IgM and IgG is also binding IgE. The existence of an alternative ligand was further supported by the fact that the IgE binding was of significant strength to withstand an acid treatment, which previously has been shown to disrupt CD23-IgE binding [29]. We acknowledge the possibility that the increased IgE level could be solely due to class switching although we believe To test if this excessive binding made NOD B cells more efficient in rescuing IgE-mediated immune responses, we performed the adoptive transfer experiment described by Henningsson et al [27].…”

Section: Discussionmentioning

confidence: 89%

“…To elucidate the role of CD23 in the increased IgE capture of NOD B cells, we used a protocol by Rogosch et al [29] where a short incubation in a low pH buffer leads to the dissociation of CD23 and IgE. As shown in Figure 3(A), IgE levels decreased after acid treatment, but the difference remained significant between NOD and B6 B cells, indicating that increased CD23 mediated IgE binding in the NOD cannot be the sole explanation for this feature.…”

Section: Capture Of Ige Is Increased Across All Ages In Nod Mice and mentioning

confidence: 99%

Contribution of autoallergy to the pathogenesis in the NOD mice

et al. 2015

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The immunoglobulin isotype IgE is commonly associated with allergy. However, its involvement in autoimmune disease in general, and Type 1 diabetes (T1D) in particular, is still not completely clarified, nonetheless IgE has been observed in patients with T1D. In this article, we aimed to elucidate the contribution of IgE in the pathogenesis of the disease in a spontaneous model for T1D, i.e. the NOD mouse. We observed increased levels of IgE in splenic, lymph node and peripheral blood B cells in the NOD mice compared to the control C57BL/6 (B6) mice. No correlation was found between the IgE levels on B cells and those in the sera of these mice, indicating a B cell intrinsic property mediating IgE capture in NOD. Functionally, the B cells from NOD were similar to B6 in rescuing the IgE-mediated immune response via the low affinity receptor CD23 in a transgenic adoptive transfer system. However, the involvement of IgE in diabetes development was clearly demonstrated, as treatment with anti-IgE antibodies delayed the incidence of the diabetes in the NOD mice compared to the PBS treated group. Pancreas sections from a 13-week-old NOD revealed the presence of tertiary lymphoid structures with T cells, B cells, germinal centers and IgE suggesting the presence of autoantigen specific IgE. Our study provides an insight to the commonly overlooked immunoglobulin IgE and its potential role in autoimmunity.

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Plasma Cells and Nonplasma B Cells Express Differing IgE Repertoires in Allergic Sensitization

Abstract: Material

Cited by 13 publications

References 52 publications

IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection

IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection

IgE Transcripts in the Circulation of Allergic Children Reflect a Classical Antigen-Driven B Cell Response and Not a Superantigen-Like Activation

Contribution of autoallergy to the pathogenesis in the NOD mice

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