Immunoglobulin class switching appears to be regulated by <scp>B</scp>‐cell antigen receptor‐specific <scp>T</scp>‐cell action

Lange, Hans; Hecht, Oliver; Zemlin, Michael; Trad, Ahmad; Tănasă, Radu Iulian; Schroeder, Harry W.; Lemke, Hilmar

doi:10.1002/eji.201141857

Cited by 10 publications

(25 citation statements)

References 61 publications

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“…In accordance with historical studies, in WT mice the anti-phOx response exhibited a drastic CSR-associated reduction in the variability of the V H and V L repertoires (10) (Figures 2A,D), especially in the class switched secondary response. No such reduction in V H or V L variability was observed in the D-altered ΔD-DμFS and ΔD-iD mice (Figures 2B,E and C,F).…”

Section: Resultssupporting

confidence: 88%

“…A compilation of previous data (9, 10) shows that mAb with the gene combination V H 171/V κ 072 (the “genetic” Id Ox1 ) first dominate after CSR among IgG mAb (Figure 2G). This gene combination is counter-selected in secondary response mAb, but increases again in tertiary and quaternary responses.…”

Section: Resultsmentioning

confidence: 71%

“…A comparison of these mAb with those of previously published mAb (10) from WT mice revealed crucial differences induced by the change in D H sequence content. Unlike WT mice, where the majority of hybridomas ( >80%) isolated during late primary responses and on day 3 of secondary and tertiary responses produce IgG, and thus reflect T cell aided CSR (15); only half of the hybridomas obtained from the D-altered ΔD-DμFS and ΔD-iD mice produced IgG.…”

Section: Resultsmentioning

confidence: 88%

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Clonal Progression during the T Cell-Dependent B Cell Antibody Response Depends on the Immunoglobulin DH Gene Segment Repertoire

et al. 2014

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The diversity of the third complementarity determining region of the IgH chain is constrained by natural selection of immunoglobulin diversity (DH) sequence. To test the functional significance of this constraint in the context of thymus-dependent (TD) immune responses, we immunized BALB/c mice with WT or altered DH sequence with 2-phenyloxazolone-coupled chicken serum albumin (phOx-CSA). We chose this antigen because studies of the humoral immune response to the hapten phOx were instrumental in the development of the current theoretical framework on which our understanding of the forces driving TD responses is based. To allow direct comparison, we used the classic approach of generating monoclonal Ab (mAb) from various stages of the immune response to phOx to assess the effect of changing the sequence of the DH on clonal expansion, class switching, and affinity maturation, which are hallmarks of TD responses. Compared to WT, TD-induced humoral IgM as well as IgG antibody production in the D-altered ΔD-DμFS and ΔD-iD strains were significantly reduced. An increased prevalence of IgM-producing hybridomas from late primary, secondary, and tertiary memory responses suggested either impaired class switch recombination (CSR) or impaired clonal expansion of class switched B cells with phOx reactivity. Neither of the D-altered strains demonstrated the restriction in the VH/VL repertoire, the elimination of VH1 family-encoded antibodies, the focusing of the distribution of CDR-H3 lengths, or the selection for the normally dominant Ox1 clonotype, which all are hallmarks of the anti-phOx response in WT mice. These changes in clonal selection and expansion, as well as CSR indicate that the genetic constitution of the DH locus, which has been selected by evolution, can strongly influence the functional outcome of a TD humoral response.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 88%

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Clonal Progression during the T Cell-Dependent B Cell Antibody Response Depends on the Immunoglobulin DH Gene Segment Repertoire

et al. 2014

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“…This idea is consistent with the suggestion by Davies et al (56,64,65) that atopic sensitization is predominantly caused by IgE production through the direct route, as even low-affinity IgE is sufficient to catch allergen and to trigger basophils. Moreover, several studies indicate that maximum Ag affinity neither is achieved by a maximum somatic mutation rate nor is the primary criterion for class switch recombination (66). Of note, although IgG4 transcripts contained a higher somatic mutation rate, on average they less frequently showed indications of Ag-driven selection than IgE transcripts.…”

Section: Discussionmentioning

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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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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“…Several studies by Schroeder Jr et al elucidated detailed features of the CDRH3 repertoire in various murine B cell populations, in terms of length, amino acid composition, and average hydrophobicity. Among them, the key feature of CDRH3 repertoire development in both BALB/c and C57BL/6 mice is an increase in average CDRH3 length with B cell maturation [24][25][26]. However, use of all the above features as accurate reflections of the entire BCR repertoire has been challenged, as they were deduced from the analysis of a limited number of μ chain transcripts containing only V H 7183 family members.…”

Section: Introductionmentioning

confidence: 99%

Development of the expressed immunoglobulin &Mgr; chain repertoire during maturation of mice B cells

Liu¹,

Luo²,

Sun³

et al. 2014

Front. Agr. Sci. Eng.

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In the bone marrow and spleen, the developing B cell populations undergo both negative and positive selections to shape their B cell receptor repertoire. To gain insight into the shift of the immunoglobulin heavy (IgH) chain repertoire during B cell development, we undertook large scale Ig μ chain repertoire analysis of pre-B, immature B and spleen B cell populations. We found that the majority of V H gene segments, V H families, J H and D gene segments, were observed to have significantly different usage frequencies when three B cell populations were compared, but the usage profile of the V H, D, and J H genes between different B cell populations showed high correlations. In both productive and nonproductive rearrangements, the length of CDRH3 shortened significantly on average when B cells entered the periphery. However, the CDRH3 length distribution of nonproductive rearrangements did not follow a Gaussian distribution, but decreased successively in the order 3n -2, 3n -1 and 3n, suggesting a direct correlation between mRNA stability and CDRH3 length patterns of nonproductive rearrangements. Further analysis of the individual components comprising CDRH3 of productive rearrangements indicated that the decrease in CDRH3 length was largely due to the reduction of N addition at the 5′ and 3′ junctions. Moreover, with development, the amino acid content of CDRH3 progressed toward fewer positively charged and nonpolar residues but more polar residues. All these data indicated that the expressed Ig μ chain repertoire, especially the repertoire of CDRH3, was fine-tuned when B cells passed through several checkpoints of selection during the process of maturation.

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Immunoglobulin class switching appears to be regulated by B‐cell antigen receptor‐specific T‐cell action

Cited by 10 publications

References 61 publications

Clonal Progression during the T Cell-Dependent B Cell Antibody Response Depends on the Immunoglobulin DH Gene Segment Repertoire

Clonal Progression during the T Cell-Dependent B Cell Antibody Response Depends on the Immunoglobulin DH Gene Segment Repertoire

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

Development of the expressed immunoglobulin &Mgr; chain repertoire during maturation of mice B cells

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