IL-4 receptor blockade is a global repressor of naïve B cell development and responses in a dupilumab-treated patient

Mountz, John D.; Gao, Min; Ponder, David M.; Liu, Shanrun; Sun, Chengzhen; Alduraibi, Fatima; Sullivan, Kathryn; Pat, Betty; Dell’Italia, Louis J.; Hsu, Hui‐Chen

doi:10.1016/j.clim.2022.109130

Cited by 8 publications

(11 citation statements)

References 79 publications

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“…Including our own data generated above, our analysis involved four data sets comprising both mouse and human, various models of type 2 immunity, enhanced and abrogated IL-4/IL-13 signaling, and with or without Ag re-exposure ( Fig. 2A ) ( 17 , 32 , 33 ). For each dataset, unsupervised clustering was performed on B cells ( Cd79a + ), which resolved clusters of MBCs classified by absence of Ighd , Tcl1a (human), and Bcl6 (mouse) and the presence of Hhex (mouse) expression ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Pathogenic IgE-fated B cell memory retains functional plasticity

Bruton,

Phelps,

Ariaz

et al. 2023

Preprint

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Long-lived immunoglobulin (Ig) E responses against innocuous environmental and dietary antigens (Ags) are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for IL-4 responsiveness. In this work, we investigated the plasticity of the MBC compartment fated for IgE class switch recombination upon Ag re-exposure. Antibody-mediated IL-4R( blockade augmented the germinal center response and uncovered an IL-4/IL-13 dependency within the type 2 memory B cell (MBC2) skewed phenotype. In the absence of IL-4/IL-13 signaling during the recall response, a long-lived Ag-specific IgG2c MBC population emerged, shifting the MBC response away from a type 2 phenotype and towards type 1. The emergence of this IgG2c response was dependent on IFN-( signaling and arose from both unswitched and class-switched Ag-specific B cells in vivo. We further demonstrated that a type 1-polarizing adjuvant can augment the redirection of type 2-polarized class-switched MBCs, suggesting with the correct cues pathogenic MBCs can be functionally reprogrammed.One Sentence SummaryB cell responses to allergens can be reprogrammed away from a pathogenic fate through IL-4/IL-13 signaling blockade.

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Section: Resultsmentioning

confidence: 99%

Pathogenic IgE-fated B cell memory retains functional plasticity

Bruton,

Phelps,

Ariaz

et al. 2023

Preprint

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“…As is well known, IFNγ is the key cytokine for IgG isotype switching, whereas IL-4 stimulates the proliferation, maturation, and differentiation of B lymphocytes in plasma cells actively secreting IgE and IgG4 [ 67 ]. In addition, IL-4 is essential to maintain naïve B cells and the production of memory B cells after exposure to an antigen or vaccination [ 68 ]. Therefore, a genetically determined increased release of IL-4 might be involved in maintaining optimal IgG production after IFNγ-mediated isotype switch.…”

Section: Discussionmentioning

confidence: 99%

Age and Cytokine Gene Variants Modulate the Immunogenicity and Protective Effect of SARS-CoV-2 mRNA-Based Vaccination

et al. 2023

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The introduction of anti-SARS-CoV-2 vaccines in late 2020 substantially changed the pandemic picture, inducing effective protection in the population. However, individual variability was observed with different levels of cellular response and neutralizing antibodies. We report data on the impact of age, gender, and 16 single nucleotide polymorphisms (SNPs) of cytokine genes on the anti-SARS-CoV-2 IgG titers measured 31 and 105 days after administration of the second dose of BNT162b2 vaccine to 122 healthy subjects from the health care staff of the Palermo University Hospital, Italy. The higher titers at 31 days were measured in the younger subjects and in subjects bearing T-positive genotypes of IL-1R1 rs2234650 or the GG homozygous genotype of IL-6 rs1800795 SNP. T-positive genotypes are also significantly more common in subjects with higher titers at day 105. In addition, in this group of subjects, the frequency of the CT genotype of IL-4 rs2243250 is higher among those vaccinated with higher titers. Moreover, these SNPs and TNFA rs1800629 are differently distributed in a group of subjects that were found infected by SARS-CoV-2 at day 105 of evaluation. Finally, subjects that were found to be infected by SARS-CoV-2 at day 105 were significantly older than the uninfected subjects. Taken together, these data seem to suggest that age and polymorphisms of key cytokines, which regulate inflammation and humoral immune response, might influence the magnitude of the antibody response to vaccination with BNT162B2, prompting speculation about the possible benefit of a genetic background-based assessment of a personalized approach to the anti-COVID vaccination schedule.

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“…Dupilumab treatment resulted in upregulation of genes associated with apoptosis and inhibition of B cell receptor signaling and downregulation of class-switch and memory B cell development genes. Their data suggest that intact and persistent IL-4 signaling is necessary for maintaining robust survival and development of naive B cells [ 35 ]. Hadebe et al.…”

Section: Discussionmentioning

confidence: 99%

The association between eosinophils (CD16+ eosinophils), basophils (CD203+ basophils), and CD23 B lymphocytes in patients with atopic dermatitis on dupilumab therapy: pilot study

Čelakovská

Čermáková

Boudková

et al. 2023

Dermatol Ther (Heidelb)

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Background Eosinophils, basophils, and the molecule CD23 on B cells are involved in the pathophysiology of atopic dermatitis (AD). The molecule CD23 is involved in the regulation of IgE synthesis and is expressed by activated B cells. The molecule CD16 is used to assess the activation of eosinophils and CD203 of basophils. The association between the count of eosinophils, basophils, CD16 + eosinophils, CD203 + basophils and the expression of the activation marker CD23 on B cells in patients with AD (with and without dupilumab therapy) is not described. Objective The aim of this pilot study is to evaluate the association between the blood count of eosinophils, basophils, relative CD16 + eosinophils, relative CD203 + basophils, and the expression of molecule CD23 on B cells and on their subsets (total, memory, naive, switched, non-switched) in patients suffering from AD (with and without dupilumab therapy) and in control group. Methods A total of 45 patients suffering from AD were examined; 32 patients without dupilumab treatment (10 men, 22 women, average age 35 years), 13 patients with dupilumab treatment (7 men, 6 women, average age 43.4 years), and 30 subjects as a control group (10 men, 20 women, average age 44.7 years). Immunophenotype was examined by flow cytometry in which monoclonal antibodies with fluorescent molecules were used. For statistical analysis we used non-parametric Kruskal–Wallis one-factor analysis of variance with post hoc by Dunn’s test with Bonferroni modification and the Spearman’s rank correlation coefficient; for coefficients higher than 0.41, we report R 2 (percent of variation explained). Results The absolute count of eosinophils was significantly higher in patients with AD (with and without dupilumab) in comparison to healthy subjects. The difference in the relative count of CD16 + eosinophils in patients with AD (with and without dupilumab therapy) compared with control is not statistically significant. In patients with dupilumab therapy the significantly lower count of relative CD203 + basophils was confirmed compared with control. The higher association between the count of eosinophils (absolute and relative) and the expression of CD23 marker on B cells was confirmed in patients with dupilumab therapy; in contrast, this association was low in patients with AD without dupilumab therapy and in healthy subjects. Conclusion The higher association between the count of eosinophils (absolute and relative) and the expression of CD23 marker on B cells was confirmed in patients with AD under dupilumab therapy. It suggests that IL-4 production by eosinophils may play a role in B lymphocyte activation. The significantly lower count of CD203 + ...

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IL-4 receptor blockade is a global repressor of naïve B cell development and responses in a dupilumab-treated patient

Cited by 8 publications

References 79 publications

Pathogenic IgE-fated B cell memory retains functional plasticity

Pathogenic IgE-fated B cell memory retains functional plasticity

Age and Cytokine Gene Variants Modulate the Immunogenicity and Protective Effect of SARS-CoV-2 mRNA-Based Vaccination

The association between eosinophils (CD16+ eosinophils), basophils (CD203+ basophils), and CD23 B lymphocytes in patients with atopic dermatitis on dupilumab therapy: pilot study

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