Chemokine Receptor Activation Enhances Memory B Cell Class Switching Linked to IgE Sensitization to Alpha Gal and Cardiovascular Disease

Tanyaporn Pattarabanjird; Jeffrey M Wilson; Loren D Erickson; Lisa J Workman; Hui Qiao; Yanal Ghosheh; Rishab Gulati; Chistopher Durant; Jenifer Vallejo; Ryosuke Saigusa; Thomas A E Platts-Mills; Angela M Taylor; Klaus Ley; Coleen A McNamara

doi:10.3389/fcvm.2021.791028

Chemokine Receptor Activation Enhances Memory B Cell Class Switching Linked to IgE Sensitization to Alpha Gal and Cardiovascular Disease

Front Cardiovasc Med. 2022 Jan 13:8:791028. doi: 10.3389/fcvm.2021.791028. eCollection 2021.

Authors

Tanyaporn Pattarabanjird^{1

2

3}, Jeffrey M Wilson⁴, Loren D Erickson^{1

5}, Lisa J Workman⁴, Hui Qiao^{1

5}, Yanal Ghosheh⁶, Rishab Gulati⁶, Chistopher Durant⁶, Jenifer Vallejo⁶, Ryosuke Saigusa⁶, Thomas A E Platts-Mills⁴, Angela M Taylor⁷, Klaus Ley⁶, Coleen A McNamara^{1

2

7}

Affiliations

¹ Carter Immunology Center, University of Virginia, Charlottesville, VA, United States.
² Cardiovascular Research Center, University of Virginia, Charlottesville, VA, United States.
³ Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States.
⁴ Division of Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, United States.
⁵ Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, United States.
⁶ La Jolla Institute of Immunology, La Jolla, CA, United States.
⁷ Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, United States.

Abstract

Background: Recent studies have suggested that IgE sensitization to α-gal is associated with coronary artery disease (CAD). However, the B cell subtype(s) responsible for production of IgE to α-gal and mechanisms mediating this production remain elusive. Methods: Single cell multi-omics sequencing, was utilized to phenotype B cells obtained from 60 subjects that had undergone coronary angiography in whom serum IgE was evaluated by ImmunoCAP. Bioinformatics approaches were used to identify B cell subtype(s) and transcriptomic signatures associated with α-gal sensitization. In vitro characterization of chemokine/chemokine receptor pairs on switched memory B cells associated with IgE to α-gal was performed. Results: Of the 60 patients, 17 (28%) were positive for IgE to α-gal. CITESeq identified CCR6+ class-switched memory (SWM) B cells and CXCR4 expresssion on these CCR6+ SWM B cells as significantly associated with IgE sensitization to α-gal but not to other common allergens (peanut or inhalants). In vitro studies of enriched human B cells revealed significantly greater IgE on SWM B cells with high CCR6 and CXCR4 expression 10 days after cells were treated with IL-4 and CD40 to stimulate class switch recombination. Both CCL20 (CCR6 ligand) and CXCL12 (ligand for CXCR4) increased the expression of IgE on SWM B cells expressing their receptors. However, they appeared to have unique pathways mediating this effect as only CCL20 increased activation-induced cytidine deaminase (AID), while CXCL12 drove proliferation of CXCR4+ SWM B cells. Lastly, correlation analysis indicated an association between CAD severity and the frequency of both CCR6+ SWM and CXCR4+ SWM B cells. Conclusions: CCR6+ SWM B cells were identified as potential producers of IgE to α-gal in CAD patients. Additionally, our findings highlighted non-chemotaxis roles of CCL20/CCR6 and CXCL12/CXCR4 signaling in mediating IgE class switching and cell proliferation of SWM B cells respectively. Results may have important implications for a better understanding and better therapeutic approaches for subjects with IgE sensitization to α-gal.

Keywords: B cells; CITESeq; IgE class switching; alpha-gal; coronary artery disease.

Abstract

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