The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans

Carole Le Coz; Melissa Trofa; Dorothy L Butler; Samuel Yoon; Tian Tian; Whitney Reid; Emylette Cruz Cabrera; Ainsley V C Knox; Caroline Khanna; Kathleen E Sullivan; Jennifer Heimall; Patricia Takach; Olajumoke O Fadugba; Monica Lawrence; Soma Jyonouchi; Hakon Hakonarson; Andrew D Wells; Steven Handler; Karen B Zur; Vinodh Pillai; Jeffrey C Gildersleeve; Neil Romberg

doi:10.1016/j.jaci.2024.04.018

The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans

J Allergy Clin Immunol. 2024 Apr 29:S0091-6749(24)00418-4. doi: 10.1016/j.jaci.2024.04.018. Online ahead of print.

Authors

Carole Le Coz¹, Melissa Trofa², Dorothy L Butler³, Samuel Yoon², Tian Tian⁴, Whitney Reid², Emylette Cruz Cabrera², Ainsley V C Knox², Caroline Khanna², Kathleen E Sullivan⁵, Jennifer Heimall⁶, Patricia Takach⁷, Olajumoke O Fadugba⁷, Monica Lawrence⁸, Soma Jyonouchi⁶, Hakon Hakonarson⁹, Andrew D Wells¹⁰, Steven Handler¹¹, Karen B Zur¹¹, Vinodh Pillai¹², Jeffrey C Gildersleeve³, Neil Romberg¹³

Affiliations

¹ Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA; Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, CNRS, Inserm, Toulouse, France.
² Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.
³ Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD.
⁴ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
⁵ Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
⁶ Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.
⁷ Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, Philadelphia, PA.
⁸ Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA.
⁹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
¹⁰ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.
¹¹ Pediatric Otolaryngology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Otolaryngology: Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA.
¹² Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA; Division of Hematopathology, The Children's Hospital of Philadelphia, Philadelphia, PA.
¹³ Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address: rombergn@email.chop.edu.

PMID: 38692308
DOI: 10.1016/j.jaci.2024.04.018

Abstract

Background: Autoantibody-mediated cytopenias (AICs) regularly occur in profoundly IgG-deficient common variable immunodeficiency (CVID) patients. The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear.

Objective: To determine reactivity, clonality and provenance of AIC-associated IgM autoantibodies in CVID patients.

Methods: We utilized glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan binding profiles were used to identify auto-reactive clones across B cell subsets, specifically circulating marginal zone-like (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes and responses of tonsillar MZ B cells to different T helper cell subsets were determined by confocal microscopy, RNA-sequencing, and co-cultures, respectively.

Results: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating marginal zone (MZ) B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL10/IL-21 secreting FOXP3^-CD25^hiTfh cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3⁺ regulatory T cells, and rare FOXP3^-CD25⁺ cells that represented likely CD25^hiTfh cells, all localized outside of GCs. In CVID+AIC lymph nodes, cellular positions were similar but CD25^hiTfh cells greatly outnumbered regulatory cells.

Conclusions: Our findings indicate glycan-reactive IgM autoantibodies produced outside of GCs may contribute to the autoimmune pathogenesis of CVID.

Keywords: autoantibodies; autoimmune cytopenias; common variable immune deficiency; glycans; i antigen; marginal zone B cell.