The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans - 25/05/24

Doi : 10.1016/j.jaci.2024.04.018

Carole Le Coz, PhD ^a,^b, Melissa Trofa, MD ^a, Dorothy L. Butler, PhD ^c, Samuel Yoon, BS ^a, Tian Tian, PhD ^d, Whitney Reid, MD ^a, Emylette Cruz Cabrera, MS ^a, Ainsley V.C. Knox, BA ^a, Caroline Khanna, MD ^a, Kathleen E. Sullivan, MD, PhD ^a,^e,^f, Jennifer Heimall, MD ^a,^e, Patricia Takach, MD ^g, Olajumoke O. Fadugba, MD ^g, Monica Lawrence, MD ^h, Soma Jyonouchi, MD ^a,^e, Hakon Hakonarson, MD, PhD ^d,^f, Andrew D. Wells, PhD ^f,^i,^j, Steven Handler, MD, MBE ^k,^l, Karen B. Zur, MD ^k,^l, Vinodh Pillai, MD, PhD ^m,ⁿ, Jeffrey C. Gildersleeve, PhD ^c, Neil Romberg, MD ^a,^e,^f,^⁎
^a Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, Pa
^b Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, CNRS, Inserm, Toulouse, France
^c Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Md
^d Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pa
^e Department of Pediatrics, Perelman School of Medicine, Philadelphia, Pa
^f Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
^g Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, Philadelphia, Pa
^h Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, Va
ⁱ Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pa
^j Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pa
^k Pediatric Otolaryngology, Children’s Hospital of Philadelphia, Philadelphia, Pa
^l Department of Otolaryngology—Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pa
^m Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pa
ⁿ Division of Hematopathology, Children’s Hospital of Philadelphia, Philadelphia, Pa

^∗Corresponding author: Neil Romberg, MD, Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA 19104.Division of Immunology and AllergyChildren’s Hospital of PhiladelphiaAbramson Research CenterPhiladelphiaPA19104

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Abstract

Background

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

Objective

We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID.

Methods

We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different T_H- cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, 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 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 IL-10/IL-21–secreting FOXP3⁻CD25^hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3⁺ regulatory T cells, and rare FOXP3⁻CD25⁺ cells that represented likely CD25^hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25^hi Tfh cells greatly outnumbered regulatory cells.

Conclusions

Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID.

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Key words : Common variable immune deficiency, autoimmune cytopenias, autoantibodies, glycans, i antigen, marginal zone B cell

Abbreviations used : AIC, AIHA, APC, CDR, CVID, ES, FACS, FITC, GC, HD, IRB, iTfr, ITP, IVIG, LacNAc, LNnO, MNC, MZ, PBST, PMT, RFU, RNA-seq, Tfh, Tfr, TLR, Treg