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

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 25 May 2024

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