The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans - 25/05/24
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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 TH- 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−CD25hi 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 CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi 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.
Le texte complet de cet article est disponible en PDF.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
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