Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses

Neil Romberg, Carole Le Coz, Salomé Glauzy, Jean Nicolas Schickel, Melissa Trofa, Brian Edward Nolan, Michele Paessler, Mina L. Xu, Michele P. Lambert, Saquib A. Lakhani, Mustafa K. Khokha, Soma Jyonouchi, Jennifer Heimall, Patricia Takach, Paul J. Maglione, Jason Catanzaro, F. Ida Hsu, Kathleen E. Sullivan, Charlotte Cunningham-Rundles, Eric Meffre*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Background: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. Objective: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID−AIC). Methods: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID−AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. Results: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID−AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID−AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria. Conclusions: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.

Original languageEnglish (US)
Pages (from-to)258-265
Number of pages8
JournalJournal of Allergy and Clinical Immunology
Volume143
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • B-cell tolerance
  • Common variable immunodeficiency
  • autoimmune cytopenias
  • commensal bacteria
  • follicular helper T cell
  • germinal center responses
  • regulatory T cell
  • somatic hypermutation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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