CVID patients with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses

Publication date: Available online 20 June 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Neil Romberg, Carole Le Coz, Salomé Glauzy, Jean-Nicolas Schickel, Melissa Trofa, Brian E. Nolan, Michele Paessler, Mina LuQing Xu, Michele 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
BackgroundThe lack of pathogen-protective, isotype-switched antibodies in common variable immunodeficiency (CVID) suggests germinal center hypoplasia, yet a subset of CVID patients is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy.ObjectiveWe sought to compare the physical characteristics and immunological output of germinal center responses in CVID patients with AICs (CVID+AIC) and without AICs (CVID-AICs).MethodsWe analyzed germinal center size and shape in excisional lymph node biopsies from 14 CVID+AIC and 4 CVID-AIC patients. Using paired peripheral blood samples, we determined how AICs specifically impacted B and T cell compartments and antibody responses in CVID patients.ResultsWe found that CVID+AIC patients displayed irregularly-shaped, hyperplastic germinal centers (GCs), whereas GCs were scarce and small in CVID-AIC patients. GC hyperplasia was also evidenced by an increase in circulating T follicular helper cells, which correlated with decreased regulatory T cell frequencies and function. In addition, CVID+AIC patients showed serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than CVID-AIC counterparts. Moreover, IgG⁺ B cells from CVID+AIC patients expressed VH4-34 antibodies with unmutated AVY and NHS motifs which recognize both erythrocyte I/i self-antigens and commensal bacteria.ConclusionsCVID patients with autoimmune cytopenias fail to contain mucosal microbiota and exhibit hyperplastic yet inefficient germinal center responses that favor the production of untolerized IgG+ B cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.

Teaser

Common variable immunodeficiency patients with autoimmune cytopenias exhibit hyperplastic germinal center reactions that fail to generate isotype-switched, somatically-mutated, immune-protective antibodies and instead produce poorly mutated, non-tolerized antibodies that recognize commensal bacteria and hematopoietic self-antigens.


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