Title |
Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses
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Published in |
The Journal of Allergy and Clinical Immunology, June 2018
|
DOI | 10.1016/j.jaci.2018.06.012 |
Pubmed ID | |
Authors |
Neil Romberg, Carole Le Coz, Salomé Glauzy, Jean-Nicolas Schickel, Melissa Trofa, Brian E 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 |
Abstract |
The 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. We 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). We 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. We 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. CVID 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Ecuador | 1 | 9% |
United States | 1 | 9% |
Unknown | 9 | 82% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 9 | 82% |
Science communicators (journalists, bloggers, editors) | 1 | 9% |
Practitioners (doctors, other healthcare professionals) | 1 | 9% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 51 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 8 | 16% |
Student > Ph. D. Student | 7 | 14% |
Student > Bachelor | 7 | 14% |
Student > Master | 5 | 10% |
Student > Doctoral Student | 3 | 6% |
Other | 9 | 18% |
Unknown | 12 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Immunology and Microbiology | 14 | 27% |
Medicine and Dentistry | 11 | 22% |
Biochemistry, Genetics and Molecular Biology | 6 | 12% |
Agricultural and Biological Sciences | 4 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 2% |
Other | 3 | 6% |
Unknown | 12 | 24% |