Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses - 04/01/19
, Carole Le Coz, PhD a, Salomé Glauzy, PhD h, Jean-Nicolas Schickel, PhD h, Melissa Trofa, BA a, Brian E. Nolan, MD b, Michele Paessler, DO c, f, Mina L. Xu, MD i, Michele P. Lambert, MD d, e, Saquib A. Lakhani, MD j, m, Mustafa K. Khokha, MD j, k, m, Soma Jyonouchi, MD a, e, Jennifer Heimall, MD a, e, Patricia Takach, MD g, Paul J. Maglione, MD, PhD n, Jason Catanzaro, MD j, F. Ida Hsu, MD l, Kathleen E. Sullivan, MD, PhD a, e, Charlotte Cunningham-Rundles, MD, PhD n, Eric Meffre, PhD h, l, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Key words : Common variable immunodeficiency, autoimmune cytopenias, germinal center responses, somatic hypermutation, B-cell tolerance, commensal bacteria, follicular helper T cell, regulatory T cell
Abbreviations used : AIC, AID, APC, AVY, CQ, CSR, cTFH, CVID, GC, HD, ITP, NHS, PD-1, PE, PerCP, SHM, TFH, Treg, Tresp
Plan
| Supported by grant number K23AI115001 from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID), the Jeffrey Modell Foundation (to N.R.), and AI-061093, AI-071087, and AI-082713 from the NIH/NIAID (to E.M.). |
|
| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 1
P. 258-265 - janvier 2019 Retour au numéro
Article précédent
- Loss of GTPase of immunity-associated protein 5 (Gimap5) promotes pathogenic CD4+ T-cell development and allergic airway disease
- Andrew R. Patterson, Paige Bolcas, Kristin Lampe, Rachel Cantrell, Brandy Ruff, Ian Lewkowich, Simon P. Hogan, Edith M. Janssen, Jack Bleesing, Gurjit K. Khurana Hershey, Kasper Hoebe
- Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase ? syndrome type 1
- Tsubasa Okano, Kohsuke Imai, Yuki Tsujita, Noriko Mitsuiki, Kenichi Yoshida, Chikako Kamae, Kenichi Honma, Kanako Mitsui-Sekinaka, Yujin Sekinaka, Tamaki Kato, Katsuyuki Hanabusa, Eri Endo, Takehiro Takashima, Haruka Hiroki, Tzu-Wen Yeh, Keisuke Tanaka, Masakazu Nagahori, Ikuya Tsuge, Yuki Bando, Fuminori Iwasaki, Yoshiaki Shikama, Masami Inoue, Tomiko Kimoto, Naohiko Moriguchi, Yuki Yuza, Takashi Kaneko, Kyoko Suzuki, Tomoyo Matsubara, Yoshihiro Maruo, Tomoaki Kunitsu, Tomoko Waragai, Hideki Sano, Yuko Hashimoto, Kazuhiro Tasaki, Osamu Suzuki, Toshihiko Shirakawa, Motohiro Kato, Toru Uchiyama, Masataka Ishimura, Tetsuzo Tauchi, Hiroshi Yagasaki, Shiann-Tarng Jou, Hsin-Hui Yu, Hirokazu Kanegane, Sven Kracker, Anne Durandy, Daiei Kojima, Hideki Muramatsu, Taizo Wada, Yuzaburo Inoue, Hidetoshi Takada, Seiji Kojima, Seishi Ogawa, Osamu Ohara, Shigeaki Nonoyama, Tomohiro Morio
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?