Ectopic lymphoid tissues support local immunoglobulin production in patients with chronic rhinosinusitis with nasal polyps - 08/12/17

Doi : 10.1016/j.jaci.2017.10.014

Jia Song, MD ^a,^{∗
These authors contributed equally to this work.}, Hai Wang, MD ^a,^{∗
These authors contributed equally to this work.}, Ya-Na Zhang, MD, PhD ^b, Ping-Ping Cao, MD, PhD ^a, Bo Liao, MD, PhD ^a, Zhe-Zheng Wang, MD ^a, Li-Li Shi, MD, PhD ^a, Yin Yao, MD ^a, Guan-Ting Zhai, MD ^a, Zhi-Chao Wang, MD ^a, Li-Meng Liu ^c, Ming Zeng, MD, PhD ^a, Xiang Lu, MD, PhD ^a, Heng Wang, MD, PhD ^a, Xiang-Ping Yang, PhD ^d, Di Yu, PhD ^e, Claus Bachert, MD, PhD ^f, Zheng Liu, MD, PhD ^a,^⁎
^a Department of Otolaryngology–Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
^d Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
^b Department of Otolaryngology-Head and Neck Surgery, Guangzhou Women and Children's Medical Center, Guangzhou, China
^c No.1 Middle School affiliated to Central China Normal University, Wuhan, China
^e Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
^f Upper Airways Research Laboratory, Ghent University, Ghent, Belgium

^∗Corresponding author: Zheng Liu, MD, PhD, Department of Otolaryngology–Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Ave, Wuhan 430030, China.Department of Otolaryngology–Head and Neck SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyNo. 1095 Jiefang AveWuhan430030China

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Abstract

Background

The contribution of ectopic lymphoid tissues (eLTs) to local immunoglobulin hyperproduction in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear.

Objective

We sought to explore the cellular basis, formation mechanisms, and function of eLTs in patients with CRSwNP.

Methods

We graded lymphoid aggregations in sinonasal mucosa and histologically studied their structures. The expression of lymphorganogenic factors and molecules required for immunoglobulin production was measured by using real-time PCR, and their localization was analyzed by means of immunohistochemistry and immunofluorescence. The phenotype of follicular helper T cells was analyzed by performing flow cytometry. Immunoglobulin levels were quantified by using the Bio-Plex assay or ImmunoCAP system. Nasal tissue explants were challenged ex vivo with Dermatophagoides pteronyssinus group 1 (Der p 1), and the expression of Iε-Cμ and Iε-Cγ circle transcripts was detected by using seminested PCR.

Results

Increased formation of eLTs with germinal center–like structures was discovered in patients with eosinophilic (20.69%) and noneosinophilic (17.31%) CRSwNP compared with that in patients with chronic rhinosinusitis without nasal polyps (5.66%) and control subjects (3.70%). The presence of eLTs was associated with increased expression of lymphorganogenic and inflammatory chemokines and cytokines, as well as their receptors. The expression of molecules required for immunoglobulin production, generation of follicular helper T cells, and production of IgE in eosinophilic polyps and IgG and IgA in both eosinophilic and noneosinophilic polyps were predominantly upregulated in patients with eLTs. After Der p 1 challenge ex vivo, Iε-Cμ transcript was detected only in eosinophilic polyps with eLTs but not in polyps without eLTs and noneosinophilic polyps.

Conclusion

eLTs might support local immunoglobulin production and therefore significantly contribute to the development of CRSwNP.

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Key words : Ectopic lymphoid tissue, immunoglobulin, lymphoid aggregate, lymphorganogenesis

Abbreviations used : AID, BAFF, Bcl, CD21L, CRSsNP, CRSwNP, DC, eLT, FDC, GC, HEV, ICAM-1, ICOS, LT, LTβR, NP, sIgE, T_FH, VCAM-1

Plan

Methods

Subjects

Histology

Immunohistochemistry and immunofluorescence

Measurement of immunoglobulin, chemokine, and cytokine levels

RT-PCR

Ex vivo allergen challenge

Flow cytometry

Statistics

Results

Increased formation of lymphoid aggregates in NPs

Diversified structures of lymphoid aggregates in NPs

Upregulated expression of lymphorganogenic chemokines and cytokines in eLTs in NPs

Polyp eLTs correlated to local production of IgG, IgE, and IgA but not IgM

Formation of eLTs associated with disease severity

Discussion

Supported by National Natural Science Foundation of China (NSFC) grants 81630024, 81570899 and 81325006 (to Z.L.), 81500777 (to L.-L.S.), 81400449 (to P.-P.C.), and 81670911 (to X.L.); the 12th Five Year Science and Technology Support Program (2014BAI07B04); and an Australian National Health and Medical Research Council Fellowship (to D.Y.).

Disclosure of potential conflict of interest: P.-P. Cao personally received grant 81400449 from the National Natural Science Foundation of China for this work. L.-L. Shi personally received grant 81500777 from the National Natural Science Foundation of China for this work. X. Lu personally received grant 81670911 from the National Natural Science Foundation of China for this work. X.-P. Yang's institution received a grant from the National Natural Science Foundation of China for other works. D. Yu's institution received a grant from the Australian National Health and Medical Research Council for this work and for other works and is employed by the Australian National University. Z. Liu received grants 81630024, 81570899, and 81325006 from the National Natural Science Foundation of China and grant 2014BAI07B04 from the Ministry of Science and Technology of the People's Republic of China for this work. The rest of the authors declare that they have no relevant conflicts of interest.