Presence of Tertiary Lymphoid Organ in Nasal Inverted Papilloma Is Correlated with Eosinophil Infiltration and Local Immunoglobulin Production

Abstract

<b><i>Introduction:</i></b> Nasal inverted papilloma (NIP) is a benign tumour with multiple inflammatory cell infiltration. Tertiary lymphoid organs (TLOs) support local antibody production and play important roles in airway inflammation. However, the evidence of TLOs and local immunoglobulins in NIP has not been reported yet. We investigated the presence of TLOs and immunoglobulins in NIP tissues and their association with the clinical-pathological characteristics of NIPs. <b><i>Methods:</i></b> We analyzed the occurrence and composition of TLOs and local immunoglobulins by immunohistochemistry and evaluated the lymph organogenesis associated genes and cytokines by quantitative qPCR and Luminex assays, respectively, in papilloma tissues from 84 NIP cases. <b><i>Results:</i></b> TLOs were present in 54% (45/84) of the NIP patients but not in control subjects. TLOs were composed of T cells, B cells, follicular dendritic cells, macrophages, and natural killer cells. Compared to NIP tissues without TLOs, tissues with TLOs showed significantly higher eosinophil infiltration levels (3.5-fold), elevation of lymphorganogenic genes (CXCL12, CXCL13, CCL20, CCL21, CD21L, and lymphotoxin alpha and beta), and increased Th17 (IL-21, IL-22, and GM-CSF) and Th2 (IL-5 and IL-13) cytokine production. Moreover, NIP with TLOs demonstrated a higher number of follicular T helper cells and immunoglobulin-producing plasma cells (CD138+ IgA+, CD138+ IgM+, CD138+ IgE+, and CD138+ IgG+) than those without TLOs, and these antibody-producing cells were positively correlated with the eosinophil number. <b><i>Conclusion:</i></b> The high frequency of TLOs and excess local immunoglobulin production are associated with an eosinophilic and Th2 skew microenvironment in the NIP mucosa, which would contribute to an important immunopathogenic response during NIP pathogenesis.

Increased Neutrophil Infiltration and Epithelial Cell Proliferation in Sinonasal Inverted Papilloma Compared to Contralateral Nasal Polyps

“…9 Moreover, various inflammatory cells, such as neutrophils, macrophages, eosinophils, B cells and T cells, have been observed in sinonasal IP tissue. [10][11][12] Therefore, these findings support a potential role of chronic inflammation in the pathogenesis of IP. Some authors have speculated that IP is derived from NP.…”

Tumor-Associated Tertiary Lymphoid Structures: From Basic and Clinical Knowledge to Therapeutic Manipulation

“…Thus, one can hypothesize that these anti-ICP therapies stimulate Tfh and the formation and/or maintenance of TLS in responder patients. Interestingly, an increase of IL-21 and IL21R transcripts and of IL-21 secretion is associated with the presence of TLS in Nasal Inverted Papilloma, a benign tumor, strengthening the idea that IL-21/IL21R axis plays a critical role in the response to anti-ICP therapy, possibly through the formation of TLS ( 67 ).…”

Machine Learning-Based Characterization and Identification of Tertiary Lymphoid Structures Using Spatial Transcriptomics Data

“…Local production of immunoglobulins by plasma cells within TLS has been well established [16]. It is reported that TLSs consistently contain AID + CD20+ B cells, and immunoglobulin-producing plasma cells are more abundant within TLS regions compared to areas without TLS [16,25,[28][29][30]. These findings confirm the capability of immunoglobulin genes to discern between TLSs and No-TLS regions since TLSs have higher immunoglobulin-producing plasma cell enrichment than other regions and immunoglobulin gene expression is highly correlated with these plasma cells.…”