ABSTRACT
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Subject(s)
Eosinophilia/pathology , Immunoglobulins/immunology , Lymphoid Tissue/immunology , Nasal Mucosa/immunology , Papilloma, Inverted/immunology , Papilloma, Inverted/pathology , Tumor Microenvironment/immunology , Biomarkers , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation , Humans , Immunoglobulins/biosynthesis , Immunohistochemistry , Inflammation Mediators/metabolism , Lymphoid Tissue/metabolism , Lymphoid Tissue/pathology , Nasal Mucosa/metabolism , Tumor Microenvironment/geneticsABSTRACT
The neuroblastoma breakpoint family (NBPF) consists of 24 members that play an important role in neuroblastoma and other cancers. NBPF is an evolutionarily recent gene family that encodes several repeats of Olduvai domain and an abundant N-terminal region. The function and biochemical properties of both Olduvai domain and the N-terminal region remain enigmatic. Human NBPF15 encodes a 670 AA protein consisting of six clades of Olduvai domains. In this study, we synthesized and expressed full-length NBPF15, and purified a range of NBPF15 truncations which were analyzed using dynamic light scattering (DLS), superdex200 (S200), small-angle X-ray scattering (SAXS), far-UV circular dichroism (CD) spectroscopy, transmission electron microscope (TEM), and crystallography. We found that proteins containing both the N-terminal region and Olduvai domain are heterogeneous with multiple types of aggregates, and some of them underwent a liquid-to-solid phase transition, probably because of the entanglement within the N-terminal coiled-coil. Proteins that contain only the Olduvai domain are homogeneous extended monomers, and those with the conserved clade 1 (CON1) have manifested a tendency to crystallize. We suggest that the entanglements between the mosaic disorder-ordered segments in NBPF15 N terminus have triggered the multiple types of aggregates and phase transition of NBPF15 proteins, which could be associated with Olduvai-related cognitive dysfunction diseases.
Subject(s)
Cognitive Dysfunction/genetics , Intracellular Signaling Peptides and Proteins/genetics , Protein Aggregates/genetics , Circular Dichroism , Cognitive Dysfunction/pathology , Gene Expression/genetics , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Microscopy, Electron, Transmission , Phase Transition , Protein Domains/genetics , Repetitive Sequences, Amino Acid/genetics , Scattering, Small Angle , X-Ray DiffractionABSTRACT
OBJECTIVE: Neutrophil infiltration in patients with sinonasal inverted papilloma (SNIP) is significantly high. Whether IL-17, which is a potent factor mediating neutrophilic inflammation, is involved in the neutrophilic phenotype of SNIP is investigated in the current study. STUDY DESIGN: Laboratorial study. PARTICIPANTS: Nasal papilloma and inferior turbinate were collected from patients with SNIP (n = 50) and control subjects with septal deviation (n = 15). METHODS: IL-17 + cells were evaluated in tissues obtained from patients with SNIP and control subjects with septal deviation, by immunohistochemistry and flow cytometry. MAIN OUTCOME MEASURES: The IL-17 + cells were mainly localised in mononuclear cells and neutrophils, and were up-regulated in the SNIP samples compared with those in the controls. The IL-17 + T-cell subsets mainly included CD4+ (Th17, 60.0%) and CD8+ (Tc17, 30.0%), and both subsets were enhanced in the SNIP samples than controls. The total level of IL-17 + cells was significantly correlated with neutrophil infiltration in the SNIP tissues. Furthermore, the SNIP homogenates could significantly promote IL-17 production in peripheral blood mononuclear cells. CONCLUSIONS: An increase in IL-17 + cells is evident in SNIP and may be involved in neutrophil infiltration in local tissues. IL-17 could be a potential therapeutic target to relieve the neutrophilic pathological change in SNIP.
