森本 侑樹

Carcinoma ex pleomorphic adenoma (CXPA) is a rare malignant salivary gland tumor, and its prognosis is determined by the histological progression beyond the adenoma capsule. However, a preoperative evaluation of the histological progression remains challenging, and there is no consensus regarding treatment strategies for CXPA. Herein, we aimed to predict the histological progression preoperatively and develop an appropriate treatment strategy for CXPA. We retrospectively reviewed 22 patients with parotid gland CXPA recorded at our hospital. The clinicopathological characteristics were assessed, and survival analysis was performed. T3≤ or N+ were common in widely invasive CXPA (WICXPA) (p < 0.05). A tumor diameter > 40 mm and the N+ status were associated with poor prognosis considering overall survival (OS) and locoregional recurrence rate (LRC) (p < 0.05). Patients with facial nerve paralysis exhibited better OS and LRC than those without facial nerve paralysis. More than 90% of patients with WICXPA experienced distant metastases. Meanwhile, there were no cases of recurrence or death due to intracapsular and minimally invasive CXPA. A preoperative advanced T stage or N+ status was suspected as WICXPA. Tumors > 40 mm in size and N+ status necessitate high-intensity local treatment. Facial nerve invasion can be controlled by nerve resection. Postoperative systemic therapy could control distant metastases.

Allergic conjunctivitis is a chronic inflammatory disease that is characterized by severe itch in the conjunctiva, but how neuro-immune interactions shape the pathogenesis of severe itch remains unclear. We identified a subset of memory-type pathogenic Th2 cells that preferentially expressed Il1rl1-encoding ST2 and Calca-encoding calcitonin-gene-related peptide (CGRP) in the inflammatory conjunctiva using a single-cell analysis. The IL-33-ST2 axis in memory Th2 cells controlled the axonal elongation of the peripheral sensory C-fiber and the induction of severe itch. Pharmacological blockade and genetic deletion of CGRP signaling in vivo attenuated scratching behavior. The analysis of giant papillae from patients with severe allergic conjunctivitis revealed ectopic lymphoid structure formation with the accumulation of IL-33-producing epithelial cells and CGRP-producing pathogenic CD4+ T cells accompanied by peripheral nerve elongation. Thus, the IL-33-ST2-CGRP axis directs severe itch with neuro-reconstruction in the inflammatory conjunctiva and is a potential therapeutic target for severe itch in allergic conjunctivitis.

アレルギー疾患はいまだ根治的治療法がなく、病態形成機構をはじめさまざまな側面で精力的に研究がなされており、アレルギー性炎症を誘導する2型自然リンパ球の同定、病原性Th2細胞の同定、粘膜上皮細胞由来の上皮性サイトカインとしてのIL-33、IL-25、TSLPの作用機序などが近年明らかになってきている。本稿では、アレルギー性気道炎症の病態制御について以下の項目で概説した。1)自然免疫と獲得免疫、2)病原性Th2細胞-Pathogenic Th2 cells-の同定とIL-33による誘導、3)線維化誘導-病原性ヘルパーT細胞、4)CD69-Myl9システムによる活性化T細胞の気道炎症巣へのリクルート。

Tissue-resident memory T cells (TRM cells) are crucial mediators of adaptive immunity in nonlymphoid tissues. However, the functional heterogeneity and pathogenic roles of CD4+ TRM cells that reside within chronic inflammatory lesions remain unknown. We found that CD69hiCD103lo CD4+ TRM cells produced effector cytokines and promoted the inflammation and fibrotic responses induced by chronic exposure to Aspergillus fumigatus. Simultaneously, immunosuppressive CD69hiCD103hiFoxp3+ CD4+ regulatory T cells were induced and constrained the ability of pathogenic CD103lo TRM cells to cause fibrosis. Thus, lung tissue-resident CD4+ T cells play crucial roles in the pathology of chronic lung inflammation, and CD103 expression defines pathogenic effector and immunosuppressive tissue-resident cell subpopulations in the inflamed lung.

Background: Allergic rhinitis (AR) consists of three developmental stages that are based on the presence/absence of antigen-specific IgE and symptoms. The pathogenic Th2 (Tpath2) cells constitute a population of Th2 cells with additional potentially pathogenic characteristics. We examined the relationship between Tpath2 cells and the stages of allergic rhinitis by focusing on ST2, which is an IL-33 receptor. Methods: Patients with Japanese cedar pollen-induced AR (JCP-AR) and healthy volunteers were divided into “nonsensitized,” “asymptomatic sensitized (AS),” and “JCP-AR” groups. We analyzed the ST2 expression and the Th2 function of cultured CD4+ T cells. Next, we observed the progress of patients in the AS stage around the time of seasonal pollen dispersal, with the characteristics of Th2 cells. Results: The ST2 expression of T cells was only upregulated in the AR group. The production of IL-4 and IL-13 was found in CD4+ T cells obtained from AS by stimulation with JCP, but reactivity to IL-33 was not observed. Although IL-33 did not induce the elevation of IL-4 production in the JCP-AR group, IL-33 substantially increased the production of IL-5 and IL-13 in comparison with antigen stimulation alone. In newly afflicted patients, the increased expression of ST2 and elevated reactivity to IL-33 was observed, even before the pollen dispersal season. Conclusions: Our study demonstrated that the pathogenicity of memory Th2 cells is linked to sensitization and the stage of allergic rhinitis. Therefore, Tpath2 cells may provide useful insights into the mechanism of the onset and progression of allergic rhinitis.

Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. Morimoto and colleagues find that the IL-33-ST2-amphiregulin-EGRF-osteopontin axis directs fibrotic responses in chronic allergic inflammation with the involvement of airway epithelial cells, pathogenic memory Th2 cells, and inflammatory eosinophils in both mouse and human.

Background: Biomarkers that enable objective evaluation of the clinical effects of immunotherapy for allergic rhinitis have yet to be identified. Methods: This study included 40 patients who were enrolled in a large randomized, double-blind, placebo-controlled, multi-center study examining the efficacy of sublingual immunotherapy (SLIT) using Japanese cedar (JC) pollen extract during two consecutive pollen seasons from 2010 to 2012. Based on changes in total nasal symptom medication score, patients in the SLIT and placebo groups were subdivided into two subgroups: good responders and poor responders.The levels of JC pollen-specific IL-10(+)Foxp3(+) cells and specific Th2 cytokine-producing cells were measured and the association with the efficacy of SLIT was analysed. Results: The total nasal symptom medication score was significantly lower in the SLIT group compared with the placebo group. The number of JC pollen-specific Th2 cytokine-producing cells increased during the pollen season in the placebo group and in poor responders in the SLIT group; however, the increases were inhibited in the good responders in the SLIT group. The number of JC pollen-specific IL-10(+)Foxp3(+) cells increased only in these good responders. Conclusions: Changes in levels of allergen-specific Th2 cytokine-producing cells and IL-10(+)Foxp3(+) cells could be objective biomarkers for SLIT.