Calpeptin may reverse glucocorticoid-resistance of allergic rhinitis associated with cigarette smoke exposure by down-regulating interferon regulatory factor 1.

Cigarette smoke exposure is an important factor in chronic inflammation in patients with allergic rhinitis (AR); however, the relationship between cigarette smoke and AR-related glucocorticoid resistance requires further study. In mice, calpeptin significantly reduces inflammation of the lower respiratory tract caused by cigarette smoke, but whether it can treat glucocorticoid-resistant AR caused by cigarette smoke requires further research. In this study, we confirmed that cigarette smoke exposure can aggravate the Th2 inflammatory response in AR leading to glucocorticoid resistance. The underlying mechanism may be related to decreased expression of DNA methyltransferase 3a (Dnmt3a), and increased expression of interferon regulatory factor 1 (IRF1). In addition, we found that calpeptin can inhibit the expression of IRF1 and thus treat AR-associated glucocorticoid resistance in rats exposed to cigarette smoke. These data suggest that calpeptin may downregulate IRF1 and therefore treat glucocorticoid resistance in AR-associated with cigarette smoke exposure.

Primary Hyper-IgE-Related Salivary Gland Disease: A New Disease Entity.

OBJECTIVES: To clarify the clinicopathological characteristics of primary hyper-IgE-related salivary gland disease (PHIESD), which is a newly proposed entity. METHODS: Fifteen consecutive patients pathologically diagnosed with chronic sialadenitis were enrolled, and their clinicopathological features were comprehensively analyzed. INCLUSION CRITERIA: (1) multiple salivary gland enlargement; (2) elevated serum IgE and/or IgE-positive cell infiltration in salivary gland tissues; (3) histology-confirmed lymphoplasmacytic infiltration; (4) exclusion of other known diseases. RESULTS: The male-to-female ratio was 5:10. The median age was 21 (range, 3-63) years. The average number of affected glands was 3.7 ± 1.4. Submandibular, parotid, and sublingual glands were involved in 15, 8, and 2 patients, respectively. Comorbid diseases included allergic diseases in seven patients and autoimmune diseases in two. Elevated serum IgE (median 175 kU/L) was seen in all patients. Serum IgG4 was slightly elevated in three patients. Histologically, most patients had mild lesions, including mild lymphocyte infiltration (60%) and focal fibrosis (66.7%). Lymphoid follicular formation (53.3%), moderate to severe lymphocytic inflammation (40%) and severe fibrosis (33.3%) were also observed. Immunohistochemically, IgE-positive cells infiltrated mainly around the ducts, with scattered infiltration of IgG4-positive, mast, and interleukin-4 positive cells. During follow-up (median, 46 months) of ten patients without intervention and two with immunosuppressive therapy, no significant changes in gland size or serum IgE level were noted. CONCLUSIONS: PHIESD manifests as homogeneous enlargement of multiple salivary glands and elevated serum IgE. Histopathology further verifies the diagnosis. It might be associated with anaphylaxis or autoimmune dysfunction. Conservative treatment is suggested. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2132-2138, 2022.

Eosinophilic Sialodochitis: A Type of Chronic Obstructive Sialadenitis Related to Allergy.

OBJECTIVES: To investigate the clinical, laboratory, radiological, histopathological, and immunohistochemical features, and the expression of allergy-related cytokines in eosinophilic sialodochitis (ES). METHODS: Thirty-eight patients diagnosed with chronic obstructive sialadenitis (COS) who had undergone glandular excision or incisional biopsy were enrolled. Seventeen patients with comorbid atopic disease and increased ductal tissue eosinophils comprised the ES group, while 21 patients comprised the COS group. The clinicopathological features and allergy-related cytokine expression were compared between groups. RESULTS: The ES group frequently involved multiple, bilateral major salivary glands, and the number of glands was significantly greater than the COS group (2.8 ± 1.1 vs. 1.2 ± 0.4, P < .001). Serum immunoglobulin (Ig) E was elevated in 91% of patients in ES group (419 ± 357 kU/L) and peripheral blood eosinophil was significantly greater compared with the COS group (7.6% ± 4.6% vs. 2.5% ± 1.4%, P < .001). Histologically, eosinophil infiltration in ES group was observed around the main and interlobular ducts (50 ± 39/high power field [HPF]). Follicular hyperplasia (76%), epithelial mucous metaplasia (82%), and mucus plugs with eosinophils (41%) were observed. IgE-positive cell count was 20.7 ± 18.3/HPF and tryptase-positive mast cell count was 23.5 ± 15.1/HPF, which was significantly greater than the respective cell counts in COS group, which mainly infiltrated around the ducts. The levels of interleukin-4, interleukin-13, and eotaxin in tissue were significantly greater in ES than the COS group. CONCLUSIONS: The clinicopathological characteristics of ES are significantly different from COS and ES might have an allergy-related pathogenesis. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E800-E806, 2021.

Disruption of tight junction structure contributes to secretory dysfunction in IgG4-related sialadenitis.

IgG4-related sialadenitis (IgG4-RS) is a chronic fibro-inflammatory disease characterized by swelling of salivary glands and varying degrees of xerostomia. Tight junctions (TJs) play an essential role in maintaining secretory function by regulating the paracellular flow of ions and water. However, whether TJs are altered and contribute to the hyposecretion in IgG4-RS is not fully understood. Here, a total of 399 differentially expressed proteins were identified in IgG4-RS submandibular glands (SMGs) and enriched in the regulation of actin cytoskeleton and the salivary secretion. Real-time PCR results showed that the mRNA levels of claudin-3, -4, -6, -7, -8, -10, -12, occludin, and ZO-1 were significantly lower, whereas claudin-1 and -5 were higher in IgG4-RS SMGs. Immunohistochemical and immunofluorescence staining revealed that claudin-1, -3, -4, occludin, and ZO-1 were mainly distributed at apicolateral membranes in acini and ducts of SMGs from controls, whereas claudin-1 protein intensity at apicolateral membrane was elevated, while the staining of claudin-3, -4, and ZO-1 were reduced in IgG4-RS SMGs. Occludin was dispersed into cytoplasm of acini and ducts in SMGs of patients. Among them, claudin-3 and ZO-1 protein levels were positively correlated with saliva flow rate. Furthermore, the decreased fluorescence intensity of F-actin at peri-apicolateral membranes and the loss of ZO-1 staining at the same location were observed in acinar and ductal cells of IgG4-RS SMGs, which might be responsible for disorganization of TJ complex. Taken together, these findings indicate that the integrity of TJ complex of SMGs is impaired and might contribute to hyposalivation of IgG4-RS patients.