Activation of TLR9-dependent p38MAPK pathway in the pathogenesis of primary Sjögren's syndrome in NOD/Ltj mouse.

OBJECTIVE: The objective of this study was to investigate the potential role of Toll-like receptor 9-dependent p38 MAPK signaling pathway in the pathogenesis of primary Sjögren's syndrome (pSS) in NOD/Ltj mouse, aiming to identify an ideal target therapy model for human pSS. METHODS: NOD/Ltj mice were chosen as a model of pSS. The Toll-like receptor 9 and p-p38 MAPK double-positive peripheral blood mononuclear cells (PBMCs) of 4-, 5-, 8-, 10-, and 15-week-old NOD/Ltj mouse were analyzed by flow cytometry. The expressions of Toll-like receptor 9 and p-p38 MAPK in the submandibular gland (SMG) were also examined by immunohistochemistry. The change of stimulated salivary flow rate was dynamically measured, and the histopathology of SMG was evaluated by hematoxylin and eosin stain. RESULTS: The stimulated salivary flow rate in NOD/Ltj was reduced to 50-60% of the flow rate of control mice since the fifth week onwards. The Toll-like receptor 9 and p-p38 MAPK double-positive PBMCs in both groups increased gradually from 5 weeks, peaked at 8 weeks and then gradually decreased at 10 weeks, yet the percentage of Toll-like receptor 9 and p-p38MAPK double-positive PBMCs in 5-, 8-, and 10-week-old NOD/Ltj mouse was significantly increased compared with those in control subjects. After the 10th week onwards, there were no significant differences in the Toll-like receptor 9 and p-p38 MAPK double-positive PBMCs between NOD/Ltj mice and controls. Immunohistochemical staining showed that Toll-like receptor 9 was positive in the acinar epithelium cells and infiltrating lymphocytes in NOD/Ltj mice. p-p38 MAPK was detected in infiltrating lymphocytes and few ductal or acinar epithelium cells adjacent to infiltrating lymphocytes in NOD/Ltj mice. CONCLUSIONS: From the fifth week till the tenth week, Toll-like receptor 9 and p-p38 MAPK double-positive PBMCs were significantly increased in NOD/Ltj mice, accompanied with reduced stimulated salivary flow rate and Toll-like receptor 9 or p-p38 MAPK positive infiltrating lymphocytes observed in the SMG of NOD/Ltj mouse. Our results indicated that activation of Toll-like receptor 9-depended p38 MAPK signal pathway in PBMCs was an early event in pSS which made NOD/Ltj as an ideal therapy model to test the treatment effects of p38 MAPK or Toll-like receptor 9 inhibitors on pSS.

Clinical features and treatment outcomes of immunoglobulin g4-related sclerosing sialadenitis.

Idiopathic enlargement of salivary glands used to be confusing in diagnosis until immunoglobulin G4 (IgG4)-related sclerosing sialadenitis was proposed as a possible answer. In this case series, we reported the clinical features and management outcomes in 16 patients with IgG4-related sclerosing sialadenitis. We retrospectively studied 16 patients in clinical examination, serology, pathology, and sonography features. All patients were treated by corticosteroids and followed up for at least 3 months. The results of clinical features showed that all of the patients presented persistent, symmetric bilateral swelling of the salivary glands, elevated levels of serum IgG4, and/or IgG4-positive plasmacytes infiltration and tissue fibrosis. The results of all autoantibody tests were negative. The typical sonographic manifestation revealed multiple hypoechoic foci with an irregular netlike diffuse lesion in salivary glands. Most patients showed excellent response to steroids treatment. We conclude that, for patients who present (1) symmetric swelling of bilateral salivary glands for more than 3 months, (2) elevated serum IgG4 level (>135 mg/dL), and (3) enlargement in bilateral salivary glands with multiple hypoechoic areas (irregular netlike appearance) in the sonography, the diagnosis of IgG4-related sclerosing sialadenitis should be considered. A comprehensive understanding of the medical condition and appropriate pathology examination are the key to diagnose. Steroids treatment is effective, and a treatment plan should be set up and followed in the long-term.

Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.

Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.

Function of the parotid gland in juvenile recurrent parotitis: a case series.

Our aim was to find out how the parotid gland functions in 44 patients with juvenile recurrent parotitis, and to assess the value of measuring the serum amylase activity. Clinical and personal details were recorded, and all patients had their serum amylase activity measured together with sialography during the chronic phase. The function of the gland was classified by sialographic images. The chi square test and Spearman's rank correlation coefficient were used in the statistical analyses. There was a significant association between the degree of glandular function and serum amylase activity (p=0.014). The patients with unilateral and bilateral disease differed significantly in their degree of glandular function (p=0.020), those with bilateral disease having poorer function. There were no significant correlations between other clinical variables and glandular function. Serum amylase activity is an important diagnostic variable in juvenile recurrent parotitis, and poor parotid function reflects the severity of the disease.