Induced Overexpression of B Cell-Activating Factor by Triiodothyronine Results in Abnormal B Cell Differentiation in Mice.

Breakdown of tolerance and abnormal activation in B cells is an important mechanism in the pathogenesis of Graves' disease (GD) and high levels of thyroid hormones (THs) can drive the progression of GD. However, the interactions between THs and abnormal activation of B cells in the context of GD are not well understood. The aim of this study was to investigate B cell-activating factor (BAFF) mediating the cross talk between THs and B cells and the possible underlying mechanisms. A high-level triiodothyronine (T3) mouse model was used to verify T3-mediated induction of overexpression of BAFF and B cell abnormal differentiation. The possible promotion of BAFF overexpression in the mice spleen macrophages during polarization to M1 by T3 was also studied. We showed that high levels of T3 can induce BAFF overexpression and lead to abnormal differentiation of B cells in the mice. While the overexpression of BAFF was observed across many tissue types in the mice, high levels of T3 could induce M1 macrophages polarization by IFN (interferon-gamma)-γ in the spleen of the mice, which in turn generated BAFF overexpression. Our findings provide a novel insight into the interactions between the endocrine and immune systems, as well as provide insight into the role of TH in the pathogenesis of GD.

Activation of Toll-like receptor 4 by thyroid hormone triggers abnormal B-cell activation.

OBJECTIVE: Breakdown of tolerance and abnormal activation of B cells is an important mechanism in the pathogenesis of Graves' disease (GD). High levels of thyroid hormones (THs) play important roles in GD progression. However, the interactions between THs and abnormal activation of B cells remain elusive. This study aimed to explore the effect of high levels of THs on TLR4 expression and abnormal B cell differentiation. MATERIALS AND METHODS: Blood samples were collected from patients with GD and healthy controls (HCs) to evaluate the frequency of B cells, their subsets, and TLR4 expression in B cells. A high-level T3 mouse model was used to study the interaction between THs and the TLR4 signalling pathway. RESULTS: We found that the frequencies of CD19+ , CD19+ TLR4+ , CD19+ CD86+ , and CD19+ CD138+ B cells were significantly higher, as were the expression levels of MRP8/MRP14 and MRP6 and MRP8, MRP14, and MRP6 messenger RNA (mRNA) in peripheral blood mononuclear cells in patients with GD. In high-level T3 mice models, the serum MRP8/MRP14 and MRP6 levels and the TLR4 mRNA expression in PBMCs were significantly higher. TLR4 mRNA, protein expression, and cytokines downstream of TLR4, such as myeloid differentiation factor 88 (MyD88) and nuclear transcription factor-κB, were also increased in mouse spleen mononuclear cells. CONCLUSION: The present study indicated that high levels of T3 can induce abnormal differentiation and activation of B cells by promoting TLR4 overexpression and provide novel insights into the roles of THs in the pathogenesis of GD.

Effects of Glycemic Variability on Regulatory T Cells in Patients with Type 2 Diabetes and Kidney Disease.

Purpose: To investigate the pathogenesis of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM), we evaluated the effects of short-term glycemic variability (GV) on the profile of T cell subpopulations. Methods: A total of 47 T2DM patients with normoalbuminuria, 47 microalbuminuria, and 49 macroalbuminuria were enrolled. The continuous glucose monitoring (CGM) determined the GV of enrolled patients. Flow cytometry was used to determine the proportion of T cell subpopulations. Results: The frequency of T helper (Th) 17 and Th1 cells significantly increased while regulatory T cells (Tregs) significantly decreased in the macroalbuminuria group compared to normoalbuminuria and microalbuminuria groups (P < 0.01). The suppressive function of Tregs was significantly lower in the macroalbuminuria group than the normoalbuminuria group (P < 0.05). Compared with the normoalbuminuria group, the mean amplitude of glucose excursions (MAGE) of the macroalbuminuria group was significantly higher (P<0.05). Furthermore, there were negative associations between the proportion of Tregs and MAGE. Conclusions: Increased GV could decrease the proportion of Tregs and may impair their function. This may lead to increases in Th1 and Th17 cells, and some inflammatory cytokines, which might contribute to the development and progression of DKD in T2DM.

Zinc finger protein 467 regulates Wnt signaling by modulating the expression of sclerostin in adipose derived stem cells.

Osteoporosis is a metabolic disease in which a disruption of the balance between bone formation by osteoblasts and bone resorption by osteoclasts leads to the progressive deterioration of bone density and quality. Tissue engineering approaches to the treatment of osteoporosis depend on the identification of factors that promote the differentiation of progenitor cells towards an osteoblastic phenotype. In the present study, we expanded on prior findings on the role of zinc finger protein 467 (Zfp467) in the osteoblastic differentiation of adipose-derived stem cells (ADSCs) and explored the underlying mechanisms. We showed that Zfp467 binds to and regulates the expression of the SOST gene, which encodes a secreted glycoprotein named sclerostin (Sost) that is expressed exclusively by osteocytes and functions as a negative regulator of bone formation through the modulation of Wnt signaling. Overexpression of Zfp467 in ADSCs inhibited Wnt signaling by promoting binding of Sost to the Wnt coreceptors LRP5/6 and disrupting Wnt induced Frizzled-LRP6 complex formation, and siRNA mediated Sost silencing reversed the inhibition of Wnt signaling by Zfp467 in ADSCs. Our results indicate that Zfp467 regulates the differentiation of ADSCs via a mechanism involving Sost-mediated inhibition of Wnt signaling, suggesting potential therapeutic targets for the treatment of osteoporosis.