FcγRIIB inhibits inflammation in a murine model of psoriasis.

BACKGROUND: Psoriasis is a chronic, inflammatory cutaneous disease. FcγRIIB is a low-affinity receptor for the IgG Fc fragment that provides a negative feedback pathway to down-regulate B-cell antigen receptor signaling. OBJECTIVE: The aim of this study was to investigate the role of FcγRIIB in the development of murine imiquimod (IMQ)-induced, psoriasis-like skin inflammation. METHODS: The experimental psoriasis-like skin inflammation was induced by the topical application of IMQ to the ears of FcγRIIB deficient (FcγRIIB-/-) and wild-type (WT) mice. After 6 days, epidermal thickness and inflammatory cell infiltration of the skin were histopathologically assessed and cytokine and chemokine expression levels were measured with RT-PCR. RESULTS: Skin inflammation was significantly worse in FcγRIIB-/- mice than WT mice. In the skin, the numbers of Gr-1+ neutrophils, CD11c+ dendritic cells, and Foxp3+ T cells were significantly higher in FcγRIIB-/- mice than WT mice. In the spleen, the numbers of CD25+Foxp3+ T cells and CD19+IL-10+ B cells were also significantly higher in FcγRIIB-/-mice than WT mice. The mRNA expression of Il-6, Il-17a, and Il-23a was significantly enhanced in FcγRIIB-/- mice. An adoptive transfer of splenic leukocytes from FcγRIIB-/- mice into WT mice also exacerbated skin inflammation compared to WT mice that received splenic leukocytes from WT mice. Intravenous immunoglobulin significantly reduced skin inflammation in WT mice, but this improvement was not observed in FcγRIIB-/- mice. CONCLUSION: These results indicate that FcγRIIB likely plays a suppressive role in IMQ-induced, psoriasis-like skin inflammation. Furthermore, signal modulation via FcγRIIB is a potential therapeutic target for psoriasis.

Study about renal injury of unilateral ureteral obstruction model with time / 中国医师杂志

Objective:The unilateral (left) ureteral obstruction (UUO) model was established in mice to explore the changes of renal injury with time and the related mechanisms.Methods:Fifty mice were randomly divided into two groups: sham group and UUO group (UUO model was made by unilateral ureteral ligation). The biochemical indexes, left kidney weight/final weight (LR/BW) and right kidney weight/final weight (RR/BW) of the two groups at different time points were observed, and the left kidney weight/right kidney weight ratio (LR/RR) was calculated. Hematoxylin-eosin (HE), Masson and periodic acid-Schiff (PAS) staining were used to detect the pathological changes of the kidney in mice. Immunofluorescence staining was used to observe the loss of peritubular capillaries (PTC), proliferation of renal parenchymal cells (Ki67 + cells), macrophages (CD68 + markers), infiltration of fibroblasts and expression of Wnt/β-catenin in the kidney of mice. Results:The weight of mice in UUO group decreased rapidly [(18.2±1.1)g vs (22.4±1.2)g] on the third day of modeling, then slowly increased until the 28th day, and significantly decreased [(17.5±0.8)g] on the 60th day; LR/RR and LR/BW increased significantly in the third day, and then decreased gradually; Renal function of mice in UUO group deteriorated significantly on the 60th day [serum creatinine (0.89±0.09)mg/dl, urea nitrogen (41.26±5.65)mg/dl]. In UUO group, renal tubulointerstitial fibrosis and glomerulosclerosis were observed under light microscope in the obstructed kidney; with the passage of time, PTC loss gradually increased; macrophages increased significantly in the left renal parenchyma at first, but began to decrease 28 days later; the number of fibroblasts increased significantly in the first 14 days of the obstructed side (left side) kidney, and then decreased to the normal level; There was no significant difference in the cell number of the non obstructive kidney between UUO group and sham group; The immunofluorescence intensity expression of Wnt/β- catenin of obstructive side (left side) in UUO group was significantly up-regulated in the first 14 days after renal injury, and decreased after 28 days.Conclusions:The development of UUO renal fibrosis involves many changes, including PTC loss, macrophage infiltration, fibroblast activation and expression, but these changes weaken with time.

Immunomodulating role of the JAKs inhibitor tofacitinib in a mouse model of bleomycin-induced scleroderma.

BACKGROUND: Janus kinase (JAK)-signal transducer and activator of transcription (STAT) was hyperactivated in biopsies from patients with systemic sclerosis (SSc) and in several autoimmune disease models. Tofacitinib, a pan-JAK inhibitor, blocks the downstream signaling of multiple cytokines and has exhibited therapeutic efficacy in various autoimmune diseases, although its immunomodulating property in scleroderma is unclear. OBJECTIVE: To evaluate the effect of tofacitinib on the modulation of cytokine-producing T and B cells, and proinflammatory cells in a mouse model of SSc. METHODS: Bleomycin (BLM)-induced SSc was generated by intradermal injection of BLM or PBS for control. Mice received intraperitoneal tofacitinib (20 mg/kg) or vehicle 3 times per week from day 0-28. Mice were sacrificed at day 28 after the last BLM/PBS injection. RESULTS: Tofacitinib administration significantly alleviated fibrosis of the skin and lungs in scleroderma mouse model. Furthermore, tofacitinib suppressed adaptive and innate immune responses by reducing splenocytes, total lymphocytes, CD4+ T helper cells (especially Th2 and Th17 subtypes), IL-6-producing effector B cells, PDCA-1+ dendritic cells in the spleen, and infiltration of F4/80+, CD206+ and CD163+ macrophages in the skin and lungs. Conversely, tofacitinib increased the proportions of splenic regulatory T and B cells. The mRNA expression of extracellular matrix proteins and fibrogenic cytokines was downregulated by tofacitinib in both the skin and lungs. CONCLUSION: These observations suggest JAK inhibition as a therapeutic approach for the treatment of inflammatory and fibrotic diseases, and highlight the potential of tofacitinib as a promising candidate for treating patients with scleroderma.

Effects of T helper type 1 cells to T helper type 2 cells ratio and the related cytokines on the prognosis of patients with colorectal cancer / 肿瘤研究与临床

Objective:To explore effects of T helper type 1 cells (Th1) to T helper type 2 cells (Th2) ratio and the related cytokines on the prognosis of patients with colorectal neoplasms.Methods:A total of 98 colorectal neoplasms patients undergoing the surgery admitted in Suqian Hospital Affiliated to Xuzhou Medical University from December 2015 to December 2017 were enrolled, and all patients were selected as the colorectal cancer group. According to Dukes staging criteria, patients were divided into stage A (25 cases), stage B (30 cases) and stage C (43 cases). In addition, 72 healthy subjects who underwent physical examination in Suqian Hospital Affiliated to Xuzhou Medical University during the same period were selected as the healthy control group. Preoperative venous blood on an empty stomach was extracted from the healthy control group and the colorectal cancer group. Flow cytometry was used to analyze the Th1/Th2 ratio in peripheral blood. The levels of cytokines interferon (IFN)-γ, interleukin (IL)-2, IL-4 and IL-10 in serum samples were detected by using enzyme-linked immunosorbent assay (ELISA). After operation, patients were followed up by telephone or outpatient service. The Th1/Th2 ratio and levels of IFN-γ, IL-2, IL-4 and IL-10 of both groups at different stages of both groups were compared. The correlation between Th1/Th2 ratio and the clinicopathological characteristics of colorectal cancer patients was analyzed. Kaplan-Meier method was used to make survival analysis and Cox regression model was used to analyze influencing factors for overall survival (OS).Results:The Thl/Th2 ratio in colorectal cancer patients was lower than that in the healthy control group (5.13±2.04 vs. 11.82±2.76, t = 18.177, P < 0.01). The lymphovascular invasion and Dukes stage C ratio in patients with decreased Th1/Th2 ratio were higher than those in patients with increased Th1/Th2 ratio ( χ2 values were 16.403, 16.248, both P < 0.01). The levels of IFN-γ and IL-2 in serums of colorectal patients were (95±15) ng/L and (78±10) ng/L, respectively, which were lower than those in the healthy control group [(157±17) ng/L and (123±12) ng/L, t values were 25.160, 26.622, all P < 0.01]. The levels of IL-4 and IL-10 in the colorectal cancer group were (87±16) ng/L and (178±18) ng/L, respectively, which were higher than those in the healthy control group [(46±9) ng/L and (124±12) ng/L] ( t values were 19.577, 22.095, all P < 0.01). The follow-up time ranged from 31.0 to 55.0 months, and the median follow-up time was 37.2 months and the median OS time was 21.0 months. Survival analysis showed that the OS of patients with increased Th1/Th2 ratio was better than that of patients with reduced Th1/Th2 ratio ( χ2 = 7.287, P = 0.007). Multivariate Cox regression analysis showed that lymph node metastasis, tumor stage, and Th1/Th2 ratio were independent influencing factors for OS in colorectal cancer patients ( OR values were 8.541, 3.442, 1.275, all P < 0.05). Conclusion:The imbalance of related cytokines secreted by Th1 and Th2 cells and the decrease in the ratio of Th1/Th2 are related to the progression and the poor prognosis of colorectal cancer.

Expression and significance of CD80/CD86 in renal tissue of lupus nephritis / 中华内科杂志

Objective To measure the expression of CD80 and CD86 in renal tissue of lupus nephritis (LN) and explore its mechanism in the development of LN.Methods Forty-nine patients with active LN and 9 patients with minor glomerular abnormalities tissues as controls were studied.The expression of CD80, and CD86 in renal tissues was detected by immunohistochemical methods.Results CD86 was expressed extensively in glomerulus, periglomerular area, tubular epithelial cells and peritubular interstitium, while CD80 was expressed only in tubular epithelial cells and peritubular interstitium.Moreover, the percentage of CD+80 and CD+86 cells in tubular epithelial cells and peritubular interstitium showed a tendency to increase with tubulointerstitial damage.The expression of CD80 and CD86 in renal tissue correlated with the systemic lupus erythematosus (SLE) disease activity index score, the degree of proteinuria, creatinine clearance and anti- dsDNA antibody.Conclusions This study shows that increased CD80 and CD86 expression with the progression of tubulointerstitial lesion might play an important role in the development of lupus nephropathy, and the tubulointerstitial expression of CD80 and CD86 could potentially serve as a surrogate marker of SLE disease activity.The co-stimulatory molecules CDg, and CD86 might play an important role in the pathogenesis of LN.