Peripheral CD3+CD4+ T cells as indicators of disease activity in thyroid eye disease: age-dependent significance.

PURPOSE: To provide an in-depth analysis of the association of peripheral lymphocytes and the disease activity of thyroid eye disease (TED). METHODS: This retrospective study enrolled 65 active TED patients and 46 inactive TED patients. Comparative analyses of peripheral lymphocyte subsets were conducted between active and inactive patients. Subgroup analyses were performed based on sex, age, disease duration, and severity. Correlation analyses explored the associations between lymphocyte subsets and TED activity indicators. Prediction models for TED activity were established using objective indicators. RESULTS: Significantly elevated levels of CD3+CD4+ T cells were observed in active TED patients compared to inactive patients (P = 0.010). Subgroup analyses further revealed that this disparity was most prominent in females (P = 0.036), patients aged 50 years and younger (P = 0.003), those with long-term disease duration (P = 0.022), and individuals with moderate-to-severe disease (P = 0.021), with age exerting the most substantial impact. Subsequent correlation analysis confirmed the positive association between CD3+CD4+ T cells and the magnetic resonance imaging indicator of TED activity among patients aged 50 years and younger (P = 0.038). The combined prediction models for TED activity, established using objective indicators including CD3+CD4+ T cells, yielded areas under curve of 0.786 for all patients and 0.816 for patients aged 50 years and younger. CONCLUSIONS: Peripheral CD3+CD4+ T cells are associated with disease activity of TED, especially in patients aged 50 years and younger. Our study has deepened the understanding of the peripheral T cell profiles in TED patients.

Immune-related visual dysfunction in thyroid eye disease: a combined orbital and brain neuroimaging study.

OBJECTIVES: To investigate the pathological interplay between immunity and the visual processing system (VPS) in thyroid eye disease (TED). METHODS: A total of 24 active patients (AP), 26 inactive patients (IP) of TED, and 27 healthy controls (HCs) were enrolled. Orbital magnetic resonance imaging (MRI) and resting-state functional MRI (rs-fMRI) were conducted for each participant. Multiple MRI parameters of the intraorbital optic nerve (ON) were assessed. The amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were calculated. Correlation analyses were carried out on the above parameters and clinical characteristics. RESULTS: Visual functioning scores differentiated between the AP and IP groups. The ON subarachnoid space and ON sheath diameter were significantly higher in AP than in IP. Six vision-related brain regions were identified in TED patients compared with HCs, including right calcarine (CAL.R), right cuneus (CUN.R), left postcentral gyrus (PoCG.L), right middle temporal gyrus (MTG.R), left superior frontal gyrus (SFG.L), and left caudate (CAU.L). The brain activity of MTG.R, SFG.L, and CAU.L differentiated between the AP and IP groups. The correlation analysis revealed a close association among the vision-related brain regions, MRI parameters of ON, and clinical characteristics in AP and IP, respectively. CONCLUSIONS: Combined orbital and brain neuroimaging revealed abnormalities of the VPS in TED, which had a close correlation with immune statuses. Vision-related brain regions in TED might be possibly altered by peripheral immunity via a direct or indirect approach. CLINICAL RELEVANCE STATEMENT: The discovery of this study explained the disparity of visual dysfunction in TED patients with different immune statuses. With the uncovered neuroimaging markers, early detection and intervention of visual dysfunction could be achieved and potentially benefit TED patients. KEY POINTS: • Patients with different immune statuses of thyroid eye disease varied in the presentation of visual dysfunction. • The combined orbital and brain neuroimaging study identified six altered vision-related brain regions, which had a significant correlation with the MRI parameters of the intraorbital optic nerve and immunological characteristics. • Peripheral immunity might possibly give rise to alterations in the central nervous system part of the visual processing system via a direct or indirect approach.

Choroidal thickness in patients with thyroid-associated ophthalmopathy, as determined by swept-source optical coherence tomography.

AIM: This study used swept-source optical coherence tomography (SS-OCT) to investigate subfoveal choroidal thickness (SFCT) in patients with thyroid-associated ophthalmopathy (TAO) who displayed different levels of disease activity and severity. METHODS: Thirty patients with TAO (60 eyes) and 38 healthy controls (67 eyes) in Shanghai, China, were recruited for this study. Disease activity and severity were graded using European Group on Graves' Orbitopathy standardised criteria. SFCT values were determined by SS-OCT. RESULTS: In total, 129 eyes were included in the final analysis. The mean SFCT was significantly thicker among patients with active disease (276.23±84.01 µm) than among patients with inactive disease (224.68±111.61 µm; p=0.049) or healthy controls (223.56±78.69 µm; p=0.01). There were no differences in SFCT among patients with moderate-to-severe disease, patients with severe disease and healthy controls (p>0.05). Changes in SFCT demonstrated strong predictive ability to distinguish active TAO from inactive TAO (area under the curve=0.659, 95% CI 0.496 to 0.822). CONCLUSIONS: SFCT was strongly associated with Clinical Activity Score in patients with TAO. Choroidal thickening was observed during active TAO. SS-OCT offers a non-invasive method for follow-up assessment.

Pathogenic role of Th17 cells in autoimmune thyroid disease and their underlying mechanisms.

Autoimmune thyroid disease, encompassing Graves' disease and Hashimoto's thyroiditis, has a very complex etiology. Pathogenesis of the disease involves both genetic susceptibility and environmental triggers. Traditionally, imbalance of T helper cell 1 and 2 was thought to result in the immune disorders in Graves' disease and Hashimoto's thyroiditis. However, increasing evidence recently revealed the important role of T helper 17 cell and its relative cellular and secretory components in the pathogenesis and progression of autoimmune thyroid disease. This review is aimed to summarize the published studies on the involvement of T helper 17 cell in autoimmune thyroid disease and discuss the underlying regulatory mechanisms, which could possibly serve as the foundation of discovering new therapeutic targets.

M1-Like Macrophages Modulate Fibrosis and Inflammation of Orbital Fibroblasts in Graves' Orbitopathy: Potential Relevance to Soluble Interleukin-6 Receptor.

Background: Graves' orbitopathy (GO) is a disfiguring and sight-threatening autoimmune disease. Previous studies have shown the infiltration of macrophages in GO orbital connective tissues. However, the immunophenotypes of macrophages and their modulatory effects on orbital fibroblasts (OFs) have not been examined so far. In this study, we sought to determine the pathophysiology of macrophages in GO. Methods: In this case-control study, orbital connective tissues collected from 40 GO patients and 20 healthy controls were immunohistochemically stained for cytokines and macrophage cell surface antigens. The polarization of orbital-infiltrating macrophages was investigated by flow cytometry and immunofluorescence. Effects of interleukin (IL)-6 combined with soluble IL-6 receptor (sIL-6R) on the proliferation, differentiation, and inflammation of different OF subsets were examined by CCK-8, Western blotting, and Luminex assays, respectively. The antigen-presenting abilities of different OF subsets under IL-6/sIL-6R signaling were studied by proteomics. Finally, the differentiation of CD8+ IL-17A-producing T cells by sIL-6R was tested. Results: GO orbital connective tissues displayed increased IL-6, sIL-6R, STAT3, and IL-17A levels. CD86+ M1-like macrophages were predominant in active GO patients, while stable GO patients tended to have more CD163+ M2-like macrophages. The expression of IL-6 was higher in M1-like macrophages, and the expression of transforming growth factor-ß was higher in M2-like macrophages both in GO orbital connective tissues in situ in vivo and in cell culture system in vitro. The IL-6/sIL-6R stimulation promoted the fibrosis of both CD34+ and CD34- OFs. Monocyte chemoattractant protein-1 expression was also induced by IL-6/sIL-6R stimulation in both OF subsets. IL-6/sIL-6R stimulation enhanced the antigen processing of CD34+ OFs through upregulating the intact major histocompatibility complex I and antigen transporters. However, the protein expressions of the thyrotropin receptor and insulin-like growth factor 1 receptor could not be directly increased by IL-6/sIL-6R stimulation in CD34+ OFs. Furthermore, sIL-6R was conducive to the differentiation of CD8+ IL-17A-producing T cells. Conclusions: Our study demonstrated the immunophenotypes of orbital-infiltrating macrophages that may activate OFs depending on the IL-6/sIL-6R signaling in GO. Our preclinical findings implicate, at least in part, the molecular rationale for blocking sIL-6R as a promising therapeutic agent for GO.

A Multicenter, Single-Blind, Case-Control, Immunohistochemical Study of Orbital Tissue in Thyroid Eye Disease.

Background: Thyroid eye disease (TED) involves several pathogenic pathways and a battery of infiltrating mononuclear cells, cytokines, and chemokines in the orbit. Revealing the main molecules, which play a major role in the pathogenesis of TED, will help developing novel treatment strategies. Methods: In a multicenter, single-blind, case-control study, 60 tissue samples were collected during orbital decompression (44 TED patients) or non-TED related oculoplastic (16 controls) surgeries. Formalin-fixation and paraffin embedding preserved orbital tissue. Tissue sections were immunostained with 18 antibodies by the micro-polymer labeling technique. Immunostaining slides were scanned by Panoramic Desk and blindly evaluated by a user-independent viewer software. Results: Marked lymphocyte infiltration was observed in orbital tissue specimens of patients with clinically active TED (n = 22) and to a much lesser extent in inactive cases (n = 22), while it was absent in controls. Increased vascularity was noted in all samples, with orbital congestion in specimens of clinically active TED. Tissue fibrosis was present in TED samples but not in controls. Immunohistochemistry of orbital tissue clearly differentiated between TED and controls, as well as between active and inactive TED. In contrast to controls and with the exception of cluster of differentiation 20 (CD20), 17 out of 18 antibodies were highly expressed in orbital connective tissue of TED patients. Especially, thyrotropin receptor (TSH-R), insulin-like growth factor 1 receptor (IGF-1R), CD40, cluster of differentiation 40 ligand (CD40L), CD3, CD68, interleukin-17A (IL-17A), IL-23A, IL-1ß, IL-4, regulated on activation, normal T cell expressed and secreted (RANTES), macrophage chemoattractant protein 1 (MCP-1), IL-16, and B cell activating factor (BAFF) were overexpressed in clinically active TED (all p < 0.001). Also, the expression of CD40L, IL-17A, IL-23A, IL-6, IL-1ß, RANTES, and BAFF was very high (TED/control ratio >3), moderate (ratio >2), and low in active (p < 0.001), inactive TED and controls, respectively. The expression of TSH-R, IGF-1R, CD40, CD40L, CD3, CD68, CD20, IL-17A, IL-23A, RANTES, MCP-1, and BAFF positively and significantly correlated with both serum TSH-R stimulatory antibody concentrations and clinical activity scores while it negatively correlated with TED duration. Orbital irradiation decreased TSH-R (p < 0.001) and IGF-1R expression (p = 0.012); in contrast, neither smoking, age, nor gender did impact immunohistochemical staining. Conclusions: Adaptive and cell-mediated immunity, overexpression of TSH-R/IGF-1R and CD40/CD40L are the relevant pathomechanisms in TED. Targeting these key players in the active phase of the disease offers specific and novel treatment approaches.

Immunophenotype of Lacrimal Glands in Graves Orbitopathy: Implications for the Pathogenesis of Th1 and Th17 Immunity.

Background: Recent studies have reported a wide spectrum of ocular surface injuries in the context of autoimmune reactions in Graves' orbitopathy (GO). Increased expression of inflammatory mediators in tears of GO patients suggests that the lacrimal glands could be a target for immune responses. However, the immunophenotype for GO lacrimal microenvironment is not known. This study aimed to elucidate the pathological changes of GO lacrimal glands. Methods: In this case-control study, lacrimal glands were surgically collected from GO patients who underwent orbital decompression surgery and control subjects who underwent other ocular-related surgery. Bulk RNA-sequencing, flow cytometry with dimensional reduction, and immunohistochemical and multiplexed stainings were conducted. Western blotting and multipathway assays were performed in CD34+ fibroblasts derived from lacrimal and orbital tissues. Results: Increased expression of cytokines and chemokines accompanied by a variety of immune cell infiltrations mainly involving T cells, B cells, and monocytes was found in GO lacrimal glands. An in-depth investigation into T cell subsets revealed interferon (IFN)-γ-producing T helper (Th)1 and interleukin (IL)-17A-producing Th17 cell-dominated autoimmunity in the active GO lacrimal microenvironment. Both fibrosis and adipogenesis were observed in GO lacrimal tissue remodeling. IL-17A, not IFN-γ, stimulated transforming growth factor-ß-initiated myofibroblast differentiation as well as 15-deoxy-Δ12,14-prostaglandin J2-initiated adipocyte differentiation in CD34+ lacrimal fibroblasts (LFs) and orbital fibroblasts (OFs), respectively. IL-17A activated many fibrotic and adipogenic-related signaling pathways in CD34+ LFs and OFs. A novel anti-IL-17A monoclonal antibody SHR-1314 could reverse the promoting effect of IL-17A on fibrosis and adipogenesis in CD34+ LFs and OFs. Conclusions: Our findings provide evidence for the infiltration of different lymphocytes into GO lacrimal microenvironment, where Th1 and Th17 cells characterize the onset of active lacrimal inflammation and contribute to tissue remodeling. These findings may have potential future therapeutic implications regarding the utility of anti-IL-17A therapy, which should be studied in future research.

Age-related difference in extraocular muscles and its relation to clinical manifestations in an ethnically homogenous group of patients with Graves' orbitopathy.

PURPOSE: To evaluate the age-related difference in EOMs and its relation to clinical manifestations by computed tomography (CT) measurement of EOMs. METHODS: The medical records and CT image review of 40 patients (80 orbits) with moderate-to-severe Graves' orbitopathy were performed. The patients were divided into two age groups, group 1 (≤ 40 years) and group 2 (> 40 years). CT scans of 30 gender- and age-matched normal controls were also obtained. The maximal cross-sectional area (MCA) and its position (pMCA) of each EOM were measured. RESULTS: Group 1 presented with more severe proptosis (p < 0.001), while group 2 had a higher risk of diplopia (p < 0.001). Motility restriction in supraduction was more likely to occur in Group 2 (p = 0.027) with even higher severity (p = 0.047). The pMCA was higher in the inferior (p = 0.001), medial (p = 0.021), and lateral rectus (p = 0.013) in group 1. Proptosis was positively correlated to pMCA while diplopia was correlated to MCA in both groups. Significant correlation was noted between restrictions levels and MCA (superior, r = 0.467, p < 0.001; inferior, r = 0.358, p = 0.007; medial, r = 0.314, p = 0.018; lateral, r = 0.308, p = 0.021) or pMCA (inferior, r = - 0.534, p < 0.001) only in group 2. CONCLUSIONS: The muscle enlargement patterns are significantly different between younger and older patients. Older patients tended to have enlarged muscle bellies more posterior in the orbit, which is responsible for more diplopia and motility restriction. Proptosis is more likely to be affected by the most enlarged position than muscle size. So younger patients tended to develop more proptosis and be less bothered by motility restriction even with enlarged muscles.

In Search of Excellence: From a Small Clinical Unit to an Internationally Recognized Center for Orbital Diseases Research and Surgery at the Department of Ophthalmology, Shanghai Ninth People's Hospital, China.

ABSTRACT: "Where there is a will, there is a way." It is never easy to make progress and development but with full dedication and firm commitment, many aspirations can still be realized. We would like to share with the readers the story of how we develop our division of orbital diseases and surgery from scratch to strengths over a period of 2 decades at the Department of Ophthalmology of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China.

Mechanisms That Underly T Cell Immunity in Graves' Orbitopathy.

Graves' orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is the most common ocular abnormality of Graves' disease. It is a disfiguring, invalidating, and potentially blinding orbital disease mediated by an interlocking and complicated immune network. Self-reactive T cells directly against thyroid-stimulating hormone receptor-bearing orbital fibroblasts contribute to autoimmune inflammation and tissue remodeling in GO orbital connective tissues. To date, T helper (Th) 1 (cytotoxic leaning) and Th2 (antibody leaning) cell subsets and an emerging role of Th17 (fibrotic leaning) cells have been implicated in GO pathogenesis. The potential feedback loops between orbital native residential CD34- fibroblasts, CD34+ infiltrating fibrocytes, and effector T cells may affect the T cell subset bias and the skewed pattern of cytokine production in the orbit, thereby determining the outcomes of GO autoimmune reactions. Characterization of the T cell subsets that drive GO and the cytokines they express may significantly advance our understanding of orbital autoimmunity and the development of promising therapeutic strategies against pathological T cells.

Application of Magnetic Resonance Imaging in the Evaluation of Disease Activity in Graves' Ophthalmopathy.

OBJECTIVE: To evaluate magnetic resonance imaging parameters, T2 signal intensity ratios (SIRs), and normalized apparent diffusion coefficients (n-ADC) of the extraocular muscles (EOMs) in the identification of different stages of Graves' ophthalmopathy (GO) and to find out the correlation of T2-SIRs and n-ADC values with disease changes after anti-inflammatory treatment. METHODS: Altogether, 43 patients (86 orbits) were enrolled and classified into "active" or "inactive" stages by clinical activity score (CAS). Twenty-three (53.5%) patients received anti-inflammatory treatment and underwent a follow-up evaluation. Fifteen age- and gender-matched control participants (30 orbits) were included. T2-SIRs and n-ADC values of EOMs were calculated among GO and healthy controls and were correlated with CAS. Changes in these parameters were also evaluated before and after anti-inflammatory treatment. RESULTS: Mean T2-SIRs and n-ADC values were both significantly higher in GO patients than in controls and higher in active GO than in inactive GO. In the inactive stage, n-ADC values of inferior rectus muscles were still higher than those in healthy controls. Both T2-SIRs and n-ADC values decreased after intravenous steroid pulse therapy. The cutoff value of pretreatment n-ADC was 1.780 to detect stages with specificity of 93.7% and sensitivity of 48.3% (P = .035). CONCLUSION: T2-SIRs and n-ADC values are valuable magnetic resonance imaging indicators of the inflammatory activity in GO by detecting involvement of EOMs. They are also ideal tools to monitor the efficacy of anti-inflammatory treatment in patients with active stage GO. n-ADC values, when combined with CAS, can be promising predictive factors in the detection of stages of diseases.

Progress in the pathogenesis of thyroid-associated ophthalmopathy and new drug development.

Thyroid-associated ophthalmopathy (TAO) is the most common extrathyroidal manifestation of toxic diffuse goiter (Graves' disease), also known as Graves' ophthalmopathy/orbitopathy. As an organ-specific autoimmune disease, the pathogenesis of TAO is still unclear. In recent years, great progress has been made in revealing the mechanism of TAO. Various biological and immunosuppressive agents have emerged in an endless stream, showing encouraging results. Strengthening the basic research, establishing ideal animal models, deeply understanding the pathogenesis, and developing novel targeted drugs are of great significance to guide the clinical diagnosis and management of TAO and improve the prognosis of patients.

Associations between abdominal obesity indices and diabetic complications: Chinese visceral adiposity index and neck circumference.

BACKGROUND AND AIMS: Obesity, especially abdominal obesity, has been considered a risk factor for diabetic complications. Many abdominal obesity indices have been established, including neck circumference (NC), waist-to-hip ratio (WHR), lipid accumulation product (LAP), visceral adiposity index (VAI) and the Chinese visceral adiposity index (CVAI). However, studies investigating the associations between these indices and diabetic complications are limited. The objective of this study was to investigate the associations of the abdominal obesity indices with cardiovascular and cerebrovascular disease (CVD), diabetic kidney disease (DKD) and diabetic retinopathy (DR). METHODS: A total of 4658 diabetic participants were enrolled from seven communities in Shanghai, China, in 2018. Participants completed questionnaires and underwent blood pressure, glucose, lipid profile, and urine albumin/creatinine ratio measurements; fundus photographs; and anthropometric parameters, including height, weight, waist circumference (WC), NC and hip circumference (HC). RESULTS: In men, a one standard deviation (SD) increase in CVAI level was significantly associated with a greater prevalence of CVD (OR 1.35; 95% CI 1.13, 1.62) and DKD (OR 1.38; 95% CI 1.12, 1.70) (both P < 0.05). In women, a one SD increase in CVAI level was significantly associated with a greater prevalence of CVD (OR 1.32; 95% CI 1.04, 1.69) and DKD (OR 2.50; 95% CI 1.81, 3.47) (both P < 0.05). A one SD increase in NC was significantly associated with a greater prevalence of CCA plaque in both men (OR 1.26; 95% CI 1.10, 1.44) and women (OR 1.20; 95% CI 1.07, 1.35). These associations were all adjusted for potential confounding factors. CONCLUSIONS: CVAI was most strongly associated with the prevalence of CVD and DKD among the abdominal obesity indices, and NC was unique associated with the prevalence of CCA plaque in Chinese adults with diabetes. Trial registration ChiCTR1800017573, www.chictr.org.cn . Registered 04 August 2018.

Associations between different bilirubin subtypes and diabetic microvascular complications in middle-aged and elderly individuals.

AIMS: Some studies have reported associations between bilirubin and diabetic microvascular complications. However, these studies focused only on total bilirubin (TBIL) without distinguishing different bilirubin subtypes. In this study, we aimed to investigate the associations of TBIL, direct bilirubin (DBIL) and indirect bilirubin (IBIL) levels with albuminuria/creatinine ratio (ACR) and the prevalence of diabetic retinopathy (DR) among diabetic adults. METHODS: We analyzed 4368 individuals out of 4813 diabetic participants enrolled from seven communities in 2018 in a cross-sectional study. Participants underwent several checkups, including the measurement of anthropometric parameters, blood pressure, glucose, lipid profile, TBIL, DBIL, IBIL and ACR. DR was detected by high-quality fundus photographs and was remotely read by ophthalmologists. RESULTS: Compared with the first quartile of DBIL, participants in the fourth quartile had a lower prevalence of high ACR (odds ratio (OR) 0.76; 95% confidence interval (CI) 0.59, 0.99) (p for trend < 0.05). Neither TBIL nor IBIL was associated with the prevalence of high ACR. In DR, higher DBIL and TBIL by one standard deviation was associated with a 19% (OR 0.81; 95% CI 0.69, 0.94) and a 12% (OR 0.88; 95% CI 0.78, 0.99) lower frequency of DR, respectively (both p for trend < 0.05). However, IBIL was not associated with the prevalence of DR. These associations were adjusted for potential confounding factors. CONCLUSION: DBIL had a stronger association with high ACR and DR than TBIL or IBIL did in diabetic adults. The effect of DBIL on diabetic complications should be noted and investigated in further studies.

The unique association between the level of peripheral blood monocytes and the prevalence of diabetic retinopathy: a cross-sectional study.

OBJECTIVE: The attraction and influx of monocytes into the retina has been considered a critical step in the development of diabetic retinopathy (DR). However, large population studies about the association between peripheral blood monocyte levels, an inexpensive and easily measurable laboratory index, and DR are limited. Thus, we aimed to investigate the association between peripheral blood monocyte levels and DR. METHODS: A total of 3223 participants out of 3277 adults with diabetes were enrolled from seven communities in China in this cross-sectional survey. Participants underwent several medical examinations, including the measurement of anthropometric factors, blood pressure, routinely analyzed leukocyte characteristics, glucose, lipid profiles, urine albumin/creatinine ratio and fundus photographs. RESULTS: The prevalence of DR among the participants in the highest quartile of peripheral blood monocyte levels significantly decreased by 41% (OR 0.59; 95% CI 0.43, 0.81) compared with the participants in the first quartile (P for trend < 0.05). However, there were no associations between the monocyte level and the prevalence of cardiovascular and cerebrovascular diseases (CVD) and diabetic kidney disease (DKD) (both P for trend > 0.05). Associations between leukocyte, neutrophil and lymphocyte levels and DR were also not found (all P for trend > 0.05). These associations were all fully adjusted for age, sex, education status, duration of diabetes history, current smoking, BMI, HbA1c, dyslipidemia, systolic blood pressure and insulin therapy. CONCLUSION: Decreased peripheral blood monocyte levels were associated with increased odds of DR after adjusting for potential confounders in diabetic adults. However, causation remains to be demonstrated.

Associations between the Neutrophil-to-Lymphocyte Ratio and Diabetic Complications in Adults with Diabetes: A Cross-Sectional Study.

OBJECTIVE: The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive and easily measurable laboratory index indicating systemic inflammation, while the application of many other inflammatory markers has been limited in daily clinical practice. However, large population studies about investigating the associations of the NLR level with diabetic complications including cardiovascular and cerebrovascular diseases (CVD), diabetic kidney disease (DKD), and diabetic retinopathy (DR) in the same population were limited. The aim of our study is to evaluate the associations between the NLR level and the prevalence of CVD, DKD, and DR in adults with diabetes simultaneously. METHODS: A cross-sectional survey of 4,813 diabetic adults was conducted in seven communities in China. Persons underwent several medical examinations, including the measurement of anthropometric factors, blood pressure, routinely analyzed leukocyte characteristics, glucose, lipid profiles, urine albumin/creatinine ratio, and fundus photographs. RESULTS: Compared with the first quartile of the NLR level, the odds of having CVD was significantly increased by 21% for participants in the highest quartile (OR 1.21; 95% CI 1.00, 1.47) (P for trend < 0.05). Similarly, the prevalence of DKD among participants in the highest quartile of the NLR level was significantly increased by 150% (OR 2.50; 95% CI 1.95, 3.19) (P for trend < 0.05). However, no association was found between the NLR level and the prevalence of DR (P for trend > 0.05). These associations were all fully adjusted. CONCLUSIONS: A higher NLR level was associated with an increased prevalence of CVD and DKD, other than DR, in diabetic adults.

Evidence for Associations Between Th1/Th17 "Hybrid" Phenotype and Altered Lipometabolism in Very Severe Graves Orbitopathy.

PURPOSE: The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. METHODS: Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. RESULTS: In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ-producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ-producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. CONCLUSIONS: Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.

Different associations between serum urate and diabetic complications in men and postmenopausal women.

AIMS: The objective of this study was to investigate the different associations of the serum urate (SUA) level with cardiovascular and cerebrovascular diseases (CVD), diabetic kidney disease (DKD) and diabetic retinopathy (DR) in Chinese adults. METHODS: We analyzed 4767 participants out of 4813 adults with diabetes enrolled from seven communities in a cross-sectional survey. Participants underwent several medical examinations, including the measurement of anthropometric factors, blood pressure, SUA, glucose, lipid profiles, urine albumin/creatinine ratio (ACR) and fundus photographs. RESULTS: Compared with the first SUA tertile, the third tertile increased the prevalence of CVD by 22% (OR 1.22; 95% CI 1.01, 1.46) (P for trend <0.05) and increased the prevalence of DKD by 59% (OR 1.59; 95% CI 1.28, 1.97) for KDOQI definition. Compared with the first tertile, the OR (95% CI) of the number of diabetic complications, ranging from 0 to 2, associated with SUA level in ordinal logistic regression was 1.75 (1.44, 2.12) for the third tertile (P for trend <0.01). These associations were all fully adjusted. No association was found between the prevalence of DR and the SUA level. CONCLUSIONS: A higher SUA level was associated with an increased prevalence of CVD and DKD and a variety of diabetic complications, other than DR, in men and postmenopausal women with T2DM. However, the causation remains to be demonstrated.

Immunological Features of Paranasal Sinus Mucosa in Patients with Graves' Orbitopathy.

Background: Previous studies showed that patients with Graves' orbitopathy (GO) had concomitant mucosal abnormality within the paranasal sinuses. It remains unknown whether the immunological reactions in sinus mucosa affect the orbit inflammation in GO. Methods: Patients with GO underwent sinus computed tomography (CT) scans for sinus mucosal disease by two independent reviewers using the Lund-MacKay systems. Ethmoid mucosal samples were collected during orbital decompression surgeries for patients with GO and correction surgeries for patients with old orbital fractures as controls. Histological analysis and immunofluorescence were performed in all sinus mucosa tissues. Flow cytometry analysis was used to examine the immunological features of sinus mucosa in both GO and control groups. Results: Immunohistochemistry showed that the paranasal sinus mucosa of patients with GO grew swelling, with goblet cell and small vessel proliferation, endothelial cell swelling, and inflammatory cell infiltration. The number of T helper (Th)1, Th17, and gamma-delta T cells in nasal sinus mucosa of patients with GO increased significantly compared with those from controls. Further, the proportion of Th1 cells was significantly correlated with clinical activity score. In addition, there was a decreased number of regulatory T cells in patients with GO. The number of Th2 cells showed no significant difference between the two groups. Finally, the proportion of interleukin-22-producing cell subsets in gamma-delta T cells of patients with GO was significantly increased compared with those from controls. Conclusions: Our observations illustrated a potential pathogenic role of mucosal-infiltrating T cells, which may have the possibility to aggravate inflammatory responses in GO.