Abnormal Functional Connectivity Density in Patients with Dysthyroid Optic Neuropathy.

OBJECTIVE: Functional connectivity density (FCD) mapping was used to investigate abnormalities and factors related to brain functional connectivity in cortical regions of patients with dysthyroid optic neuropathy (DON) and to analyze the pathogenesis of DON further. METHODS: Patients diagnosed with thyroid-associated opthalmology (TAO) in the Eye Hospital were enrolled. All patients underwent comprehensive eye examinations and best-corrected visual acuity, visual field (VF) test. MRI data collection and analysis were completed in the 2nd Affiliated Hospital of Wenzhou Medical University. The patients were divided into 2 groups: the DON group, with an average VF, mean deviation (MD) of both eyes < -5 dB, and the non-DON group (nDON group), with an average VF MD of both eyes ≥ -2 dB. RESULTS: A total of 30 TAO patients (14 men, 16 women) with complete data who met the experimental requirements were enrolled. The average age was 48.79 (40-57) years. There were 16 patients in the DON group and 14 patients in the nDON group. No significant differences in age, gender, education level, and the maximum horizontal diameter of either medial rectus muscle were found between the 2 groups. The difference of brain FCD between the 2 groups showed significant abnormal connectivity in the right orbital gyri of the frontal lobe (Frontal_Inf_Orb_R) and the left precuneus in the DON group compared with the nDON group. As demonstrated by decreased FCD values in the right inferior frontal gyrus/orbital part, the relevant brain regions were the left middle temporal gyrus, left precuneus, left middle frontal gyrus, right postcentral gyrus, and brain gyri (excluding the supramarginal gyrus and angular gyrus) below the left parietal bone. The FCD associated with the left precuneus was increased, and the relevant brain areas were the left middle temporal gyrus, right cuneus, superior occipital gyrus, and right fusiform gyrus. A significant correlation was identified between the MD of the binocular VF and brain FCD. CONCLUSION: The abnormal FCD in the cortex of DON patients suggests that a central nervous system mechanism may be related to the pathogenesis of the DON.

The circulating IL-35+ regulatory B cells are associated with thyroid associated opthalmopathy.

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is the most common orbital disease in adults, potentially leading to disfigurement and visual impairment. However, the causes of TAO are not fully understood. IL-35+B cells are a newly identified regulatory B cells (Bregs) in maintaining immune balance in various autoimmune diseases. Yet, the influence of IL-35+Bregs in TAO remains unexplored. METHODS: This study enrolled 36 healthy individuals and 14 TAO patients. We isolated peripheral blood mononuclear cells and stimulated them with IL-35 and CpG for 48 h. Flow cytometry was used to measure the percentages of IL-35+Bregs. RESULTS: The percentage of circulating IL-35+Bregs was higher in TAO patients, and this increase correlated positively with disease activity. IL-35 significantly increased the generation of IL-35+Bregs in healthy individuals. However, B cells from TAO patients exhibited potential impairment in transitioning into IL-35+Breg phenotype under IL-35 stimulation. CONCLUSIONS: Our results suggest a potential role of IL-35+Bregs in the development of TAO, opening new avenues for understanding disease mechanisms and developing therapeutic approaches.

Single-cell BCR and transcriptome analysis reveals peripheral immune signatures in patients with thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is the most prevalent orbital disease in adults caused by an autoimmune disorder, which can lead to disfigurement and vision impairment. Developing effective treatments for this condition presents challenges due to our limited understanding of its underlying immune aberrations. In this study, we profiled the immune components in the peripheral blood of patients with TAO as well as healthy individuals, utilizing single-cell RNA sequencing and B-cell receptor repertoires (BCR) analysis. We observed a significant reduction in the proportions of regulatory B cells (Bregs) and type 2 conventional dendritic cells (DCs) in patients with TAO during the active phase. Conversely, there was a significant increase in the proportion of type 1 DCs. Further analysis of cell differentiation trajectory revealed potential impairment in the transition of B cells towards Breg phenotype during the active phase of TAO. Besides, the activation process of TAO appeared to involve inflammation and immune dysfunction, as indicated by the dynamic changes in the activities of key regulators. The abnormalities in the peripheral immune system, such as the reduced capacity of Bregs to suppress inflammation, were primarily driven by the enhanced interaction among Breg, DCs, and monocytes (i.e., CD22-PTPRC and BTLA-TNFRSF14). Collectively, our findings offer a comprehensive insight into the molecular regulation and cellular reconfiguration during the active phase of TAO at the single-cell level, in order to explore the pathogenesis of TAO and provide new ideas for the future treatment of TAO.

Elevated pulse pressure correlated with reduced retinal peripapillary capillary in thyroid-associated ophthalmology with visual field defect.

Purpose: To quantify the retinal vessel density in thyroid-associated ophthalmology (TAO) patients with visual field (VF) defect and examine its associations with mechanical and system vascular risk factors for underlying pathogenesis of VF defect in TAO. Methods: The cohort was composed of 62 TAO eyes (39 with VF defect and 23 without VF defect). The pulse pressure (PP), intraocular pressure (IOP), ophthalmic rectus muscular index (MI), superficial retinal capillary plexus (SRCP), radial peripapillary capillary (RPC) density, and other related parameters were measured. The associations among these factors and VF mean deviation (MD) were analyzed. Results: In TAO patients with VF defect, reduced RPC density, higher PP, and larger horizontal and vertical MI were found (all P < 0.03) when compared to TAO patients without VF defect. The RPC density was correlated with VF MD value (r = 0.242, P = 0.029), while SRCP density was not (P = 0.419). In univariable general estimating equation (GEE) analysis with RPC density as the outcome, PP and its fluctuation showed a significant association (both P < 0.04). In the final RPC model with multivariable GEE analysis, only PP (ß = -0.082, P = 0.029) showed significance while PP fluctuation (P = 0.080) did not. Conclusions: The elevated PP was correlated with reduced retinal peripapillary perfusion in TAO resulting in VF defect. These data suggested that the system vascular factor may be important in the pathogenesis of reduced retinal perfusion resulting in visual impairment in TAO.

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.