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-1β, 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-1β, 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.

Purpose: Orbital fibroblasts (OF) are considered the central target cells in the pathogenesis of thyroid-associated orbitopathy (TAO), which comprises orbital inflammation, orbital tissue edema, adipogenesis, fibrosis, oxidative stress and autophagy. Certain active ingredients of traditional Chinese medicine (TCM) demonstrated inhibition of TAO-OF in pre-clinical studies and they could be translated into novel therapeutic strategies. Methods: The pertinent and current literature of pre-clinical studies on TAO investigating the effects of active ingredients of TCM was reviewed using the NCBI PubMed database. Results: Eleven TCM compounds demonstrated inhibition of TAO-OF in-vitro and three of them (polydatin, curcumin, and gypenosides) resulted in improvement in TAO mouse models. Tanshinone IIA reduced inflammation, oxidative stress and adipogenesis. Both resveratrol and its precursor polydatin displayed anti-oxidative and anti-adipogenic properties. Celastrol inhibited inflammation and triptolide prevented TAO-OF activation, while icariin inhibited autophagy and adipogenesis. Astragaloside IV reduced inflammation via suppressing autophagy and inhibited fat accumulation as well as collagen deposition. Curcumin displayed multiple actions, including anti-inflammatory, anti-oxidative, anti-adipogenic, anti-fibrotic and anti-angiogenic effects via multiple signaling pathways. Gypenosides reduced inflammation, oxidative stress, tissue fibrosis, as well as oxidative stress mediated autophagy and apoptosis. Dihydroartemisinin inhibited OF proliferation, inflammation, hyaluronan (HA) production, and fibrosis. Berberine attenuated inflammation, HA production, adipogenesis, and fibrosis. Conclusions: Clinical trials of different phases with adequate power and sound methodology will be warranted to evaluate the appropriate dosage, safety and efficacy of these compounds in the management of TAO.

X-linked lymphoproliferative disease (XLP) is a rare genetic disorder characterized by immune dysregulation. The three most common clinical phenotypes are EBV-associated infectious mononucleosis (FIM), abnormal gammaglobulinemia, and lymphoma. We present a rare case of XLP1 with neurovasculitis, which is non-EBV-related and involves multiple systems, a condition rarely seen in children. The patient initially presented with an unsteady gait, which progressively evolved into language and consciousness disorders. Additionally, CT scans revealed multiple nodules in the lungs. Subsequent genetic testing and brain tissue biopsy confirmed the diagnosis: XLP1-related cerebral vasculitis and cerebral hemorrhage. Tragically, during the diagnostic process, the child experienced a sudden cerebral hemorrhage and herniation, ultimately resulting in fatality. This case offers a comprehensive insight into XLP1-related cerebral vasculitis and cerebral hemorrhage, underscoring the significance of early diagnosis and prompt treatment, while also imparting valuable clinical experience and lessons to the medical community.

Context: High-throughput proteomics (HTP) helps identify characteristic signaling networks specific to certain diseases, thus offering a range of potential applications in basic research and precision medicine. Immunohistochemistry can uncover local orbital immunity. Objective: To investigate key proteins linked to the progression of Graves' orbitopathy (GO). Methods: Thirty-one orbital connective tissue samples from patients with GO (11 with clinically severe and 12 with mild GO), and from 8 control subjects were examined using HTP. We focused on the intersection of differentially expressed proteins (DEPs) that differ between severe GO and both mild GO and control. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes were used to analyze DEPs. Immunohistochemical verification was performed using 11 severe and 7 mild GO orbital tissues. Immunostaining was quantitatively analyzed using reliable and automated software that ensures objective, operator-independent evaluation. Results: A total of 4579 proteins were identified: 847, 790, and 208 DEPs were registered when comparing mild GO vs control, severe GO vs control, and severe vs mild GO, respectively (all P < .05). Using a cutoff threshold of fold change ≥2.0 during screening, 5 significantly upregulated DEPs (Latent-transforming growth factor β-binding protein 2, Lysyl oxidase homolog, Ras-interacting protein 1, Integrin beta 3, Coagulation factor XII) overlapped between severe GO and both mild GO and control, while 163 upregulated DEPs were involved in various biological processes (angiogenesis, inflammation, tissue remodeling, and fibrosis). Subsequent immunohistochemical tissue validation confirmed the HTP findings. Conclusion: For the first time, combined proteomics and immunohistochemistry detected upregulated orbital tissue proteins potentially implicated in GO progression.

Background: The interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) gene is strongly associated with disease activity index of childhood systemic lupus erythematosus (SLE). However, whether IFIT1-regulated gene expression is the molecular basis of the pathogenesis of SLE has not been fully investigated. Methods: Dataset GSE11909 was used to analyze the expression profiles of IFIT1 gene in 103 SLE cases and 12 healthy individuals. Differentially expressed genes (DEGs)-affected by IFIT1 gene were screened between the case group and control group, followed by gene function analysis. The clinical diagnostic potential of the least absolute shrinkage and selection operator (LASSO) model, established based on the expression profiles of IFIT1 and IFIFT1-affected DEGs, was evaluated. Analysis of association between IFIFT1-affected DEGs and immune infiltration was performed. Results: IFIT1 was highly expressed in childhood SLE patients. IFIT1 and IFIT1-affected DEGs showed the potential to serve as a diagnostic marker for childhood SLE with area under the curve (AUC) value of 0.947. Childhood SLE patients showed 826 upregulated DEGs and 4,111 downregulated DEGs compared to the control group. Among them, 208 upregulated DEGs and 214 downregulated DEGs were identified in the IFIT1-high group compared to the IFIT1-low group. The LASSO model for the diagnosis of childhood SLE involved 7 marker genes that were related to immune checkpoint and tertiary lymphoid structure in SLE. Conclusions: Our results confirmed the clinical diagnostic potential of IFIT1 and IFIT1-affected genes in childhood SLE. Moreover, this study elucidated that IFIT1-induced changes in the transcriptome are involved in immune checkpoint and tertiary lymphoid structure in childhood.