Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment.

Autoimmune thyroid disease (AITD) is the most common organic specific illness of the thyroid gland. It may manifest as the overproduction or the decline of thyroxine and triiodothyronine. Hyperthyroidism develops due to the overproduction of hormones as an answer to the presence of stimulatory antibodies against the TSH receptor. Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid. Due to the progressive destruction of cells, AITD can lead to subclinical or overt hypothyroidism. Pathophysiology of AITD is extremely complicated and still not fully understood, with genetic, environmental and epigenetic factors involved in its development. Due to increasing incidence and social awareness of this pathology, there is an urgent need to expand the background concerning AITD. A growing body of evidence suggests possible ways of treatment apart from traditional approaches. Simultaneously, the role of potential new biomarkers in the diagnosis and monitoring of AITD has been highlighted recently, too. Therefore, we decided to review therapeutic trends in the course of AITD based on its pathophysiological mechanisms, mainly focusing on HT. Another aim was to summarize the state of knowledge regarding the role of new biomarkers in this condition.

[The role of Th17 cells and IL-17 in Hashimoto's thyroiditis: Review].

Patients with Hashimoto's thyroiditis had increased numbers of Th17 cells in serum and thyroid tissue, significantly elevated levels of interleukin 17 (IL-17), and an imbalance in the ratio of Th17 cells to regulatory T cells (Tregs). The reduced Tregs' ratio leads to a reduction in immunosuppressive function within the thyroid gland, while Th17 cells are involved in the development of HT by regulating the expression of pro-inflammatory cytokines in the thyroid gland and mediating thyroid tissue fibrosis through the secretion of IL-17.

Targeting the aryl hydrocarbon receptor with FICZ regulates IL-2 and immune infiltration to alleviate Hashimoto's thyroiditis in mice.

Hashimoto's thyroiditis (HT) is the most frequent autoimmune disorder. Growing work points to the involvement of aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, in the regulation of immune homeostasis. However, the roles of AhR and its ligands in HT remains unclear. In this study, we leveraged public human database analyses to postulate that the AhR expression was predominantly in thyroid follicular cells, correlating significantly with the thyroid infiltration levels of multiple immune cells in HT patients. Using a thyroglobulin-induced HT mouse model and in vitro thyroid follicular epithelial cell cultures, we found a significant downregulation of AhR expression in thyrocytes both in vivo and in vitro. Conversely, activating AhR by FICZ, a natural AhR ligand, mitigated inflammation and apoptosis in thyrocytes in vitro and conferred protection against HT in mice. RNA sequencing (RNA-seq) of thyroid tissues indicated that AhR activation moderated HT-associated immune or inflammatory signatures. Further, immunoinfiltration analysis indicated that AhR activation regulated immune cell infiltration in the thyroid of HT mice, such as suppressing cytotoxic CD8+ T cell infiltration and promoting anti-inflammatory M2 macrophage polarization. Concomitantly, the expression levels of interleukin-2 (IL-2), a lymphokine that downregulates immune responses, were typically decreased in HT but restored upon AhR activation. In silico validation substantiated the binding interaction between AhR and IL-2. In conclusion, targeting the AhR with FICZ regulates IL-2 and immune infiltration to alleviate experimental HT, shedding new light on the therapeutic intervention of this prevalent disease.

Clinical and Pathological Characteristics of Patients With Papillary Thyroid Carcinoma Coexisting With Hashimoto's Thyroiditis: A Retrospective Cohort Study.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma, and Hashimoto's thyroiditis (HT) has been postulated to have a relationship with PTC. This study aims to assess clinical and pathological characteristics of patients with papillary thyroid carcinoma coexisting with Hashimoto's thyroiditis. METHODS: A retrospective study was conducted in a cohort of patients with thyroid carcinoma at the Department of Surgery, Shanghai General Hospital from January 2017 to December 2018. Medical records of patients who had PTC with or without HT were reviewed and clinical and histopathological characteristics of these patients were analyzed. RESULTS: A total of 632 patients with thyroid carcinoma were identified. Among them, 614 (97.15%) had PTC and 120/614 (19.0%) harbored PTC together with HT. PTC was significantly associated with HT, as compared with other histological subtypes (P < .001). Patients with coexisting PTC and HT (PTC + HT group) were significantly younger than patients with PTC alone (PTC group) (P = .008). There were more women in the PTC + HT group than in the PTC group (88.3% vs. 73.1%, P < .001). TSH, TGAb, and TPOAb levels were significantly higher in the PTC + HT group than in the PTC group (P ≤ .001). In addition, tumor diameter was smaller in the PTC + HT group than in the PTC group (P = .034). The PTC + HT group showed a significant better recurrence-free survival than the PTC group. Furthermore, immunohistochemical analysis revealed that patients in the PTC + HT group had a higher positive rate and higher expression intensity of Ki67 than patients in the PTC group. CONCLUSIONS: Our study revealed that patients with coexisting PTC and HT were younger, had smaller tumor diameters, a better prognosis, and higher positive rates and expression intensity of Ki67, than did patients with PTC alone.

MIF promotes Th17 cell differentiation in Hashimoto's thyroiditis by binding HVEM and activating NF-κB signaling pathway.

Hashimoto's thyroiditis is a typical thyroid autoimmune disease and Th17 cells are crucial in its development. In recent years, MIF (Macrophage Migration Inhibitory Factor) has been found to promote the secretion of IL-17A and the production and differentiation of Th17 cells. However, the specific mechanism of it remains unclear. Here, we found that the expression of MIF, IL-17A and HVEM (Herpes Virus Entry Mediator) were up-regulated in HT patients. The proportion of Th17 cells in peripheral blood mononuclear cells was positively correlated with the serum MIF protein level. We further found that the expression of HVEM and the phosphorylation level of NF-κB in peripheral blood mononuclear cells of HT patients were significantly increased. Therefore, we speculated that MIF promotes Th17 cell differentiation through HVEM and NF-κB signaling pathways. Further mechanism studies showed that MIF could directly bind to HVEM, and the stimulation of rhMIF in vitro could increase the expression of HVEM and activate NF-κB signaling pathways to promote Th17 cell differentiation. After blocking HVEM with HVEM antibody, the effect of MIF on Th17 cell differentiation disappeared. The results above show that the differentiation of Th17 cells is promoted by MIF combined with HVEM through NF-κB signaling pathways. Our research provides a new theory to the regulation mechanism of Th17 cell differentiation and gives hint to new potential therapeutic targets for HT.

How does Hashimoto's thyroiditis affect bone metabolism?

Bone marrow contains resident cellular components that are not only involved in bone maintenance but also regulate hematopoiesis and immune responses. The immune system and bone interact with each other, coined osteoimmunology. Hashimoto's thyroiditis (HT) is one of the most common chronic autoimmune diseases which is accompanied by lymphocytic infiltration. It shows elevating thyroid autoantibody levels at an early stage and progresses to thyroid dysfunction ultimately. Different effects exert on bone metabolism during different phases of HT. In this review, we summarized the mechanisms of the long-term effects of HT on bone and the relationship between thyroid autoimmunity and osteoimmunology. For patients with HT, the bone is affected not only by thyroid function and the value of TSH, but also by the setting of the autoimmune background. The autoimmune background implies a breakdown of the mechanisms that control self-reactive system, featuring abnormal immune activation and presence of autoantibodies. The etiology of thyroid autoimmunity and osteoimmunology is complex and involves a number of immune cells, cytokines and chemokines, which regulate the pathogenesis of HT and osteoporosis at the same time, and have potential to affect each other. In addition, vitamin D works as a potent immunomodulator to influence both thyroid immunity and osteoimmunology. We conclude that HT affects bone metabolism at least through endocrine and immune pathways.

A Comprehensive Review of Thyroid Hormone Metabolism in the Gut and Its Clinical Implications.

Background: The gut is a target organ of thyroid hormone (TH) that exerts its action via the nuclear thyroid hormone receptor α1 (TRα1) expressed in intestinal epithelial cells. THs are partially metabolized via hepatic sulfation and glucuronidation, resulting in the production of conjugated iodothyronines. Gut microbiota play an important role in peripheral TH metabolism as they produce and secrete enzymes with deconjugation activity (ß-glucuronidase and sulfatase), via which TH can re-enter the enterohepatic circulation. Summary: Intestinal epithelium homeostasis (the finely tuned balance between cell proliferation and differentiation) is controlled by the crosstalk between triiodothyronine and TRα1 and the presence of specific TH transporters and TH-activating and -inactivating enzymes. Patients and experimental murine models with a dominant-negative mutation in the TRα exhibit gross abnormalities in the morphology of the intestinal epithelium and suffer from severe symptoms of a dysfunctional gastrointestinal tract. Over the past decade, gut microbiota has been identified as an essential factor in health and disease, depending on its compositional and functional profile. This has led to a renewed interest in the so-called gut-thyroid axis. Disruption of gut microbial homeostasis (dysbiosis) is associated with autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis, Graves' disease, and Graves' orbitopathy. These studies reviewed here provide new insights into the gut microbiota roles in thyroid disease pathogenesis and may be an initial step toward microbiota-based therapies in AITD. However, it should be noted that cause-effect mechanisms remain to be proven, for which prospective cohort studies, randomized clinical trials, and experimental studies are needed. Conclusion: This review aims at providing a comprehensive insight into the interplay between TH metabolism and gut homeostasis.

Papillary thyroid cancer with Hashimoto's thyroiditis attenuates the tumour aggressiveness through the up-regulation of E-cadherin and TGF-ß expression.

Human papillary thyroid cancer (PTC) is often associated with Hashimoto's thyroiditis (HT), and their coexistence improves the prognosis of PTC. Aim of the study. The objective of our study is to investigate the expression of cadherins and TGF-ß which are regulators in the tumour aggressiveness with metastatic spread in PTC patients and its relationship with HT. The expression of E-cadherin and N-cadherin was measured in thyroid tissues of healthy volunteers and PTC patients with HT (PTC/HT) or without. The E-cadherin expression was also determined in thyroid cancer cells (TPC1, SNU373, SNU790, 8505C, CAL62, and FTC133). Cell migration was measured by wound healing assay. The expression of N-cadherin, ICAM1, and TGF-ß was measured in thyroid tissues and plasma. The E-cadherin expression was significantly increased in PTC/HT patients compared with PTC alone. Meanwhile, the N-cadherin expression was significantly decreased in PTC/HT patients. The E-cadherin expression was only observed in FTC cells, and the overexpression of E-cadherin inhibited cancer cell migration. The TGF-ß expression was significantly increased in PTC/HT patients, and the plasma levels were higher in PTC/HT patients than in PTC alone. The expression of N-cadherin and ICAM-1 was significantly decreased in PTC/HT patients. Our results indicate that the expression of E-cadherin and TGF-ß was higher in PTC/HT patients than in PTC alone. This suggests that the presence of PTC with HT may attenuate the tumour aggressiveness and metastasis through the up-regulation of E-cadherin and TGF-ß expression.

Comprehensive analysis of lncRNA-mediated ceRNA regulatory networks and key genes associated with papillary thyroid cancer coexistent with Hashimoto's thyroiditis.

OBJECTIVE: The incidence of papillary thyroid cancer (PTC) concomitant with Hashimoto's thyroiditis (HT) is gradually increasing over the past decades. This study aims to identify differentially expressed lncRNAs between tumor tissues of PTC with or without HT and further to confer a better understanding of lncRNA-based competing endogenous RNA (ceRNA) network in PTC with HT. METHODS: GSE138198 containing tissue mRNA data and GSE192560 containing lncRNA data were utilized to perform differentially expression analysis. The ceRNA network was constructed based on miRNA-mRNA interactions merging with lncRNA-microRNA interactions. Functional enrichment analysis and protein-protein interaction (PPI) analysis were performed. The mRNA levels of core genes in the PPI analysis in tumor tissues collected from 112 PTC patients including 35 cases coexistent with HT were determined by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A total of 57 genes and 40 lncRNAs, with value of |log2 fold change (FC)|≥ 1 and the adjusted P-value < 0.05, were deemed as differentially expressed genes and lncRNAs between PTC with and without HT. The pathways most significantly enriched by differentially expressed genes between PTC with and without HT were viral protein interaction with cytokine and cytokine receptor and cytokine-cytokine receptor interaction. CXCL10, CXCL9, CCL5, FCGR3A, and CCR2 owned degree values not less than 10 were deemed as core genes differentially expressed between PTC with and without HT. A total of 76 pairs of lncRNA-miRNA-mRNA ceRNA were obtained. Results of qRT-PCR partially demonstrated the bioinformatics results that the mRNA levels of CXCL10, CXCL9, CCL5, and CCR2 were remarkably elevated in tumor tissues collected from PTC patients coexistent with HT than those without HT (P < 0.001). CONCLUSION: Our study offers a better understanding of the lncRNA-related ceRNA network involved in PTC with HT, providing novel key genes associated with PTC coexistent with HT.

Amiodarone-drove XBP1s aggravates endoplasmic reticulum stress and apoptosis in Hashimoto's thyroiditis through regulating LINC00842/miR-214/FASL axis.

Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disease, that eventually lead to hypothyroidism. XBP1s is an endoplasmic reticulum stress related protein and participates in the pathogenesis of several diseases. Nevertheless, the potential role of XBP1s in amiodarone (AMIO)-treated HT patients remains unknown. In this study, AMIO aggravated the endoplasmic reticulum stress responses in HT patients and thyroid epithelial follicular cells. Moreover, MTT assay and flow cytometry analysis revealed that knockdown of XBP1s suppressed AMIO-induced thyroid epithelial follicular cells apoptosis. Mechanically, the Chromatin Immunoprecipitation (ChIP) and luciferase activity assay proved that XBP1s enhanced LINC00842 expression in HT patients and thyroid epithelial follicular cells via binding to LINC00842 promoter. LINC00842 functioned as a miR-214 sponge in HT patients and thyroid epithelial follicular cells. Besides, LINC00842 up-regulated Fas ligand (FASL) expression via inhibition of miR-214. In rescue experiments, overexpression of FASL reversed shXBP1s-induced suppression of cell apoptosis in AMIO-treated thyroid epithelial follicular cells. These findings concluded that AMIO-drove XBP1s aggravated endoplasmic reticulum stress and apoptosis in HT via modulating LINC00842/miR-214/FASL axis, providing a new sight for the therapeutic strategy of AMIO-induced HT.

Association Between Polymorphisms of IL-23/IL-17 Pathway and Clinical Phenotypes of Autoimmune Thyroid Diseases.

BACKGROUND: Several autoimmune and inflammatory disorders, including autoimmune thyroid diseases (AITD), have been linked to Th17 cells and the IL-23/IL-17 axis. Current data suggest that genetic variation contributes greatly to disease susceptibility to AITD. OBJECTIVES: To study the role of single nucleotide polymorphisms (SNPs) of IL-23/IL-17 pathway in AITD predisposition and test the gene-gene/gene-sex interactions in these loci. METHODS: A total of 1051 patients with AITD, including 657 patients with Graves' disease (GD) and 394 patients with Hashimoto's thyroiditis (HT), and 874 healthy controls were enrolled in this case-control association study. Six SNPs were selected and genotyped by multiplex PCR combined with high-throughput sequencing. Interactions were tested by the general multifactor dimensionality reduction (GMDR) method. RESULTS: Allele C and combinational genotype AC+CC of rs3212227 within IL-23 were significantly associated with GD with goiter (p=0.003 and 0.014, respectively). Allele G and combinational genotype AG+GG of rs4819554 within IL-17RA were significantly related to HT with family history and the severity of HT (p=0.011 and 0.027; p=0.041 and 0.035). Also, allele T and genotype CT+TT of rs9463772 within IL-17F were significantly correlated with the severity of HT (p=0.001 and 0.027, respectively). Moreover, high dimensional gene-sex interaction (IL-23R-IL-23-IL-17RA-IL-17F-sex) was identified in AITD, GD, and HT patients with GMDR analysis. CONCLUSIONS: Our study identified the novel loci and gene-sex interaction in AITD. This evidence, from another perspective, suggests that sex, IL-23/IL-17 pathway, and Th17 cells play an important role in the pathogenesis of AITD.

Diversity of complement activation in different thyroid diseases.

OBJECTIVE: To investigate complement components expression in both thyroid tissues and serum from patients with Hashimoto's thyroiditis (HT), Graves' disease (GD), and papillary thyroid cancer (PTC). METHODS: C1q, mannose binding lectin (MBL), Bb, C4d, C3d and membrane attack complex (MAC) (C5b-9) deposition and complement regulate proteins (CD46, CD55 and CD59) expression in thyroid tissues from HT, GD, PTC, and control groups were examined by IHC. C1q, MBL, Bb, C4d, C3a, and soluble C5b-9 (sC5b-9) serum levels in the HT, GD, PTC, and healthy donor (HD) groups were measured by ELISAs. RESULTS: MAC deposition was detected in thyroid tissues in the HT, GD and PTC groups, but not the control group. MBL, Bb, C4d, C3d and MAC staining intensities in thyroid tissues were significantly higher in the HT and PTC groups than in the control group (all P < 0.05). The C1q level was higher in HT tissues than in control tissues (both P < 0.05). No complement component had a significant difference in staining intensities between the GD and control groups. CD55 and CD59 expression levels in thyroid tissues were higher in the PTC group than in the HT, GD and control groups (all P < 0.05). Similarly, CD46 levels were higher in HT tissues than in control tissues. Bb, C4d, C3a and sC5b-9 serum levels were significantly increased in HT, GD and PTC patients compared with HDs (all P < 0.05). CONCLUSION: Complement is overactivated in HT and PTC, but not in GD. All the three pathways are activated in HT, and the MBL and alternative complement pathways are activated in PTC. These distinct complement activation profiles may participate in HT, GD and PTC pathogenesis.

Lymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto's thyroiditis.

Hashimoto's thyroiditis (HT) is the most common autoimmune disease characterized by lymphocytic infiltration and thyrocyte destruction. Dissection of the interaction between the thyroidal stromal microenvironment and the infiltrating immune cells might lead to a better understanding of HT pathogenesis. Here we show, using single-cell RNA-sequencing, that three thyroidal stromal cell subsets, ACKR1+ endothelial cells and CCL21+ myofibroblasts and CCL21+ fibroblasts, contribute to the thyroidal tissue microenvironment in HT. These cell types occupy distinct histological locations within the thyroid gland. Our experiments suggest that they might facilitate lymphocyte trafficking from the blood to thyroid tissues, and T cell zone CCL21+ fibroblasts may also promote the formation of tertiary lymphoid organs characteristic to HT. Our study also demonstrates the presence of inflammatory macrophages and dendritic cells expressing high levels of IL-1ß in the thyroid, which may contribute to thyrocyte destruction in HT patients. Our findings thus provide a deeper insight into the cellular interactions that might prompt the pathogenesis of HT.

Human umbilical cord mesenchymal stem cells alleviate the imbalance of CD4+ T cells via protein tyrosine phosphatase non-receptor type 2/signal transducer and activator of transcription 3 signaling in ameliorating experimental autoimmune thyroiditis in rats.

This study aimed to investigate the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on experimental autoimmune thyroiditis (EAT) and the underlying mechanisms by utilizing a porcine thyroglobulin-induced EAT rat model. The rats received four tail vein injections of vehicle or hUCMSCs at an interval of 7 days and were sacrificed on day 28 after the first injection. Hematoxylin and eosin staining and enzyme-linked immunosorbent assays (ELISAs) were used to assess the therapeutic effects of hUCMSCs on EAT. Splenic lymphocytes were isolated from rats, and the proportions of CD4+ T cell subsets were analyzed by flow cytometry. Splenic CD4+ T cells from EAT rats were cocultured with hUCMSCs. A loss-of-function assay for protein tyrosine phosphatase non-receptor type 2 (PTPN2) was performed to explore the involvement of PTPN2/signal transducer and activator of transcription 3 (STAT3) signaling on the therapeutic benefit of hUCMSCs in EAT. hUCMSC treatment significantly alleviated inflammation, reduced serum thyroid antibody levels, and decreased the ratios of IL-17α+/CD25+FOXP3+ cells and serum IFN-γ/IL-4 in EAT rats. Furthermore, hUCMSC treatment upregulated PTPN2 protein expression in splenic lymphocytes of EAT rats as well as enhanced the PTPN2 protein level and attenuated phosphorylation of STAT3 in CD4+ T cells in vitro. Importantly, knockdown of Ptpn2 significantly reversed hUCMSC-mediated suppression of cell proliferation and hUCMSC-induced alterations in the expression of inflammatory cytokines in CD4+ T cells. Thus, hUCMSC treatment alleviates thyroid inflammation and the CD4+ T cell imbalance in EAT via PTPN2/STAT3 signaling, serving as a promising therapeutic approach for autoimmune thyroiditis.

The Imbalance in Th17 and Treg Cells in Polycystic Ovarian Syndrome Patients with Autoimmune Thyroiditis.

The ratio of T helper (Th) 17 and T regulatory (Treg) cells in patients with polycystic ovary syndrome complicated with autoimmune thyroiditis (PCOS-AIT) remains unreported. The study aimed to determine the Th17/Treg cell paradigm in PCOS-AIT patients. In peripheral blood mononuclear cells from PCOS patients and controls, the percentages of Th17 and Treg cells were measured by flow cytometry, the mRNA levels of a Th17-related transcription factor (ROR-γt) and a Treg-specific transcription factor (Foxp3) were determined by qRT-PCR, and the levels of Th17-related cytokines and Treg-related cytokines were measured by ELISA. Additionally, to examine the effect of testosterone on the Th17/Treg cell balance in vitro, cultured PCOS-AIT CD4+ T cells were treated with 10 µM testosterone for 24 h, and the Th17/Treg cell proportions and expression of Th17/Treg cell-associated transcription factors and cytokines were analyzed by flow cytometry, qRT-PCR, and ELISA. The Th17 cell percentage, Th17/Treg cell ratio, and expression of Th17-related ROR-γt and IL-17 were significantly higher in peripheral blood mononuclear cells from PCOS-AIT patients than in those from controls. In CD4+ T cells derived from PCOS-AIT patients, testosterone significantly decreased the Th17 cell percentage, Th17/Treg ratio, mRNA level of ROR-γt, and production of Th17-related cytokines and increased the Treg cell percentage, mRNA level of Foxp3, and secretion of Treg-related cytokines. The Th17/Treg cell imbalance favoring proinflammatory Th17 cells is involved in the pathogenesis of PCOS-AIT. Targeting the Th17/Treg cell axis may have therapeutic potential in the treatment of PCOS-AIT.

Natural Autoimmunity to Selenoprotein P Impairs Selenium Transport in Hashimoto's Thyroiditis.

The essential trace element selenium (Se) is needed for the biosynthesis of selenocysteine-containing selenoproteins, including the secreted enzyme glutathione peroxidase 3 (GPX3) and the Se-transporter selenoprotein P (SELENOP). Both are found in blood and thyroid colloid, where they serve protective functions. Serum SELENOP derives mainly from hepatocytes, whereas the kidney contributes most serum GPX3. Studies using transgenic mice indicated that renal GPX3 biosynthesis depends on Se supply by hepatic SELENOP, which is produced in protein variants with varying Se contents. Low Se status is an established risk factor for autoimmune thyroid disease, and thyroid autoimmunity generates novel autoantigens. We hypothesized that natural autoantibodies to SELENOP are prevalent in thyroid patients, impair Se transport, and negatively affect GPX3 biosynthesis. Using a newly established quantitative immunoassay, SELENOP autoantibodies were particularly prevalent in Hashimoto's thyroiditis as compared with healthy control subjects (6.6% versus 0.3%). Serum samples rich in SELENOP autoantibodies displayed relatively high total Se and SELENOP concentrations in comparison with autoantibody-negative samples ([Se]; 85.3 vs. 77.1 µg/L, p = 0.0178, and [SELENOP]; 5.1 vs. 3.5 mg/L, p = 0.001), while GPX3 activity was low and correlated inversely to SELENOP autoantibody concentrations. In renal cells in culture, antibodies to SELENOP inhibited Se uptake. Our results indicate an impairment of SELENOP-dependent Se transport by natural SELENOP autoantibodies, suggesting that the characterization of health risk from Se deficiency may need to include autoimmunity to SELENOP as additional biomarker of Se status.

Subcortical Hypermetabolism Associated With Cortical Hypometabolism Is a Common Metabolic Pattern in Patients With Anti-Leucine-Rich Glioma-Inactivated 1 Antibody Encephalitis.

Purpose: Brain 18F-fluorodeoxyglucose positron emission tomography (FDG PET) is a sensitive technique for assisting in the diagnosis of patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. However, the common pattern of this disorder assessed by FDG PET remains unknown. The present study aimed to explore the glucose metabolic patterns of this disorder based on PET voxel analysis. Methods: This retrospective study enrolled 25 patients with anti-LGI1 encephalitis, who were admitted in Beijing Tiantan Hospital between September 2014 and July 2019. The glucose metabolic pattern was compared between the included patients and 44 age- and gender-matched healthy controls using Statistical Parametric Mapping. Then, the correlation between the metabolic pattern and scaled activities of daily living (ADLs) of the patients was assessed. Results: The median time from symptom onset to PET scans was 9 w (range:2-53w). The groupwise analysis revealed that patients with anti-LGI1 encephalitis had left hippocampal hypermetabolism and hypometabolism in almost all neocortical regions. The individual-level results showed most patients presented a decreased metabolism in neocortical regions, as well as an increase in metabolism in the hippocampus and basal ganglia. Furthermore, the metabolic gradient between hippocampus and neocortical regions was positively associated with the ADLs (frontal lobe, r=0.529, P=0.008; parietal lobe, r=0.474, P=0.019; occipital lobe, r=0.413, P=0.045; temporal lobe, r=0.490, P=0.015), respectively. In addition, the patients with facio-brachial dystonic seizures (FBDS) presented bilateral putamen hypermetabolism, when compared to patients without FBDS and healthy controls. Conclusion: Subcortical hypermetabolism associated with cortical hypometabolism presented with a common metabolic pattern in patients with anti-LGI1 encephalitis in the present study. The resolution of the metabolic gradient of the hippocampal hypermetabolism and neocortical hypometabolism may bring about improved clinical neurologic disability.

Integrative Analyses of Genes Associated with Hashimoto's Thyroiditis.

OBJECTIVE: Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, is a common autoimmune thyroiditis, which mostly occurs in young and middle-aged women. It can be manifested as hyperthyroidism in the early stage; hypothyroidism may appear with the progression of the disease. Studies have shown that multiple factors such as heredity, environment, and autoimmunity are involved in the pathogenesis, but the specific mechanism is not clear. In our study, we tried to find key genes and potential molecular mechanisms of Hashimoto's thyroiditis to provide new ideas for the therapeutic targets of Hashimoto's thyroiditis. METHOD: GSE138198 and GSE54958 were downloaded from the GEO database, and two datasets were combined for analysis. The combined data were normalized to identify the differentially expressed genes (DEGs), and GO and KEGG enrichment analyses were performed. Protein-protein interaction (PPI) networks and hub genes between DEGs were identified. We also used the miRWalk database to identify regulatory miRNAs associated with expressions of DEGs. RESULT: We identified 182 DEGs (160 upregulated and 22 downregulated) between Hashimoto's disease patients and the healthy control group. GO analysis showed that DEGs were mostly concentrated in detection of chemical stimulus involved in sensory perception, intermediate filament cytoskeleton, and olfactory receptor activity. KEGG pathway analysis showed that DEGs were mainly related to olfactory transduction. Some members of the KRTAP family and HTR5A, KNG1, DRD3, HTR1D, TAS2R16, INSL5, TAS2R42, and GRM7 are the most important hub genes in the PPI network. In addition, we recognized that OTUD4, LLPH, and ECHDC1 were the most important hub genes in the miRNA-target gene network. CONCLUSION: In this study, a series of bioinformatics analyses of DEGs were performed to identify the key genes and pathways associated with Hashimoto's thyroiditis. These genes and pathways provide a more detailed understanding of the pathogenesis of Hashimoto's disease and provide new ideas for the therapeutic targets of Hashimoto's thyroiditis.

Boldenone undecylenate disrupts the immune system and induces autoimmune clinical hypothyroidism in rats: Vitamin C ameliorative effects.

The present study was designed to evaluate the effects of boldenone undecylenate (BL) abuse alone and in combination with vitamin C (VC) on the immune responses and thyroid structure and function in rats. Thirty adult male Wistar rats were randomly divided into five equal groups and were subjected to various treatment regimens for eight weeks as follows: control group, vehicle control group, VC group orally received VC (120 mg/Kg BW/day), BL-treated group intramuscularly injected with BL (5 mg/kg BW, once/week), and BL+VC group received BL and VC. At the end of this experiment, blood and tissue samples (thyroid, thymus, and spleen) were subjected to hematological evaluation, biochemical analysis, histopathological, and immunohistochemical examinations. In comparison to controls, BL significantly increased the levels of serum proinflammatory interleukins (IL-1 ß and IL-6), immunoglobulins (IgG and IgM), and complement 3 but reduced anti-inflammatory interleukin-10, lysosome, and nitric oxide. Besides, altered platelet count and leukogram were evident in BL-injected rats. BL notably disturbed thyroid profile as revealed by a significant increase of thyroid-stimulating hormone and thyroid peroxidase antibody. In contrast, both total and free forms of thyroid hormones (tri-iodothyronine and thyroxine), thyroglobulin, and thyroid peroxidase, were significantly decreased. Moreover, BL caused histopathological changes in the thyroid, thymus, and spleen tissues.CD4+ immuno-expression was reduced, but CD8+ immunolabelling was increased in both spleen and thymus. The daily dosing of VC to BL-exposed rats significantly corrected most of the deviations in immune parameters. It restored most of the thyroid architecture and function, revealing a significant protective effect of this vitamin. This experimental study demonstrates that BL abusing disrupts the immune system by different mechanisms and addresses BL, for the first time, as an autoimmune clinical hypothyroidism inducer drug. Additionally, VC is helpful in the management of BL abuse.

DES-Tcell is a knowledgebase for exploring immunology-related literature.

T-cells are a subtype of white blood cells circulating throughout the body, searching for infected and abnormal cells. They have multifaceted functions that include scanning for and directly killing cells infected with intracellular pathogens, eradicating abnormal cells, orchestrating immune response by activating and helping other immune cells, memorizing encountered pathogens, and providing long-lasting protection upon recurrent infections. However, T-cells are also involved in immune responses that result in organ transplant rejection, autoimmune diseases, and some allergic diseases. To support T-cell research, we developed the DES-Tcell knowledgebase (KB). This KB incorporates text- and data-mined information that can expedite retrieval and exploration of T-cell relevant information from the large volume of published T-cell-related research. This KB enables exploration of data through concepts from 15 topic-specific dictionaries, including immunology-related genes, mutations, pathogens, and pathways. We developed three case studies using DES-Tcell, one of which validates effective retrieval of known associations by DES-Tcell. The second and third case studies focuses on concepts that are common to Grave's disease (GD) and Hashimoto's thyroiditis (HT). Several reports have shown that up to 20% of GD patients treated with antithyroid medication develop HT, thus suggesting a possible conversion or shift from GD to HT disease. DES-Tcell found miR-4442 links to both GD and HT, and that miR-4442 possibly targets the autoimmune disease risk factor CD6, which provides potential new knowledge derived through the use of DES-Tcell. According to our understanding, DES-Tcell is the first KB dedicated to exploring T-cell-relevant information via literature-mining, data-mining, and topic-specific dictionaries.