CHIP Haploinsufficiency Exacerbates Hepatic Steatosis via Enhanced TXNIP Expression and Endoplasmic Reticulum Stress Responses.

TXNIP is a critical regulator of glucose homeostasis, fatty acid synthesis, and cholesterol accumulation in the liver, and it has been reported that metabolic diseases, such as obesity, atherosclerosis, hyperlipidemia, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), are associated with endoplasmic reticulum (ER) stress. Because CHIP, an E3 ligase, was known to be involved in regulating tissue injury and inflammation in liver, its role in regulating ER stress-induced NAFLD was investigated in two experimental NAFLD models, a tunicamycin (TM)-induced and other diet-induced NAFLD mice models. In the TM-induced NAFLD model, intraperitoneal injection of TM induced liver steatosis in both CHIP+/+ and CHIP+/- mice, but it was severely exacerbated in CHIP+/- mice compared to CHIP+/+ mice. Key regulators of ER stress and de novo lipogenesis were also enhanced in the livers of TM-inoculated CHIP+/- mice. Furthermore, in the diet-induced NAFLD models, CHIP+/- mice developed severely impaired glucose tolerance, insulin resistance and hepatic steatosis compared to CHIP+/+ mice. Interestingly, CHIP promoted ubiquitin-dependent degradation of TXNIP in vitro, and inhibition of TXNIP was further found to alleviate the inflammation and ER stress responses increased by CHIP inhibition. In addition, the expression of TXNIP was increased in mice deficient in CHIP in the TM- and diet-induced models. These findings suggest that CHIP modulates ER stress and inflammatory responses by inhibiting TXNIP, and that CHIP protects against TM- or HF-HS diet-induced NAFLD and serves as a potential therapeutic means for treating liver diseases.

The safety and efficacy of intravenous immunoglobulin in autoimmune encephalitis.

OBJECTIVE: Although intravenous immunoglobulin (IVIG) is the first-line immunotherapy in autoimmune encephalitis, all supporting evidence comes from retrospective case series. Here, we performed a prospective clinical trial of IVIG for functional recovery in autoimmune encephalitis. METHODS: This single-arm, open-label study assessed the efficacy and safety of 10% intravenous IVIG treatment in newly diagnosed patients with possible autoimmune encephalitis. Patients received IVIG (0.4 g/kg/day) for 5 days. Rescue immunotherapy was permitted when the patient deteriorated before day 8 or showed no improvement at day 8. The primary outcome was the change in the modified Rankin Scale (mRS) score at day 8 and 29. The secondary outcomes were the mRS score improvement and the score changes and improvements on four other clinical scales. RESULTS: Overall, 23 patients received IVIG (intension-to-treat, ITT), and 18 patients completed the study according to the protocol (per-protocol, PP). mRS improved significantly at days 8 and 29 compared to baseline in both the ITT and PP populations. Other secondary outcomes also improved significantly at day 8, 15, and 29 versus baseline. In the PP population, 6/18 patients achieved favorable outcomes with IVIG alone (mRS = 0~2 at day 8), and 12/18 patients received rescue immunotherapy. Five adverse events were reported in relation to IVIG, all of which were mild. INTERPRETATION: IVIG improved neurological functional outcomes, and the improvement was evident by day 8. Adverse effects were tolerable. These data provide the prospective evidence regarding the efficacy of IVIG in improving the functional outcomes of autoimmune encephalitis.

Association of PTPN22 1858C/T Polymorphism with Autoimmune Diseases: A Systematic Review and Bayesian Approach.

The 1858T allele in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus shows one of the strongest and most consistent genetic associations with autoimmune diseases. We synthesized all meta-analyses reporting a genetic association of the PTPN22 1858T C/T polymorphism with autoimmune diseases. This work examined their validity to discover false positive results under Bayesian methods. We conducted a PubMed search to identify relevant publications and extracted the respective results, published until 30 November 2018. In observational studies, the associations of 1858 C/T genetic variant were noteworthy for 12 autoimmune or autoimmunity-related diseases (rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, juvenile idiopathic arthritis, Crohn's disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, vitiligo, Graves' disease, myasthenia gravis, Addison's disease, giant cell arteritis, and endometriosis). In contrast, we could not confirm the noteworthiness for eight diseases (systemic sclerosis, psoriasis, Behçet's disease, autoimmune thyroid disease, alopecia areata, Sjögren's syndrome, inflammatory bowel disease, and ankylosing spondylitis). From the meta-analysis of genome-wide association studies (GWAS) with a p-value < 5 × 10-8, findings verified noteworthiness for all autoimmune diseases (psoriatic arthritis, myasthenia gravis, juvenile idiopathic arthritis and rheumatoid arthritis). The results from meta-analysis of GWAS showing a p-value ranging between 0.05 and 5 × 10-8 were noteworthy under both Bayesian approaches (ANCA-associated vasculitis, type 1 diabetes mellitus, giant cell arteritis and juvenile idiopathic arthritis). Re-analysis of observational studies and GWAS by Bayesian approaches revealed the noteworthiness of all significant associations observed by GWAS, but noteworthiness could not be confirmed for all associations found in observational studies.