Sirtuin 1 overexpression contributes to the expansion of follicular helper T cells in Systemic lupus erythematosus and serves as an easy-to-intervene therapeutic target.

OBJECTIVE: SIRT1, an NAD+-dependent deacetylase, is up-regulated in CD4+ T cells from SLE patients and MRL/lpr lupus-like mice. This study aimed to explore the role of SIRT1 in Tfh cell expansion and its potential value as a therapeutic target for SLE. METHODS: Frequencies of CD4+CXCR5+PD-1+ Tfh cells in peripheral blood from SLE patients and their expression of SIRT1 and BCL-6 were determined with flow cytometry. Naïve CD4+ T cells were transfected with SIRT1-expressing lentivirus and small interfering RNA (siRNA) targeting SIRT1, respectively, and then cultured in a Tfh-polarizing condition to study the impact of SIRT1 on Tfh cell differentiation. This impact was also evaluated in both CD4+ T cells and naïve CD4+ T cells by treatment with SIRT1 inhibitors (EX527 and nicotinamide) in vitro. MRL/lpr mice and pristane-induced lupus mice were treated with continuous daily intake of nicotinamide, and their lupus phenotypes including skin rash, arthritis, proteinuria and serum anti-dsDNA autoantibodies were compared with controls. RESULTS: Expression of SIRT1 was elevated in Tfh cells from SLE patients and positively correlated with Tfh cell frequencies. SIRT1 expression gradually increased during Tfh cell differentiation. Overexpression of SIRT1 by lentiviral vectors significantly promoted Tfh cell differentiation/proliferation. Reciprocally, suppressing expression of SIRT1 by siRNA and inhibiting SIRT1 activity by EX-527 or nicotinamide hindered Tfh cell expansion. Continuous daily intake of nicotinamide alleviated lupus-like phenotypes and decreased serum CXCL13 in the two mouse models. CONCLUSION: SIRT1 overexpression contributes to the expansion of Tfh cells in SLE and may serve as a potential target for treatment.

Consecutive injections of low-dose interleukin-2 improve symptoms and disease control in patients with chronic spontaneous urticaria.

PURPOSE: To describe the effectiveness and tolerability of low-dose interleukin (IL)-2 in treating patients with chronic spontaneous urticaria (CSU) refractory to H1-antihistamines. METHODS: This retrospective study included CSU patients who received treatment with at least one cycle of IL-2, injected intramuscularly at a dose of 1.0 million international units daily for 7 consecutive days, after failing treatment with H1-antihistamines. Patients were followed up for ≥12 weeks. RESULTS: Of the 15 patients, 7 (46.7%) and 11 (73.3%) achieved complete response at Week 2 and Week 12, respectively. The mean change of urticaria control test (UCT) and weekly urticaria activity score (UAS7) from baseline was 6.6 (95% CI, 4.2 to 8.9) and - 16.9 (95% CI, -24.0 to -9.8), respectively, at Week 12. Local injection-site reactions were the most common adverse events. No serious adverse events were reported. CONCLUSION: Low-dose IL-2 treatment improves symptoms and disease control for CSU patients refractory to H1-antihistamines.

Abnormalities in Gut Microbiota and Metabolism in Patients With Chronic Spontaneous Urticaria.

Background: Increasing evidence suggests that the gut microbiome plays a role in the pathogenesis of allergy and autoimmunity. The association between abnormalities in the gut microbiota and chronic spontaneous urticaria (CSU) remains largely undefined. Methods: Fecal samples were obtained from 39 patients with CSU and 40 healthy controls (HCs). 16S ribosomal RNA (rRNA) gene sequencing (39 patients with CSU and 40 HCs) and untargeted metabolomics (12 patients with CSU and 12 HCs) were performed to analyze the compositional and metabolic alterations of the gut microbiome in CSU patients and HCs. Results: The 16S rRNA gene sequencing results showed a significant difference in the ß-diversity of the gut microbiota, presented as the Jaccard distance, between CSU patients and HCs. No significant differences were found in the α-diversity of the gut microbiota between patients and HCs. At the phylum level, the major bacteria in the gut microbiome of patients with CSU were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. At the genus level, Lactobacillus, Turicibacter, and Lachnobacterium were significantly increased and Phascolarctobacterium was decreased in patients with CSU. PICRUSt and correlation analysis indicated that Lactobacillus, Turicibacter, and Phascolarctobacterium were positively related to G protein-coupled receptors. Metabolomic analysis showed that α-mangostin and glycyrrhizic acid were upregulated and that 3-indolepropionic acid, xanthine, and isobutyric acid were downregulated in patients with CSU. Correlation analysis between the intestinal microbiota and metabolites suggested that there was a positive correlation between Lachnobacterium and α-mangostin. Conclusions: This study suggests that disturbances in the gut microbiome composition and metabolites and their crosstalk or interaction may participate in the pathogenesis of CSU.

Chronic Urticaria: Advances in Understanding of the Disease and Clinical Management.

Chronic urticaria (CU) is a common skin condition characterized by the recurrence of wheals, with or without angioedema, which lasts for at least 6 weeks. Owing to its pruritus and incurability, this disease adversely affects the patients' physical and mental health and diminishes the quality of life. CU is generally classified into two subtypes based on the relevance of eliciting factors: chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), the latter of which is further divided into several subtypes. To improve the understanding and clinical management of this highly heterogeneous disorder, the EAACI/GA2LEN/EDF/WAO guideline was developed and published in 2018 based on evidence and expert consensus. The diagnostic and treatment algorithms proposed by the guideline have largely facilitated dermatologists in clinical practice. However, several questions remained unsolved and have been widely investigated in the recent years. First, a better understanding of the association between chronic urticaria and its potential underlying causes or eliciting factors such as autoimmunity, infections, coagulation aberrance, and vitamin D deficiency is warranted. This would lead to updates in the diagnostic and treatment procedures of different subtypes of chronic urticaria. Secondly, treatment for recalcitrant cases, especially those resistant to or intolerant of second-generation antihistamines and (or) omalizumab, calls for novel therapeutic measures or strategies. In the present review, we summarized recent advances in the understanding and management of both CSU and CIndU, with special emphasis on their underlying causes or eliciting factors, pathogenic mechanisms, potential targets for intervention, and advances in treatment strategies.