A ZBP1 isoform blocks ZBP1-mediated cell death.

ZBP1 is an interferon (IFN)-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA) to promote cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here, we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppressor of the inflammatory signaling mediated by full-length ZBP1. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Zα domains of ZBP1. Cells from mice (Ripk1D325A/D325A) with cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-dependent cell death. Intriguingly, Ripk1D325A/D325A cells die spontaneously when ZBP1-S is deleted, indicating that cell death driven by ZBP1 is under the control of ZBP1-S. Thus, our findings reveal that alternative splicing of Zbp1 represents autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against autoinflammations.

ANA-positive primary immune thrombocytopaenia: a different clinical entity with increased risk of connective tissue diseases.

OBJECTIVE: Primary immune thrombocytopaenia (ITP) is highly heterogeneous. ANA-positive primary ITP may resemble the preclinical stage of connective tissue diseases (CTDs), but is still considered primary ITP due to a controversial CTD risk assessment in this group. The objective of this study was to clarify the risk of CTD in ANA-positive patients with primary ITP. METHODS: We performed a retrospective cohort study and a meta-analysis. 586 patients with newly diagnosed primary ITP were followed up and Cox regression analyses were used to analyse the associations of ANA positivity and other immune parameters with CTD development. RESULTS: The mean follow-up time was 37 (19-56) months. ANA was positive in 21.33% (125 of 586) of patients with primary ITP in our retrospective cohort, and the overall rate of ANA positivity in the meta-analysis was 17.06% (369 of 2163). The adjusted HR for CTD in ANA-positive primary ITP was 6.15 (95% CI 2.66 to 14.23, p<0.001). Five patients in the ANA-positive group developed SLE (5 of 125, 4.0%), significantly higher than in the ANA-negative group (0 of 461, 0%). A clinical model combining ANA, anti-Sjogren's syndrome A antibody and C3 was successfully developed to predict the risk of CTD in patients with primary ITP. Increased risk of CTD (risk ratio=12.43, 95% CI 7.91 to 19.55, p<0.00001), especially SLE (risk ratio=30.41, 95% CI 13.23 to 69.86, p<0.00001), among ANA-positive patients with primary ITP was confirmed by a meta-analysis of previous studies and the present study. CONCLUSIONS: The findings suggest that ANA-positive primary ITP is a clinical entity distinct from other primary ITPs and is associated with increased risk of developing CTDs, especially SLE.

Serological Evidence for the Association Between Epstein-Barr Virus Infection and Sjögren's Syndrome.

Background: Exposure to Epstein-Barr virus (EBV) infection has been hypothesized to be an important risk factor for multiple rheumatic diseases, but the serological evidence so far for its role in Sjögren's syndrome (SjS) is not clearly established yet. This study aimed to assess the seroepidemiological associations of antibodies to EBV with SjS. Methods: A seroepidemiological study containing 119 patients with SjS and 65 healthy controls was first performed, in which the associations of SjS with four commonly studied EBV antibodies including IgM-anti-viral capsid antigen (anti-VCA) antibody, IgG-anti-VCA antibody, IgG-anti-early antigen (anti-EA) antibody, and IgG-anti-EBV nuclear antigen 1 (anti-EBNA1) antibody were evaluated. A systematic review and meta-analysis of eligible seroepidemiological studies was also carried out, and data syntheses were performed using random-effect meta-analysis. Results: In the case-control study, the patients with SjS had both a significantly higher prevalence of IgG-anti-EA antibody positivity (31.9% vs. 3.1%, P < 0.001) and high titers of IgG-anti-EA antibody (P < 0.001) than healthy controls. The titer of IgG-anti-VCA antibody was significantly increased in the patients with SjS compared with healthy controls (P < 0.001). IgG-anti-EA antibody seropositive patients with SjS had lower levels of both C3 (P = 0.002) and C4 (P = 0.02), and the titer of IgG-anti-EA antibody was inversely related to the levels of both C3 (r = -0.31, P < 0.001) and C4 (r = -0.20, P = 0.03). A total of 14 eligible studies on the serological associations between EBV infection and SjS were finally included into the meta-analysis, which suggested obvious associations of SjS with IgM-anti-VCA antibody [Odds ratio (OR) = 5.77, 95%CI 1.73-19.25, P = 0.004] and IgG-anti-EA antibody (OR = 9.97, 95%CI 4.58-21.67, P < 0.00001). Conclusions: The findings from this study provide strong serological evidence for the association between EBV infection and SjS. SjS has obvious associations with IgM-anti-VCA antibody and IgG-anti-EA antibody. IgG-anti-EA antibody is linked to low levels of C3 and C4 in the patients with SjS, the significance of which needs to be addressed in further studies.

Clinical Characteristics of Secondary Immune Thrombocytopenia Associated With Primary Sjögren's Syndrome.

Objective: Clinical characteristics of immune thrombocytopenia (ITP) associated with primary Sjögren's syndrome (pSS) have not been clearly defined. This study aimed to evaluate the prevalence and clinical characteristics of secondary ITP in patients with pSS. Methods: 291 pSS patients in our hospital were retrospectively analyzed. Clinical manifestations and laboratory findings were compared between pSS patients with and without ITP. Results: The prevalence of secondary ITP in pSS patients was 12.03%. Compared to pSS patients without ITP, pSS patients with ITP were younger and had higher disease activity. The prevalence of interstitial lung diseases (ILD) was significantly lower in pSS patients with ITP (30.43 vs. 54.95%; P = 0.029), and it was the same with arthritis (17.14 vs. 3.9.11%; P = 0.014) and dry eye (33.33 vs. 54.17%, P = 0.027) compared with those without ITP. Serum creatinine level was lower in pSS patients with ITP (P = 0.009), while positivity of anti-histone autoantibodies was higher in pSS patients with ITP (P = 0.025). Conclusion: This study is an initial report describing clinical features of ITP in pSS. The lower incidence of ILD and arthritis among pSS patients with ITP indicated potential active roles of platelets in the pathogenesis of fibrosis or inflammatory arthritis, which may open the way for further experimental and clinical work.

Antinuclear antibodies positivity is a risk factor of recurrent pregnancy loss: A meta-analysis.

OBJECTIVE: Immunologic mechanisms have been proposed as part of the pathogenesis mechanisms involved in recurrent pregnancy loss (RPL). Presence of positive antinuclear antibodies (ANA) is regarded as a typical feature of autoimmunity. Many studies had tried to clarify the association of ANA with RPL, but the conclusions were controversial. The aim of this meta-analysis was to assess whether ANA was positively associated with increased RPL risk. METHODS: We searched PubMed and Embase databases for relevant literatures on the association between ANA positivity and RPL. The odds ratios (OR) with 95% confidence intervals (95%CI) were pooled using meta-analysis, and either fixed-effect or random-effect model was used based on heterogeneity across the included studies. RESULTS: Twenty-one studies with 5038 participants (including 2683 RPL patients and 2355 controls) met the inclusion criteria were included. The total positive rate of ANA was 22.0% (591/2683) in RPL group, and 8.3% (196/2355) in the control group. RPL patients had a significantly higher ANA positive rate than controls (OR = 2.97, 95%CI 1.91-4.64, P<0.00001; I² = 75%), and a significant association between positive ANA and unexplained RPL was also observed (OR = 3.27, 95%CI 2.01-5.31, P<0.00001; I² = 70%). ANA positivity was also significantly associated with increased risk of RPL in women without defined autoimmune diseases (OR = 2.23, 95%CI 1.40-3.55, P=0.0007). Subgroup analysis demonstrated low titers of ANA (1:40≤ANA≤1: 80) were not associated with RPL (OR = 2.44, 95%CI 0.42-14.06, P=0.32), while higher ANA titer (≥1:160) had a significant association with RPL (OR = 45.89, 95%CI 8.44-249.45, P<0.00001). A higher rate of homogenous pattern in RPL patients was observed (OR = 4.89, 95%CI 2.20-10.87, P<0.001), and no significant difference in speckled pattern or nucleolar pattern was found. CONCLUSIONS: This study demonstrated that ANA positivity was positively associated with increased RPL risk. ANA positivity is an important risk factor for RPL which needed to be screened among women with RPL.