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Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T cell-specific Dusp8 conditional KO (T-Dusp8 cKO) mice, mass spectrometry analysis, ChIP-Seq, and immune analysis, we found that DUSP8 interacted with Pur-[alpha], stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-[alpha] upon TGF-[beta] signaling, leading to the nuclear export of Pur-[alpha] and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels were induced in Pur-[alpha]-deficient T cells. In addition, T-Dusp8-cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of Il-9 mRNA levels in T cells and allergic responses of T-Dusp8-cKO mice was reversed by Pur-[alpha] knockout. Remarkably, DUSP8 protein levels and the DUSP8-Pur-[alpha] interaction were indeed increased in the cytoplasm of T cells from people with asthma and patients with atopic dermatitis. Collectively, DUSP8 induces TGF- [beta]-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-[alpha]. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis., Introduction Dual-specificity phosphatase 8, or DUSP8--also named M3/6 and hVH5--is a member of the dual-specificity phosphatase (DUSP) family phosphatases (1-3). The subcellular localization of DUSP8 is mainly in the cytoplasm [...]

Original citation: J Clin Invest. 2023;133(3):1-19. https://doi.org/10.n72/JCI157272. Citation for this corrigendum: J Clin Invest. 2023;133(9):171350. https://doi.org/10.1172/JCI171350. Yen-Po Tsao, [1,2,3] Fang-Yu Tseng, [4] Chih-Wei Chao, [1,4] Ming-Han Chen, [2] Yi-Chen Yeh, [...]

Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production. Peripheral blood mononuclear cells (PBMCs) derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12, with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1-dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes was linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated [Nlrp12.sup.-/-] mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12deficient lupus-prone mice. NLRP12 deficiency mediated the increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function. These were bound in an IFN-I signature- dependent manner in the mouse models. Collectively, we reveal a remarkable link between low NLRP12 expression and lupus progression, which suggests the impact of NLRP12 on homeostasis and immune resilience., Introduction Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with unknown etiology involving immune intolerance of endogenous nuclear materials, increased levels of auto-reactive B cells, and chronic inflammation, leading [...]

Objective To evaluate the risk of end-stage kidney disease (ESKD) in LN patients using tubulointerstitial lesion scores. Methods Clinical profiles and histopathological presentations of 151 biopsy-proven LN patients were retrospectively examined. Risk factors of ESKD based on characteristics and scoring of their tubulointerstitial lesions [e.g. interstitial inflammation (II), tubular atrophy (TA) and interstitial fibrosis (IF)] were analysed. Results The mean age of 151 LN patients was 36 years old, and 136 (90.1%) were female. The LN cases examined included: class I/II (n  = 3, 2%), class III/IV (n  = 119, 78.8%), class V (n  = 23, 15.2%) and class VI (n  = 6, 4.0%). The mean serum creatinine level was 1.4 mg/dl. Tubulointerstitial lesions were recorded in 120 (79.5%) patients. Prior to receiving renal biopsy, nine (6.0%) patients developed ESKD. During the follow-up period (mean, 58 months), an additional 47 patients (31.1%) progressed to ESKD. Multivariate analyses identified serum creatinine [hazard ratio (HR): 1.7, 95% CI: 1.42–2.03, P   <  0.001] and IF (HR: 3.2, 95% CI: 1.58–6.49, P   =  0.001) as independent risk factors of ESKD. Kaplan–Meier analysis further confirmed a heightened risk of ESKD associated with IF. Conclusion Tubulointerstitial involvement is commonly observed in the histopathological presentation of LN. However, IF, rather than II or TA, was found to increase the risk of ESKD in our cohort. Therefore, to predict renal outcome in LN patients prior to adjusting immunosuppressive treatment, the degree of IF should be reviewed. [ABSTRACT FROM AUTHOR]

Objectives: To assess the link between the administration of biologic disease-modifying antirheumatic drugs (bDMARDs) and the risk of malignancy in human leukocyte antigen B27 (HLA-B27)-positive patients with ankylosing spondylitis (AS) experiencing sustained inflammation. Methods: Between 2006 and 2021, 1445 HLA-B27-positive patients with AS were retrospectively evaluated. Among them, 112 patients required bDMARD therapy. The study compared conventional therapy with bDMARDs and investigated the risk factors for developing malignancies. Results: During 8253 patient-years of follow-up, 38 (2.6%) patients developed various malignancies, including lung, liver, breast, and colon cancer. The risk of malignancy was significantly higher in the bDMARD-treated group compared to PS-matched groups receiving conventional synthetic DMARDs (csDMARD) and non-steroidal anti-inflammatory drugs. The cumulative risk of malignancies increased significantly after 6 years of follow-up. All patients who developed malignancy after bDMARD therapy received tumor necrosis factor-α inhibitors. Requiring bDMARD therapy, requiring bDMARDs in combination with csDMARD therapy, and being diagnosed with AS after 30 years of age were independent risk factors for developing malignancy. Conclusions: HLA-B27-positive AS patients with sustained inflammation requiring biologic therapy, particularly if diagnosed after age 30, may have an increased risk of malignancy. Regular cancer screenings are advisable for these patients while undergoing biologic treatment. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the clinical outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) under rituximab induction and reinduction therapy in Taiwan. Methods: We performed a retrospective study in patients with GPA or MPA receiving rituximab therapy from August 2008 to July 2020 in seven medical centers in Taiwan. The clinical characteristics and outcomes of these patients were analyzed. Results: In total, 53 patients (18 with GPA and 35 with MPA) were included. Kidney involvement (82.9% vs. 22.2%, p <.001) and initial creatinine (3.25 ± 2.37 vs. 1.07 ± 0.82, p <.001) were significantly higher in MPA. Within 24 weeks after the first course of rituximab, there were seven deaths (five due to infection and two due to active disease) in patients with MPA (7/35, 20%) compared to 0 in patients with GPA. Of 33 patients receiving rituximab for kidney involvement, 23 survived and were free from renal replacement therapy at 24 weeks. Their chronic kidney disease (CKD) stages improved in 2 but progressed in 7, while 24 had stable CKD stages. Death or end‐stage renal disease (ESRD) was associated with infection and higher initial creatinine. Reinduction therapy for relapse was required in 18 (39.1%) of 46 survivors, which was associated with anti‐proteinase 3 (PR3) positive (odds ratio 3.667, p =.049) and younger age with a cutoff of 49.4 (AUC = 0.679, p =.030, sensitivity = 66.67%, specificity = 75%). Conclusion: Significant mortality occurred after rituximab induction, especially in patients with MPA. In survivors, age younger than 50 and anti‐PR3 positive were associated with the risk of relapse requiring reinduction. [ABSTRACT FROM AUTHOR]