Objective
T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Serum‐derived exosomes are increased in SLE patients and are correlated with disease severity. This ...study was undertaken to investigate whether T cell–derived exosomal proteins play a role in SLE pathogenesis.
Methods
We characterized proteins in T cell–derived exosomes from SLE patients and healthy controls by MACSPlex exosome analysis and proteomics. To study the potential pathogenic functions of the exosomal protein identified, we generated and characterized T cell–specific transgenic mice that overexpressed that protein in T cells.
Results
We identified eosinophil cationic protein (ECP, also called human RNase III) as overexpressed in SLE T cell–derived exosomes. T cell–specific ECP–transgenic mice (n = 5 per group) displayed early induction of serum interferon‐γ (IFNγ) levels (P = 0.062) and inflammation of multiple tissue types. Older T cell–specific ECP–transgenic mice (n = 3 per group) also displayed an increase in follicular helper T cell and plasma B cell numbers, and in autoantibody levels (P < 0.01). Single‐cell RNA sequencing showed the induction of IFNγ messenger RNA (P = 2.2 × 10‐13) and inflammatory pathways in ECP‐transgenic mouse T cells. Notably, adoptively transferred ECP‐containing exosomes stimulated serum autoantibody levels (P < 0.01) and tissue IFNγ levels in the recipient mice (n = 3 per group). The transferred exosomes infiltrated into multiple tissues of the recipient mice, resulting in hepatitis, nephritis, and arthritis.
Conclusion
Our findings indicate that ECP overexpression in T cells or T cell–derived exosomes may be a biomarker and pathogenic factor for nephritis, hepatitis, and arthritis associated with SLE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study ...was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS).
Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice.
The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral T cells were significantly higher in AS group than those of healthy controls (all p < 0.05), while DUSP22 (also named JKAP) mRNA levels were significantly lower in AS group than healthy controls (p < 0.001). The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in T cells were positively correlated with mRNA levels of tumor necrosis factor-α (TNF-α), whereas DUSP22 was inversely correlated (all p < 0.05). In addition, inverse correlations of DUSP22 gene expression in peripheral T cells with C-reactive protein, erythrocyte sedimentation rate, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were observed (all p < 0.05). More importantly, aged DUSP22 knockout mice spontaneously developed syndesmophyte formation, which was accompanied by an increase of TNF-α
, interleukin-17A
, and interferon-γ
CD3
T cells.
DUSP22 may play a crucial role in the pathogenesis and regulation of disease activity of AS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
HBV reactivation (HBVr) can occur in hepatitis B surface antigen (HBsAg)-positive and negative patients. Here, we determined the incidence of HBVr and its related hepatitis in patients with systemic ...lupus erythematosus (SLE). From 2000 to 2017, 3307 SLE cases were retrospectively reviewed for episodes of hepatitis. The incidence, long-term outcomes and risk factors associated with HBVr, including HBsAg reverse seroconversion (RS) were analyzed. Among them, 607 had available HBsAg status. Fifty-five (9.1%) patients were positive for HBsAg and 63 (11.4%) were HBsAg-negative/antibody to hepatitis B core antigen (anti-HBc)-positive (resolved hepatitis B infection, RHB). None of them received antiviral prophylaxis before immunosuppressive treatment. During a mean 15.4 years of follow-up, 30 (54.5%) HBsAg-positive patients developed HBVr and seven (23.3%) died of liver failure, whereas only two (3.2%) RHB cases experienced HBsAg reverse seroconversion (RS). Multivariate logistic regression analysis showed that age ≥ 40 years at diagnosis of SLE (HR 5.30, p < 0.001), receiving glucocorticoid-containing immunosuppressive therapy (HR 4.78, p = 0.003), and receiving glucocorticoid ≥ 10 mg prednisolone equivalents (HR 3.68, p = 0.003) were independent risk factors for HBVr in HBsAg-positive patients. Peak level of total bilirubin ≥ 5 mg/dL during HBVr was an independent factor of mortality (p = 0.002). In conclusion, the risk of HBVr was associated with glucocorticoid daily dose. Antiviral prophylaxis is mandatory for SLE patients diagnosed at age of ≥40 years who receive ≥ 10 mg daily dose of oral prednisone or equivalent.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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-/- mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient 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.
To compare changes in bone mineral density (BMD) in rheumatoid arthritis (RA) patients receiving three-year conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD), tumor necrosis ...factor-α inhibitors (TNFi), and abatacept.
Patients with RA were recruited from September 2014 to February 2021. Dual-energy X-ray absorptiometry was used to measure BMD at the femoral neck (FN), total hip (TH), and lumbar spine (L1-4) at enrollment and three years later. Changes in the BMD of each regimen group were analyzed. Multiple ordinary least squares regression was used with the dependent variables to develop a model to predict the change in BMD.
A total of 752 participants were enrolled and 485 completed the three-year follow-up period. Of these, 375 (Group I), 84 (Group II), and 26 (Group III) participants received csDMARDs, TNFi, and abatacept therapy, respectively. Considering both type of therapy and completion of the follow-up period, participants were divided into groups A (csDMARDs, n = 104), B (TNFi, n = 52), and C (abatacept, n = 26). Compared to baseline, BMD decreased significantly at FN (p = 0.003) and L1-4 (p = 0.002) in Group A and at L1-4 (p = 0.005) in Group B, but remained stable at all sites in Group C. In terms of regression-adjusted percent change in BMD, there was a significant difference seen at all measured sites between group C compared to both groups A and B (+0.8%, -2.7%, -1.8% at FN; +0.5%, -1.1%, -1.0% at TH; +0.8%, -2.0%, -3.5% at L1-4, respectively; all p < 0.05). Anti-osteoporosis therapy had a BMD-preserving effect in RA.
Compared with csDMARDs and TNFi, abatacept may have a better BMD-preserving effect in RA. Anti-osteoporosis therapy can prevent systemic bone loss irrespective of RA therapy.
Cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) competes with CD28 for binding CD80/CD86 on antigen-presenting cells (APCs) to limit T cell activation. B cells are believed to be important ...APCs in the pathogenesis of autoimmune diseases and express CD80/CD86 after activation; however, relatively little is known about the effect of CTLA-4-Ig on B cells. This study tested the impact of CTLA-4-Ig on human B cell responses.
Human blood B cells were purified from healthy donors and activated in the presence of CTLA-4-Ig or the L6-Ig control protein in vitro. RT-q-PCR and immunofluorescence staining were performed to detect activation marker expression. ELISA was conducted to measure cytokine secretion. The CD80/CD86 levels on the surface of the memory B cells in the blood of 18 patients with rheumatoid arthritis (RA) were detected using immunofluorescence staining.
CTLA-4-Ig suppressed the expression of Staphylococcus aureus (SAC)-induced CD80, CD86, TNFA, and IL6 in human B cells at the transcriptional level. Furthermore, CTLA-4-Ig concomitantly decreased SAC-induced CD80/CD86 surface expression on and TNF-α and IL-6 secretion from B cells. On the other hand, T cell-dependent (TD) stimulation-induced B cell activation, proliferation, plasma cell differentiation, and antibody secretion were not affected by CTLA-4-Ig. As expected, TD stimulation-induced surface CD80 was hindered by CTLA-4-Ig. Notably, a blockade of CD80/CD86 on the surface of the memory B cells was observed in the patients with RA after abatacept (CTLA-4-Ig) treatment. In a portion of the RA patients, restoration of CD80/CD86 staining on the surface of the memory B was detected starting in the 3rd month of abatacept treatment. Interestingly, the surface levels of CD80/CD86 on the patients' memory B cells positively correlated with disease activity.
We found that CTLA-4-Ig directly suppressed SAC-induced B cell activation in vitro. Obstruction of CD80 and CD86 on the surface of the memory B cells was detected in the RA patients after abatacept treatment. Blocking CD80/CD86 on B cells by CTLA-4-Ig may hinder T cell activation and associated with the disease activity of RA in vivo. Our findings indicate that CTLA-4-Ig may regulate humoral responses by modulating B cell activation and interfering T cell-B cell interaction.
Polymorphonuclear neutrophils (PMNs) are traditionally regarded as professional phagocytic and acute inflammatory cells that engulf the microbial pathogens. However, accumulating data have suggested ...that PMNs are multi-potential cells exhibiting many important biological functions in addition to phagocytosis. These newly found novel activities of PMN include production of different kinds of cytokines/chemokines/growth factors, release of neutrophil extracellular traps (NET)/ectosomes/exosomes and trogocytosis (membrane exchange) with neighboring cells for modulating innate, and adaptive immune responses. Besides, PMNs exhibit potential heterogeneity and plasticity in involving antibody-dependent cellular cytotoxicity (ADCC), cancer immunity, autoimmunity, inflammatory rheumatic diseases, and cardiovascular diseases. Interestingly, PMNs may also play a role in ameliorating inflammatory reaction and wound healing by a subset of PMN myeloid-derived suppressor cells (PMN-MDSC). Furthermore, PMNs can interact with other non-immune cells including platelets, epithelial and endothelial cells to link hemostasis, mucosal inflammation, and atherogenesis. The release of low-density granulocytes (LDG) from bone marrow initiates systemic autoimmune reaction in systemic lupus erythematosus (SLE). In clinical application, identification of certain PMN phenotypes may become prognostic factors for severe traumatic patients. In the present review, we will discuss these newly discovered biological and pathobiological functions of the PMNs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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, ChlP-Seq, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-ß signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, II-9 mRNA levels were induced in Pur-α-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 II-9 mRNA levels in T cells and allergic responses of T-Dusp8-cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8-Pur-α interaction were indeed increased in the cytoplasm of T cells from people with asthma and patients with atopic dermatitis. Collectively, DUSP8 induces TGF-ß-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.
•The estimated prevalence of sarcopenia in RA was 31%, without significant differences between various living area and diagnostic modalities.•Disease duration, DAS28 and HAQ were predictors of ...sarcopenia development in patients with RA.•Functional limitation, CRP and RF seropositivity were identified as additional risk factors.
Sarcopenia is an ever-increasingly recognized entity in aging or chronically-ill individuals. A recent surge of researches came out on sarcopenia in rheumatoid arthritis (RA). However, the results varied widely. We tried to assess the prevalence of and associated factors with sarcopenia in patients with RA.
We searched the investigations dealing with the prevalence of and associated factors with sarcopenia in RA from PubMed, EMBASE, CENTRAL, EBSCOhost, Airiti Library, CEPS, CNKI and J-STAGE from the inception to January 11, 2020. Effects regarding prevalence and associated factors were extracted and evaluated by random-effects model. Sensitivity analysis was also performed.
Seventeen studies containing 3,140 RA subjects were identified. After exclusion of outliers, the pooled prevalence of sarcopenia was 31%. Neither ongoing-study districts nor diagnostic modalities affected prevalence significantly. Any associated factors being mentioned in at least two publications were analyzed, yielding functional limitation (Steinbrocker stage III/IV), high CRP and RF seropositivity as the significant risk factors. Based on disease durations, we carried out meta-regression and found DAS28 and HAQ are predictive models. There was no alteration in the interpretation of results from sensitivity analysis after removal of any studies skewed in sampling distribution.
The prevalence of sarcopenia in patients with RA is high, compared to that in general counterparts. Disease duration rather than age, residing area or diagnostic modalities influences sarcopenia development; DAS28 and HAQ predict occurrence. High index of suspicion to facilitate early detection of sarcopenia in RA patients is important.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The peripheral benzodiazepine receptor (TSPO/PBR) is highly conserved among different species but with perplexing biochemical functions. Multiple ligands of TSPO show commendable regulatory ...activities in lots of biological functions, such as neuro‐protection, cholesterol transport, and so on. These researches support that TSPO may be a potential target for disease treatment and drug development. Previous studies have shown that its ligands benzodiazepines show a satisfactory effect on melanogenic promotion. However, the potential application of TSPO in drug development for pigmentary disorder needs further investigation. In this study, we confirmed the melanogenesis induction of TSPO ligand, Ro5‐4864 in mouse melanoma cell lines, human skin tissue, and zebrafish embryos by inducing melanin synthesis and melanosome transport. Molecular genetics and pharmacological studies showed that TSPO deficiency did not affect melanin production in B16F10 cells and zebrafish embryos, nor did it affect the melanin promotion effect of Ro5‐4864. Whether or not TSPO exists, the expression of lots of melanogenesis‐related proteins, such as TYR, TRP‐1, DCT, Mlph, and Rab27 was upregulated with the Ro5‐4864 administration. These results indicated that Ro5‐4864 induces melanogenesis in a TSPO‐independent manner, which is inconsistent with previous research. This research is a reminder that we need to be very careful during target validation in drug development.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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