I-Tsu Chyuan

Tumor Necrosis Factor-Alpha Induced by Hepatitis B Virus Core Mediating the Immune Response for Hepatitis B Viral Clearance in Mice Model

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8+ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-α blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-α blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-α blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose- and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-α blockage therapy occurred at early time points after HBV infection. In addition, TNF-α blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1highCD127low exhausted T cells. Furthermore, TNF-α blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-α blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-α blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-α-blocking agents.Cellular & Molecular Immunology advance online publication, 9 February 2015; doi:10.1038/cmi.2015.01

Galectin-3 suppresses mucosal inflammation and reduces disease severity in experimental colitis

Galectin-3, a member of the β-galactoside-binding lectin family, expresses in many different immune cells and modulates broad biological functions including cell adhesion, cell activation, cell growth, apoptosis, and inflammation. However, the role of galectin-3 in mucosal immunity or inflammatory bowel diseases is still not clear. We demonstrate here that galectin-3 knockout mice have more severe disease activity in the dextran sulfate sodium (DSS)-induced colitis model, indicating that galectin-3 may protect from inflammation in DSS-induced colitis. Furthermore, treating with galectin-3 reduced body weight loss, shortened colonic length, and ameliorated mucosal inflammation in mice having DSS-induced colitis. However, the protective effects of galectin-3 were eliminated by the administration of anti-CD25 mAb. In addition, primary T cells treated with galectin-3 ex vivo induced the expression of FOXP3, ICOS, and PD-1 with a Treg cell phenotype having a suppression function. Moreover, adoptive transfer of galectin-3-treated T cells reduced bowel inflammation and colitis in the T cell transfer colitis model. In conclusion, our results indicate that galectin-3 inhibited colonic mucosa inflammation and reduced disease severity by inducing regulatory T cells, suggesting that it is a potential therapeutic approach in inflammatory bowel disease.Key messagesGalectin-3 offers protection from inflammation in experimental colitis.Galectin-3 knockout mice have more severe disease activity in DSS-induced colitis.Adoptive transfer of galectin-3-treated T cells reduced bowel inflammation.Galectin-3 inhibited colonic mucosa inflammation by inducing regulatory T cells.Galectin-3 is a potential therapeutic approach in inflammatory bowel disease.

Increased neutrophil infiltration, IL-1 production and a SAPHO syndrome-like phenotype in PSTPIP2-deficient mice

OBJECTIVE Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) is involved in macrophage activation, neutrophil motility and osteoclast differentiation. However, the role of PSTPIP2 in inflammation and autoinflammatory diseases is still not clear. In this study, we generated PSTPIP2 knockout (Pstpip2(-/-)) mice to investigate its phenotype and role in autoinflammatory diseases. METHODS We constructed a Pstpip2-targeting vector and generated Pstpip2(-/-) mice. The phenotype and immunopathology of Pstpip2(-/-) mice were analysed. RESULTS All Pstpip2(-/-) mice developed paw swelling, synovitis, hyperostosis and osteitis, resembling SAPHO syndrome, an inflammatory disorder of the bone, skin and joints. Multifocal osteomyelitis was found in inflamed paws, with increased macrophage and marked neutrophil infiltrations in the bone, joint and skin. Profound osteolytic lesions with markedly decreased bone volume density developed in paws and limbs. Neutrophil-attracting chemokines and IL-1β were markedly elevated in inflamed tissues. CONCLUSION Our study suggests that PSTPIP2 could play a role in innate immunity and development of autoinflammatory bone disorders, and may be associated with the pathogenesis of human SAPHO syndrome.

β2-Glycoprotein I-Dependent Anti-Cardiolipin Antibodies Associated With Periodontitis in Patients With Systemic Lupus Erythematosus

BACKGROUND It was reported that patients with systemic lupus erythematosus (SLE) exhibited increased levels of anticardiolipin (anti-CL) antibodies, a class of antiphospholipid antibodies associated with thrombosis. β2-glycoprotein I (β2GPI) has been considered as the actual target antigen for anti-CL antibodies. This study investigates the association of periodontal infection with anti-CL antibodies in patients with SLE. METHODS Fifty-three SLE female patients and 56 healthy female volunteers were recruited in this case-control study. All participants received periodontal examinations. The presence of Porphyromonas gingivalis and Treponema denticola in saliva and plaque samples was detected by polymerase chain reaction. Levels of serum anti-CL and anti-β2GPI antibodies were examined using enzyme-linked immunosorbent assay. RESULTS Patients with SLE exhibited more periodontal attachment loss and increased titers of serum anti-CL and anti-β2GPI antibodies compared with healthy controls. Patients with active SLE who harbored P. gingivalis or P. gingivalis together with T. denticola intraorally exhibited significantly higher anti-CL and anti-β2GPI antibodies than those without these bacteria. Anti-CL and anti-β2GPI antibody levels correlated positively with clinical attachment level. Furthermore, increased anti-β2GPI antibody levels were significantly associated with C-reactive protein and erythrocyte sedimentation rate. CONCLUSIONS Elevated anti-CL and anti-β2GPI antibody levels were associated with periodontopathic bacteria and periodontal breakdown in patients with SLE. Periodontitis might be a modifiable risk factor for SLE.

An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T-cell activation in inflammatory arthritis

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the regulation of inflammation in rheumatoid arthritis (RA), primarily due to its ability to promote apoptosis in synoviocytes and infiltrating lymphocytes. The aim of this study was to investigate the immunomodulatory mechanism and role of TRAIL in inflammatory arthritis. We created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited T-cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL receptor (TRAIL-R)-knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R knockout mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T-cell activation. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing inflammatory arthritis and shed light on the development of effective new therapies for autoimmune inflammatory diseases.

Role of Interleukin- (IL-) 17 in the Pathogenesis and Targeted Therapies in Spondyloarthropathies

Spondyloarthropathy (SpA) is a unique type of joint inflammation characterized by coexisting erosive bone damage and pathological new bone formation. Previous genetic association studies have demonstrated that several cytokine pathways play a critical role in the pathogenesis of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and other types of SpA. In addition to several well-known proinflammatory cytokines, recent studies suggest that IL-17 plays a pivotal role in the pathogenesis of SpA. Further evidence from human and animal studies have defined that IL-17 and IL-17-producing cells contribute to tissue inflammation, autoimmunity, and host defense, leading to the following pathologic events associated with SpA. Recently, several clinical trials targeting IL-17 pathways demonstrated the positive response of IL-17 blockade in treating AS, indicating a great potential of IL-17-targeting therapy in SpA. In this review article, we have discussed the contributing role of IL-17 and different IL-17-producing cells in the pathogenesis of SpA and provided an outline of therapeutic application of the IL-17 blockade in the treatment of SpA. Other targeted cytokines associated with IL-17 axis in SpA will also be included.

TRAIL-Mediated Suppression of T Cell Receptor Signaling Inhibits T Cell Activation and Inflammation in Experimental Autoimmune Encephalomyelitis

Objective Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases. Design TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35–55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35–55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis. Results TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35–55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. Conclusion TRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.

Tumor necrosis factor: The key to hepatitis B viral clearance

The immunopathogenesis of hepatitis B virus (HBV) involves a complex interaction of innate and adaptive immune response associated with several cytokines. However, due to experimental limitations, very limited and even no activation of the innate immune response can be demonstrated in acute HBV infection. The role of innate immunity and the key innate effectors for HBV clearance is still uncertain. It is also not clear whether clinical use of TNF inhibitors in treating rheumatoid arthritis and other autoimmune disease patients with chronic HBV infection would affect viral reactivation. However, in a recent paper in Cell Mol Immunol, Chyuan et al. reported that under TNF-α blockade, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose and temporal-dependent manner.1 It demonstrates that a deficiency of TNF-α reduces viral clearance and promotes HBV persistence in a mouse model, and the impairment of HBV clearance under anti-TNF-α occurs at an early time point of HBV infection, suggesting that HBV may reactivate during therapy with TNF inhibitors. The results together with previous reports support that TNF is a key innate cytokine required to clear HBV.2,3 It also provides evidence that therapy with TNF inhibitors may impair immune response to HBV clearance. Weak or even absent activation of innate immunity seems to be the hallmark of acute HBV infection. Moreover, pro-inflammatory cytokines are often undetectable during the early phases of HBV infection. For over two decades, numerous efforts have been reported in search for critical innate effectors in HBV clearance. It is suggested that an efficient control of HBV infection requires the coordinated actions of innate immune cells and viral specific T cells; however, the innate immunity and key cytokine related to HBV clearance are still not well defined. Acute HBV infection models of both woodchucks and chimpanzees also fails to verify the role of innate immune response in HBV infection. It is an overall scenario of weak or even transcription silence in activation of innate immunity to HBV, in particular, the type I interferon (IFN-I) response. Apparent lack of the IFN-I response is observed in HBV infection and thereby considered as one of the underlying mechanisms for HBV to escape innate recognition.4,5 Different lines of evidence indicate that it is questionable if HBV can actually be sensed by the innate immunity.6 In fact, the mechanisms how innate immune system senses HBV are still not elucidated and it is also unclear which HBV molecules (DNA, RNA or viral proteins) are actually recognized by the pattern recognition receptors (PRR) and thereby trigger the antiviral response. In order to explore the role of innate sensor in response to HBV, we previously investigated a panel of gene knockout mice with deficiency in innate immune sensors or effectors for their capability in HBV clearance.2 Instead of IFN receptor deficiency, interestingly, TNF-α deficiency in knockout mice resulted in impaired clearance and prolonged persistence of HBV, suggesting that TNF-α and associated innate pathways are crucial in HBV clearance.2 The results are consistent with previous studies supporting that TNF is a key innate effector required to clear HBV.3 TNF-α is a well-known pro-inflammatory cytokine and displays multiple functions as an antitumor, immune modulation and integrating host defense system against infections. As a key cytokine, the direct anti-viral effect of TNF-α also contributes to HBV eradication.7–9 A recent study demonstrated that cellular inhibitor of apoptosis proteins (cIAPs) attenuate TNF-α signaling during HBV infection and restrict the death of infected hepatocytes, thus allowing viral persistence.10 In addition, TNF-α delivers non-cytopathic antiviral signals to hepatocytes to degrade the transcript and Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, China; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China; Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, China Correspondence: Professor P-N Hsu, Graduate Institute of Immunology, College of Medicine, National Taiwan University, 1 Jen-Ai Rd., Sec. 1, Taipei 100, Taiwan, China. E-mail: phsu8635@ntu.edu.tw Received: 10 October 2017; Accepted: 5 November 2017 Cellular and Molecular Immunology (2018) 15, 731–733 & 2018 CSI and USTC All rights reserved 2042-0226/18

Interstitial Lung Disease in Polymyositis/dermatomyositis: Association between the Onset of Interstitial Lung Disease and Clinical Outcome

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