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Acute myeloid leukemia (AML) is a blood cancer that is caused by a disorder of the process that normally generates neutrophils. Function and dysfunction of neutrophils are key to physiologic defense against pathogens as well as pathologies including autoimmunity and cancer. A major mechanism through which neutrophils contribute to health and disease is oxidative burst, which involves rapid release of reactive oxygen species (ROS) generated by a chemical reaction network catalyzed by enzymes including NADPH oxidase and myeloperoxidase (MPO). Due to the involvement of neutrophil-derived reactive oxygen species in many diseases and importance of NADPH oxidase and MPO-mediated reactions in progression and treatment of myeloid leukemia, monitoring this process and modulating it by pharmacological interventions is of great interest. In this work, we have evaluated the potential of a label-free method using ultra-weak photon emission (UPE) to monitor ROS production in neutrophil-like HL60 myeloid leukemia cells. Suppression of ROS was achieved by several drug candidates that target different parts of the reaction pathway. Our results show that UPE can report on ROS production as well as suppression by pharmacological inhibitors. We find that UPE is primarily generated by MPO catalyzed reaction and thus will be affected when an upstream reaction is pharmacologically modulated.

// Seung Seok Han 1, 2 , Seung Hee Yang 2 , Hyung Ah Jo 1 , Yun Jung Oh 2 , Minkyoung Park 2 , Joo Young Kim 2 , Hajeong Lee 1, 2 , Jung Pyo Lee 1, 2, 3 , Sang-Ho Lee 4 , Kwon Wook Joo 1, 2 , Chun Soo Lim 1, 3 , Yon Su Kim 1, 2 and Dong Ki Kim 1, 2 1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea 2 Kidney Research Institute, Seoul National University, Seoul, Korea 3 Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea 4 Department of Internal Medicine, College of medicine, Kyung Hee University, Seoul, Korea Correspondence to: Dong Ki Kim, email: dkkim73@gmail.com Keywords: APRIL; autoimmunity; BAFF; B cells; membranous nephropathy Received: July 03, 2017 Accepted: November 14, 2017 Published: December 14, 2017 ABSTRACT Background: Based on the fact that B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have a regulatory role in B cell biology, excessive levels of these cytokines can promote autoimmune pathogenesis. However, the expression and implication remain unresolved in cases of membranous nephropathy (MN). Results: The plasma BAFF levels of the primary MN patients were higher than those of healthy controls but lower than those of secondary MN patients, whereas the APRIL levels were similar between the MN patients and healthy controls. The BAFF levels were higher in relapse cases, whereas the APRIL levels were higher in the patients who did not experience remission compared with the counterpart patients. The ectopic expression of BAFF and APRIL was observed in the glomeruli or circulating B cells of MN patients, and this high expression trend was similar to that of lupus patients. Conclusions: Expression profile of BAFF and APRIL in MN is similar to that of other autoimmune disease, which affects the kidney outcomes. Methods: Plasma BAFF and APRIL levels were measured upon kidney biopsy in patients with primary ( n = 89) and secondary MN ( n = 13), and the results were compared with the levels in healthy controls ( n = 111). The kidney outcomes (e.g., remission and relapse) were traced for the median of 3 years. Aberrant expression of the cytokines was evaluated in the kidney and circulating B cells using immunohistochemistry and flow cytometry analyses, respectively.

// Hui Wang 1 , Wenrong Xu 2 , Qixiang Shao 1 and Qing Ding 1 1 Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R. China 2 Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R. China Correspondence to: Qixiang Shao, email: shao_qx@ujs.edu.cn Qing Ding, email: qing_ding69@163.com Keywords: microRNA-21, interleukin-10, regulatory B cells, experimental autoimmune encephalomyelitis Received: June 29, 2017 Accepted: September 18, 2017 Published: October 06, 2017 ABSTRACT IL-10-producing regulatory B (IL-10 + Breg) cells promote tolerance in autoimmune diseases and transplantation. However, it remains unclear whether microRNAs are involved in the development of IL-10 + Breg cells. Here, we found that microRNA-21 (miR-21) acts as an upstream regulator of IL-10 by targeting the 3' untranslated region of IL-10 mRNA. We also demonstrated that IL-10 + Breg cells exhibit lower miR-21 expression than non-Breg cells and that miR-21 acts as a potent negative regulator of the differentiation of IL-10 + Breg cells. Accordingly, specific inhibition of miR-21 using antisense oligonucleotides markedly promoted B cell IL-10 expression. Thus, IL-10 is a direct target of miR-21. Moreover, silencing of miR-21 significantly alleviated the severity of experimental autoimmune encephalomyelitis (EAE), and this change was associated with an increase in the number of IL-10 + Breg cells. Finally, we demonstrated that miR-21-silenced B cells exert their suppressive activity through effector T cells in an IL-10-dependent manner. Thus, we characterized a B cell-intrinsic microRNA pathway that inhibits the differentiation of IL-10 + Breg cells and promotes autoimmunity. miR-21 silencing therefore represents a new therapeutic strategy for the treatment of autoimmune diseases.

// Xiaolu Huang 1, * , Yiwen Zhou 1, * , Wenhui Liu 1 , Haizhou Li 1 , Xiao Liang 1 , Rui Jin 1 , Hengyu Du 1 , Jizhou He 1 , Bangda Chai 1 , Ran Duan 1 and Qingfeng Li 1 1 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R.China * These authors contributed equally to this work and should be considered as co-author Correspondence to: Qingfeng Li, email: dr.liqingfeng@shsmu.edu.cn Keywords: silicone implant, autoimmunity, microarray, WGCNA, hub genes Received: July 04, 2017 Accepted: September 21, 2017 Published: October 06, 2017 ABSTRACT Silicone implants are used widely in the field of plastic surgery and are used in a large population. However, their safety profile, especially the silicone-induced immune response, has been a major concern for plastic surgeons for decades. It has been hypothesized that there is a cause and effect relation between silicone and immunity, but this is controversial. The objective of the present study was to determine the hub genes and key pathways related to silicone implant–induced immune responses in a rat model. In addition to cluster and enrichment analyses, we used weighted gene co-expression network analysis (WGCNA) to examine the gene expression profiles in a systematic context. A total five genes ( Fes , Aif1 , Gata3 , Tlr6 , Tlr2 ) were identified as hub genes that are most likely related to the silicone-induced immune response, four of which ( Aif1 , Gata3 , Tlr6 , Tlr2 ) have been associated with autoimmunity as target genes or disease markers. The Toll-like receptor signaling pathway ( p < 0.01, fold enrichment: 7.01) and systemic lupus erythematosus signaling pathway ( p < 0.05, fold enrichment: 5.01), which are considered strongly associated with autoimmunity, were significantly enriched in the silicone-implanted skin samples. The results indicate that silicone implants might trigger the localized immune response, as various immune reaction genes were detected after silicone implantation. The identified five hub genes will hopefully serve as novel therapeutic targets for silicone-related complications and the associated autoimmune diseases.

The thymus plays a key role in myasthenia gravis (MG), a B cell-mediated autoimmune disorder affecting neuromuscular junction. Most MG patients have thymic abnormalities, including hyperplasia and thymoma, a neoplasm of thymic epithelial cells. Epstein-Barr virus (EBV) is associated with autoimmune diseases and tumors. Recently, we showed EBV persistence and reactivation in hyperplastic MG thymuses, suggesting that EBV might contribute to intra-thymic B cell dysregulation in MG patients. Here, we investigated EBV involvement in thymoma-associated MG, by searching for EBV markers in MG (n=26) and non-MG (n=14) thymomas. EBV DNA and EBV-encoded small nuclear RNA (EBER) 1 transcript were detected in 14/26 (53.8%) and 22/26 (84.6%) MG thymomas, and only in 3 of 14 (21.4%) non-MG thymomas. Latent EBNA2 and late gp350/220 lytic transcripts were undetectable in all, but one, thymomas, and early lytic BZLF1 transcript was absent in all samples, suggesting that early infection events and EBV reactivation were very rare in thymomas. EBER1 and 2-positive cells were detected in MG, but not in non-MG, thymomas, as well as cells expressing EBV latency proteins (EBNA1, LMP1, LMP2A), that were mainly of B cell phenotype, indicating EBV association with MG rather than with thymoma. Toll-like receptor (TLR) 3 transcriptional levels were higher in MG than non-MG thymomas and positively correlated with EBER1 levels, suggesting a role for EBERs in TLR3 activation. Our findings show that EBV is commonly present in thymoma-infiltrating B cells of myasthenic patients, indicating a contribution of EBV to B cell-mediated autoreactivity in MG associated with thymic tumor.

Bullous pemphigoid is a common autoimmune blistering disease of the elderly associated with autoantibody-mediated complement activation, and complement dysregulation is critical for its pathogenesis. As a crucial regulator of the complement system, CD55 has been widely studied in autoimmune diseases. Here, we investigated the involvement of CD55 in bullous pemphigoid, as little is known regarding its role in this disease. We found that CD55 levels were significantly lower in the lesions of patients with bullous pemphigoid (n = 8) compared to those in skin samples from healthy controls (n = 6). Interestingly, CD55 depletion in HaCaT human keratinocytes enhanced autoantibody-mediated complement activation. Moreover, complement activation was blocked by exogenous recombinant CD55 protein in both skin sections and keratinocytes exposed to pathogenic antibodies from patients with bullous pemphigoid. Notably, a significant increase in the expression of TNF-α and IFN-γ, administration of which downregulated CD55 levels in HaCaT cells, was observed in the sera of patients with bullous pemphigoid (n = 38) compared to that in healthy controls (n = 19). We found that ERK1/2 is involved in both TNF-α- and IFN-γ-induced CD55 downregulation. Thus, CD55 deficiency is a crucial factor in bullous pemphigoid pathogenesis, suggesting that increasing CD55 levels may exert a therapeutic effect.

// Hussein Sultan 1, 2 , Jimena Trillo-Tinoco 1 , Paulo Rodriguez 1 and Esteban Celis 1, 2 1 Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA 2 Biochemistry and Cancer Biology Department, Georgia Cancer Center, Augusta University, Augusta, GA, USA Correspondence to: Esteban Celis, email: ecelis@augusta.edu Keywords: peptide vaccine, anti-tumor effect, diabetes, IL-2 complex, anti-CD40 Received: May 12, 2017 Accepted: June 26, 2017 Published: July 29, 2017 ABSTRACT Immunotherapy has shown a tremendous success in treating cancer. Unfortunately, this success is frequently associated with severe autoimmune pathology. In this study, we used the transgenic RIP-gp mouse model to assess the antitumor therapeutic benefit of peptide vaccination while evaluating the possible associated autoimmune pathology. We report that palmitoylated gp33-41 peptide and poly-IC adjuvant vaccine (BiVax) generated ~ 5-10 % of antigen specific T cell responses in wild type and supposedly immune tolerant RIP-gp mice. Boosting with BiVax in combination with αCD40 antibody (TriVax) or BiVax in combination with IL-2/αIL-2 antibody complexes (IL2Cx) significantly increased the immune responses (~30-50%). Interestingly, although both boosts were equally effective in generating vast T cell responses, BiVax/IL2Cx showed better control of tumor growth than TriVax. However, this effect was associated with high incidence of diabetes in an antigen and CD8 dependent fashion. T cell responses generated by BiVax/IL2Cx, but not those generated by TriVax were highly resistant to PD-1/PD-L1 inhibitory signals. Nevertheless, PD-1 blockade enhanced the ability of TriVax to control tumor growth but increased the incidence of diabetes. Finally, we show that severe autoimmunity by BiVax/IL2Cx was prevented while preserving outstanding antitumor responses by utilizing a tumor antigen not expressed in the pancreas. Our data provides a clear evidence that peptide based vaccines can expand vast endogenous T cell responses which effectively control tumor growth but with high potential of autoimmune pathology.

// Yeshu Wang 1, * , Qingfeng Xie 2, * , Chun-Ling Liang 3, * , Qiaohuang Zeng 1 and Zhenhua Dai 3 1 Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China 2 Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, P.R. China 3 Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P.R. China * These authors have contributed equally to this work Correspondence to: Zhenhua Dai, email: zdai2009@outlook.com Keywords: autoimmunity, type 1 diabetes, regulatory T cells, Chinese medicine Abbreviations: CsA, cyclosporine; GAG, ginseng and astragalus granule; T1DM, type 1 diabetes mellitus; Treg, regulatory T cell Received: March 21, 2017 Accepted: April 27, 2017 Published: June 27, 2017 ABSTRACT Type 1 diabetes mellitus (T1DM) is an autoimmune disease mainly mediated by effector T cells that are activated by autoantigen, thereby resulting in the destruction of pancreatic islets and deficiency of insulin. Cyclosporine is widely used as an immunosuppressant that suppresses autoimmunity in clinic. However, continuous treatments with conventional immunosuppressive drugs may cause severe side effects. Therefore it is important to seek alternative medicine. Chinese medicine Ginseng and Astragalus granule (GAG) was used to successfully treat type 2 diabetes mellitus in clinic in China. Here we found that GAG ameliorated T1DM in autoimmune NOD mice by increasing the level of insulin and reducing the level of blood glucose. Treatments with both GAG and CsA further decreased the blood glucose level. Moreover, GAG increased both CD4+FoxP3+ and CD8+CD122+PD-1+ Treg numbers in both spleens and lymph nodes of NOD mice. In particular, GAG could reverse a decline in CD4+FoxP3+ Tregs resulted from CsA treatments. The percentage of effector/memory CD8+ T cells (CD44 high CD62L low ) was significantly reduced by GAG, especially in the presence of low-doses of CsA. Histopathology also showed that GAG attenuated cellular infiltration and lowered CD3+ T cell numbers around and in islets. Thus, we demonstrated that GAG ameliorated autoimmune T1DM by upregulating both CD4+FoxP3+ and CD8+CD122+PD-1+ Tregs while GAG synergized with CsA to further suppress autoimmunity and T1DM by reversing the decline in CD4+FoxP3+ Tregs resulted from CsA treatments. This study may have important clinical implications for the treatment of T1DM using traditional Chinese medicine.

// Jeong-Eun Lee 1,2,* , Jung-Man Lee 3,* , Young-Jun Park 1 , Byung-Seok Kim 1,2 , Young-Tae Jeon 4,5 and Yeonseok Chung 1,2 1 Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea 2 BK21 plus program, College of Pharmacy, Seoul National University, Seoul, Republic of Korea 3 Department of Anesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea 4 Department of Anesthesiology and Pain Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea 5 Department of Anesthesiology and Pain Medicine, College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea * These authors have equally contributed to this work Correspondence to: Yeonseok Chung, email: // Young-Tae Jeon, email: // Keywords : ketamine, Th17 cell, STAT3, IL-21, autoimmunity, Immunology and Microbiology Section, Immune response, Immunity Received : April 04, 2017 Accepted : May 23, 2017 Published : May 31, 2017 Abstract Ketamine is widely used in animals and humans as a systemic anesthetic. Although several immune-modulatory functions of ketamine have been reported, the effects of ketamine on the differentiation of Th17 cell are unknown. We found that ketamine significantly diminished the frequency of IL-17-producers among CD4 + T cells stimulated under Th17-skewing conditions. Mechanistic studies showed that ketamine had little effect on the production of Th17-inducing cytokines by dendritic cells and the proliferation of T cells in response to anti-CD3; however it significantly hampered IL-21 expression as well as STAT3 phosphorylation in T cells upon IL-6 stimulation. Moreover, MOG-reactive CD4 + T cells expanded in the presence of ketamine produced reduced amounts of Th17 cytokines, leading to diminished EAE severity when transferred into TCRβ-deficient mice in comparison to those treated with vehicle. These findings demonstrate that ketamine suppresses autoimmune Th17 cell responses by inhibiting the differentiation as well as the reactivation of Th17 cells.

Interferon regulatory factor 5 (IRF5) plays a critical role in the induction of type I interferon, proinflammatory cytokines and chemokines, and participates in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). However, the relationship between IRF5 and childhood-onset SLE remains elusive. In the present study, we demonstrated that levels of mRNA expression of IRF5, IFN-α, and Sp1 were significantly increased in childhood-onset SLE, as seen on quantitative real-time PCR, and the expression of Sp1 and IFN-α was positively correlated with IRF5. In addition to being used as antitumor drugs, a number of histone deacetylase inhibitors (HDACi) display potent anti-inflammatory properties; however, their effects on IRF5 expression remain unclear. In this study, we identified that HDACi trichostatin A (TSA) and histone acetyltransferase (HAT)-p300 downregulated IRF5 promoter activity, mRNA expression, and protein level, whereas the HAT-p300/CBP-associated factor had no effect. Moreover, TSA inhibited the production of TNF-α and IL-6 in differentiated THP-1cells. Furthermore, chromatin immunoprecipitation assays revealed that TSA inhibited DNA binding of Sp1, RNA polymerase II, HDAC3, and p300 to the core promoter region of IRF5. Our results suggest that HDACi may have therapeutic potential in patients with autoimmune diseases such as SLE through repression of IRF5 expression.

// Lei Tu 1,* , Jie Chen 2,* , Dandan Xu 2 , Zhongming Xie 2 , Bing Yu 3 , Ying Tao 3 , Guixiu Shi 3 and Lihua Duan 3 1 Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China 2 College of Medicine, Xiamen University, Fujian, China 3 Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China * These authors have contributed equally to this work Correspondence to: Lihua Duan, email: // Guixiu Shi, email: // Keywords : IL-33, inflammatory bowel disease, macrophage, M2, Arginase-1, Immunology and Microbiology Section, Immune response, Immunity Received : January 17, 2017 Accepted : February 28, 2017 Published : March 07, 2017 Abstract Accumulated data have shown that alternatively activated macrophage exerts a modulatory role in many diseases, including colitis. Interleukin-33 (IL-33), a critical modulator in adaptive and innate immune, has been implicated in autoimmunity and inflammation. Previously, we have reported that IL-33 functions as a protective modulator in TNBS-induced colitis, which is closely related to a Th1-to-Th2/Treg switch. Here, we present novel evidence suggesting that IL-33 primes macrophage into alternatively activated macrophages (AAM) in TNBS-induced colitis. The strong polarized effect of IL-33 was tightly associated with the markedly increased induction of Th2-type cytokines. To confirm the beneficial effects of AAM induced by IL-33, peritoneal AAMs isolated from IL-33-treated mice were transferred to recipient mice with TNBS colitis. The adoptive transfer resulted in prominent inhibition of disease activity and inflammatory cytokines in the TNBS-treated mice. In conclusion, our data provide clear evidence that IL-33 plays a protective role in TNBS-induced colitis, which is closely related to AAM polarization.

// Donghee Kim 1 , Jae Young Kim 2 and Hee-Sook Jun 1,3,4 1 Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea 2 Department of Life Science, Gachon University, Seongnam, Gyeonggi-Do, Republic of Korea 3 College of Pharmacy and Gachon Institute Pharmaceutical Science, Gachon University, Incheon, Republic of Korea 4 Gil Medical Research Institute, Gil Hospital, Incheon, Republic of Korea Correspondence to: Hee-Sook Jun, email: // Keywords : Sjogren’s syndrome, Smad4, TGF-beta, NOD mice, IL-17, Immunology and Microbiology Section, Immune response, Immunity Received : May 05, 2016 Accepted : November 07, 2016 Published : November 17, 2016 Abstract We investigated the role of Smad4, a signaling molecule of the TGF-beta pathway, in T cells on the pathology of Sjogren’s syndrome (SS) in nonobese diabetic (NOD) mice, an animal model of SS. T cell-specific Smad4-deleted (Smad4 fl/fl,CD4-Cre ; Smad4 tKO) NOD mice had accelerated development of SS compared with wild-type (Smad4 +/+,CD4-Cre ; WT) NOD mice, including increased lymphocyte infiltration into exocrine glands, decreased tear and saliva production, and increased levels of autoantibodies at 12 weeks of age. Activated/memory T cells and cytokine (IFN-γ, IL-17)-producing T cells were increased in Smad4 tKO NOD mice, however the proportion and function of regulatory T (Treg) cells were not different between Smad4 tKO and WT NOD mice. Effector T (Teff) cells from Smad4 tKO NOD mice were less sensitive than WT Teff cells to suppression by Treg cells. Th17 differentiation capability of Teff cells was similar between Smad4 tKO and WT NOD mice, but IL-17 expression was increased under inducible Treg skewing conditions in T cells from Smad4 tKO NOD mice. Our results demonstrate that disruption of the Smad4 pathway in T cells of NOD mice increases Teff cell activation resulting in upregulation of Th17 cells, indicating that Smad4 in T cells has a protective role in the development of SS in NOD mice.

// Huai-Chia Chuang 1,* , Yi-Ming Chen 2,3,4,* , Wei-Ting Hung 2 , Ju-Pi Li 1 , Der-Yuan Chen 2,3,4 , Joung-Liang Lan 5,6 and Tse-Hua Tan 1,7,8 1 Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan 2 Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan 3 Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan 4 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan 5 School of Medicine, China Medical University Hospital, Taichung, Taiwan 6 Division of Rheumatology and Immunology, China Medical University Hospital, Taichung, Taiwan 7 Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan 8 Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA * These authors have contributed equally to this work Correspondence to: Tse-Hua Tan, email: // Joung-Liang Lan, email: // Der-Yuan Chen, email: // Keywords : JKAP, DUSP22, SLE, nephritis, T cells, Immunology and Microbiology Section, Immune response, Immunity Received : March 04, 2016 Accepted : August 13, 2016 Published : August 19, 2016 Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is characterized by systemic inflammation and multiple organ failures. Dysregulation of T cells plays a critical role in SLE pathogenesis. Our previous study indicates that JKAP (also named DUSP22) inhibits T-cell activation and that JKAP knockout mice develop spontaneous autoimmunity; therefore, we investigated whether JKAP downregulation is involved in SLE patients. JKAP protein levels in purified T cells were examined by immunoblotting using blood samples from 43 SLE patients and 32 healthy controls. SLE patients showed significantly decreased JKAP protein levels in peripheral blood T cells compared to healthy controls. JKAP protein levels in peripheral blood T cells were inversely correlated with SLE disease activity index (SLEDAI) and anti-dsDNA antibody levels. JKAP downregulation in T cells was highly correlated with daily urinary protein amounts and with poor renal outcome in lupus nephritis patients. Notably, the diagnostic power of JKAP downregulation in T cells for active lupus nephritis was higher than those of serum anti-dsDNA antibody, C3, and C4 levels. Moreover, T-cell-specific transgenic mice expressing a dominant-negative JKAP mutant developed spontaneous autoimmune nephritis. Furthermore, JKAP-deficient T cells overproduced complement components, soluble ICAM-1, and soluble VCAM-1 in the kidney; these cytokines have been reported to be involved in lupus nephritis. Taken together, JKAP downregulation in T cells is a novel diagnostic and prognostic biomarker for SLE nephritis.

International audience; FOXP3 + regulatory T cell (Treg) based cellular therapies represent promising therapeutic options in autoimmunity, allergy, transplantation and prevention of Graft Versus Host (GVH) Disease. Among human FOXP3-expressing CD4 + T cells, only the CD45RA + naïve Treg (nTreg) subset is suitable for in vitro expansion. However, FoxP3 expression decays in cells using currently described culture protocols. Rapamycin alone was not able to prevent FOXP3 loss in nTregs cells, as only a half of them maintained FOXP3 expression after 14 days of culture. In contrast we report a novel combined drug regimen that can drastically stabilize FOXP3 expression in cultured Tregs. IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors act in synergy to allow expansion of human regulatory T cells with sustained high expression of FOXP3 and CD15s with potent suppressive capacities in vitro and control of murine xeno-GVH reactions. Of note, an additional subsequent infusion of expanded nTreg cells did not improve survival of mice. Combination of IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors is optimal for the expansion in vitro of pure effective nTreg maintaining high levels of FOXP3 for therapeutic purposes.

// Xiaojing Jin 1,3,* , Shujun Wang 2,* , Xuemin Zhao 1 , Qian Jin 1 , Chenling Fan 1 , Jing Li 1 , Zhongyan Shan 1 and Weiping Teng 1 1 Department of Endocrinology and Metabolism, Institute of Endocrinology, The First Affiliated Hospital, China Medical University, Liaoning Provincial Key Laboratory of Endocrine Diseases, Shenyang, P. R. China 2 Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, P. R. China 3 Present address: Department of Emergency, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, P.R. China * These authors have contributed equally to this work Correspondence to: Jing Li, email: // Keywords : autoimmunity; thyroiditis; coumestrol; phytoestrogen; T helper cell; Immunology and Microbiology Section; Immune response; Immunity Received : January 29, 2016 Accepted : June 15, 2016 Published : June 30, 2016 Abstract Coumestrol is a common phytoestrogen found in plants and Chinese medicinal herbs. Its influences on experimental autoimmune thyroiditis (EAT) were investigated in this study. Female adult CBA/J mice were fed with drinking water containing 1% Tween80 only (Control group), 0.8 mg/l (L group) and 8 mg/l coumestrol (H group) from 6 to 15 weeks of age, respectively. Their serum coumestrol concentrations were determined by high performance liquid chromatography, which were undetectable, 43.70 ± 21.74 ng/ml and 135.07 ± 70.40 ng/ml, respectively. In addition, the mice (n = 14–16/group) were immunized twice with thyroglobulin (Tg) and Freund’s adjuvant to induce EAT during the meantime. Although no overt changes in the extent of intrathyroidal mononuclear cell infiltration were shown in the two coumestrol-treated groups as compared with the controls, serum anti-Tg IgG2a, IgG3 and IgG1 titers, ratio of IgG2a to IgG1 and the percentage of T helper (Th)1 cells in the splenocytes were significantly reduced in the L group. Another consistent change was the significantly decreased expression of splenic IFN-γ mRNA after low dose of coumestrol exposure. Uterine weight was also markedly reduced in the mice of L group. These findings suggest that coumestrol treatment may have some beneficial actions against thyroid-specific autoantibody production in the development of autoimmune thyroiditis through suppression of Th1 response due to its anti-estrogenic activity.

// Eva Bauer 1 , Michaela Schlederer 1,2 , Ruth Scheicher 3 , Jaqueline Horvath 1,4 , Petra Aigner 1 , Ana-Iris Schiefer 2 , Renate Kain 2 , Heinz Regele 2 , Gregor Hoermann 5 , Gunter Steiner 6,7 , Lukas Kenner 1,2,8 , Veronika Sexl 3 , Andreas Villunger 9,10 , Richard Moriggl 1,5,11 and Dagmar Stoiber 1,4 1 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria 2 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 3 Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria 4 Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria 5 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 6 Cluster Arthritis and Rehabilitation, Ludwig Boltzmann Society, Vienna, Austria 7 Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria 8 Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria 9 Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria 10 Tyrolean Cancer Research Institute, Innsbruck, Austria 11 Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria Correspondence to: Dagmar Stoiber, email: // Keywords : ETV6/RUNX1, BCL2, glomerulonephritis, lymphoma, autoimmunity, Immunology and Microbiology Section, Immune response, Immunity Received : September 11, 2015 Accepted : January 31, 2016 Published : February 23, 2016 Abstract The t(12;21) translocation generating the ETV6/RUNX1 fusion gene represents the most frequent chromosomal rearrangement in childhood leukemia. Presence of ETV6/RUNX1 alone is usually not sufficient for leukemia onset, and additional genetic alterations have to occur in ETV6/RUNX1-positive cells to cause transformation. We have previously generated an ETV6/RUNX1 transgenic mouse model where the expression of the fusion gene is restricted to CD19-positive B cells. Since BCL2 family members have been proposed to play a role in leukemogenesis, we investigated combined effects of ETV6/RUNX1 with exogenous expression of the antiapoptotic protein BCL2 by crossing ETV6/RUNX1 transgenic animals with Vav-BCL2 transgenic mice. Strikingly, co-expression of ETV6/RUNX1 and BCL2 resulted in significantly shorter disease latency in mice, indicating oncogene cooperativity. This was associated with faster development of follicular B cell lymphoma and exacerbated immune complex glomerulonephritis. ETV6/RUNX1-BCL2 double transgenic animals displayed increased B cell numbers and immunoglobulin titers compared to Vav-BCL2 transgenic mice. This led to pronounced deposition of immune complexes in glomeruli followed by accelerated development of immune complex glomerulonephritis. Thus, our study reveals a previously unrecognized synergism between ETV6/RUNX1 and BCL2 impacting on malignant disease and autoimmunity.

// Axel R. Concepcion 1 , January T. Salas 2 , Elena Saez 1 , Sarai Sarvide 1 , Alex Ferrer 3 , Ainhoa Portu 1 , Iker Uriarte 1 , Sandra Hervas-Stubbs 1 , Ronald P.J. Oude Elferink 4 , Jesus Prieto 1 and Juan F. Medina 1 1 Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona, Spain 2 Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 3 Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA 4 Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Correspondence to: Juan F. Medina, email: // Jesus Prieto, email: // Keywords : Na + -independent Cl − /HCO3 − anion exchanger AE2, mouse model of autoimmune cholangitis, intracellular pH homeostasis, age-related changes, self-tolerance breakdown, Immunology and Microbiology Section, Immune response, Immunity Received : August 24, 2015 Accepted : August 31, 2015 Published : September 15, 2015 Abstract Primary biliary cirrhosis (PBC) is a chronic cholestatic disease of unknown etiopathogenesis showing progressive autoimmune-mediated cholangitis. In PBC patients, the liver and lymphocytes exhibit diminished expression of AE2/SLC4A2, a Cl − /HCO 3 − anion exchanger involved in biliary bicarbonate secretion and intracellular pH regulation. Decreased AE2 expression may be pathogenic as Ae2 a,b –/– mice reproduce hepatobiliary and immunological features resembling PBC. To understand the role of AE2 deficiency for autoimmunity predisposition we focused on the phenotypic changes of T cells that occur over the life-span of Ae2 a,b –/– mice. At early ages (1-9 months), knockout mice had reduced numbers of intrahepatic T cells, which exhibited increased activation, programmed-cell-death (PD)-1 expression, and apoptosis. Moreover, young knockouts had upregulated PD-1 ligand (PD-L1) on bile-duct cells, and administration of neutralizing anti-PD-L1 antibodies prevented their intrahepatic T-cell deletion. Older (≥10 months) knockouts, however, showed intrahepatic accumulation of cytotoxic CD8 + T cells with downregulated PD-1 and diminished apoptosis. In-vitro DNA demethylation with 5-aza-2’-deoxycytidine partially reverted PD-1 downregulation of intrahepatic CD8 + T cells from aged knockouts. Conclusion: Early in life, AE2 deficiency results in intrahepatic T-cell activation and PD-1/PD-L1 mediated deletion. With aging, intrahepatic CD8 + T cells epigenetically suppress PD-1, and their consequential expansion and further activation favor autoimmune cholangitis.

The central pathological feature of Alzheimer's disease (AD) is the sequential proteolytic processing of amyloid precursor protein (APP) to amyloid-β peptides (Aβ) agglomeration. The clearance of Aβ may be induced by the large zinc-binding protease insulin degrading enzyme (IDE). IDE is the common link between AD and Type II diabetes as insulin is an IDE target as well. Not surprisingly, the search for safe and effective drugs modulating IDE is ongoing. A new pregnancy derived peptide, PreImplantation Factor (PIF), inhibits neuro-inflammation and crosses the blood-brain-barrier. Importantly, we report that the (R3I4K5P6) core sequence of the PIF peptide modulates IDE function and results in decreased Aβ agglomeration in neuronal cells. Using bioinformatics we show that PIF binds to the IDE complex and sterically competes for the same place as insulin or Aβ. The predicted RIKP sequence and especially the specific I4 and P6 amino acids are essential for hydrophobic interactions with the IDE complex. In terms of potential AD treatment, PIF was successfully tested in neurodegenerative animal models of perinatal brain injury and experimental autoimmune encephalitis. Importantly, sPIF received a FDA Fast Track Approval and orphan drug designation for first-in-human trial in autoimmunity.

The PI3K/AKT/mTOR pathway is an intracellular signalling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Multiple Sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS and on oligodendrocyte function, making use of currently available whole-genome transcriptomic data. Then, the data generated in silico were subjected to an ex-vivo evaluation. To this aim, the involvement of mTOR was validated on a well-known animal model of MS and in vitro on Th17 cells. Our data indicate that there is a significant involvement of the mTOR network in the etiopathogenesis of MS and that Rapamycin treatment may represent a useful therapeutic approach in this clinical setting. On the other hand, our data showed that a significant involvement of the mTOR network could be observed only in the early phases of oligodendrocyte maturation, but not in the maturation process of adult oligodendrocytes and in the process of remyelination following demyelinating injury. Overall, our study suggests that targeting the PI3K/mTOR pathway, although it may not be a useful therapeutic approach to promote remyelination in MS patients, it can be exploited to exert immunomodulation, preventing/delaying relapses, and to treat MS patients in order to slow down the progression of disability.

Mutations in STAT3 have recently been shown to cause autoimmune diseases through increased lymphoproliferation. We describe a novel Pro471Arg STAT3 mutation in a patient with multiple autoimmune diseases, causing hyperactivation of the Th17 pathway. We show that IL-17 production by primary T cells was enhanced and could not be further increased by IL-6, while IL-10 reduced Th17 cell numbers. Moreover, specific inhibition of STAT3 activation resulted in diminished IL-17 production. We show that the Pro471Arg STAT3 mutation yields both increased levels of IgA and IgG, probably due to high IL-21 levels. When remission was reached through medical intervention, IL-17 levels normalized and the clinical symptoms improved, supporting the idea that STAT3 gain-of-function mutations can cause hyperactivation of the Th17 pathway and thereby contribute to autoimmunity.

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination in mature B-cells, while AID was also shown to play a role in developing pre-BCR/BCR-positive B-cells of the bone marrow. To further elucidate a potential function of Aid in the bone marrow prior to V(D) J-recombination, we utilized an in vivo model which exerts a B-cell developmental arrest at the pro-B cell stage with low frequencies of pro-B cell acute lymphoblastic leukemia (pro-B ALL) development. Therefore, p19ArfRag1 (AR) mice were crossed with Aid-deficient mice (ARA). Surprisingly, loss of Aid expression in pro-B cells accelerated pro-B ALL incidence from 30% (AR) to 98% (ARA). This effect was Aid dose dependent, since Aid animals of the same background displayed a significantly lower incidence (83%). Furthermore, B-cell-specific Aid up-regulation was observed in Aid-competent pro-B ALLs. Additional whole exome/sanger sequencing of murine pro-B ALLs revealed an accumulation of recurrent somatic Jak3 (p. R653H, p. V670A) and Dnm2 (p. G397R) mutations, which highlights the importance of active IL7R signaling in the pro-B ALL blast cells. These findings were further supported by an enhanced proliferative potential of ARA pro-B cells compared to Aid-competent cells from the same genetic background. In summary, we show that both Aid and Rag1 act as a negative regulators in pro-B cells, preventing pro-B ALL., J. Hauer has been supported by the German Cancer Foundation (110997), DJCLS02R/2016, KKS A2016/07 and from the “Forschungskommission” of the medical faculty of the Heinrich Heine University. A. Borkhardt has been supported by the German Children’s Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in I. Sánchez-García’s group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y León (BIO/SA51/15, CSI001 U14, UIC-017, and CSI001U16), Fundacion Inocente Inocente and by the ARIMMORA project (European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282891). I. Sánchez-García’s lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. A. Borkhardt and I. Sánchez-García have been supported by the German Carreras Foundation (DJCLS R13/26). Research in C. Vicente-Dueñas’ group is partially supported by a “Miguel Servet” Grant (CP14/00082 - AES 2013-2016 - FEDER) from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad) and by the Lady Tata International Award for Research in Leukaemia 2016-2017. A. Martín-Lorenzo was supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-13).

Autoimmune regulator (Aire) is essential in the perinatal period to prevent the multiorgan autoimmunity. Here we show that Aire-regulated single positive thymocyte trafficking in neonatal period is critical for thymic egress. Reduced thymic emigration was found in Aire-/- mice during neonatal period, leading to enhanced homeostatic expansion of peripheral T cells as early as 2 weeks of age. In neonatal Aire-/- mice, thymic expression of CCR7 ligands were dramatically reduced, resulting in decreased thymocyte motility and thymocyte emigration. This reduction of thymic egress in Aire-/- mice was alleviated beyond 3 weeks of age by an early upregulation of S1P1 signaling. As the numbers and quality of thymic emigrants are essential for the establishment and maintenance of peripheral tolerance, the reduced thymic emigration during neonatal period may deteriorate autoimmunity caused by the emigration of autoreactive T cells.

// Zhen Gao 1 , Yu-Qing Jin 2 , Wei Wu 1 1 Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2 Department of Plastic Surgery, Shanghai International Medical Center, Shanghai, China Correspondence to: Wei Wu, email: babevivi@126.com Keywords: alopecia areata, SOCS3, IFN-γ, autoimmune, hair follicle Received: October 02, 2016 Accepted: February 23, 2017 Published: March 23, 2017 ABSTRACT Alopecia areata is one of the most common autoimmune diseases resulting from T cell-mediated damage of hair follicles. CD8+ T cells infiltrate hair follicles and are responsible for destruction of hair follicles. However the underlying mechanisms for hair loss remain still obscure. In the present study, we identified that suppressor of cytokine signaling-3 (SOCS3), a classical inhibitor of cytokine signaling, significantly inhibits CD8+T cell maturation, interferon-γ (IFN-γ) production and alopecia areata. SOCS3 is downregulated in the skin of alopecia areata patients and murine autoimmune alopecia model. Furthermore, SOCS3 treatment prevents the development of alopecia areata in the graft model. SOCS3 decreases the CD44 high CD62L low effector memory CD8+ T cells, resulting in the decrease of IFN-γ production. The expression of Fas and major histocompatibility complex-1 (MHC I) is upregulated in skin from C3H/HeJ alopecia areata mice, and this increase is suppressed by SOCS3. The SOCS3 level is negative correlation with the Fas and MHC I level in patients with alopecia areata. These results suggest that SOCS3 treatment may be an effective strategy to treat autoimmune alopecia as well as to more generally prevent cytokine-dependent tissue destruction in inflammatory diseases.

// Yan-Qing Yang 1 , Wei Yang 1 , Yuan Yao 1 , Hong-Di Ma 1 , Yin-Hu Wang 1 , Liang Li 1 , Qingfa Wu 2 , M. Eric Gershwin 3 and Zhe-Xiong Lian 1,4 1 Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China 2 The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China 3 Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, United States of America 4 Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China Correspondence to: Zhe-Xiong Lian, email: // Hong-Di Ma, email: // Keywords : B1a cell, autoimmune cholangitis, dysregulation, Breg, peritoneal cavity, Immunology and Microbiology Section, Immune response, Immunity Received : March 15, 2016 Accepted : April 13, 2016 Published : April 20, 2016 Abstract Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease with progressive cholestasis and liver fibrosis. Similar to human patients with PBC, p40 -/- IL-2Rα -/- mice spontaneously develop severe autoimmune cholangitis. Although there has been considerable work on immune regulation and autoimmunity, there is a relative paucity of work directed at the functional implications of the key peritoneal cavity (PC) B cell subset, coined B1a cells in PBC. We used flow cytometry and high-resolution microarrays to study the qualitative and quantitative characteristics of B cells, particularly B1a cells, in the PC of p40 -/- IL-2Rα -/- mice compared to controls. Importantly, B1a cell proliferation was markedly lower as the expression of Ki67 decreased. Meanwhile, the apoptosis level was much higher. These lead to a reduction of B1a cells in the PC of p40 -/- IL-2Rα -/- mice compared to controls. In contrast, there was a dramatic increase of CD4 + and CD8 + T cells accompanied by elevated production of IFN-γ. In addition, we found a negative correlation between the frequency of B1a cells and the presence of autoreactive CD8 + T cells in both liver and PC of p40 -/- IL-2Rα -/- mice. From a functional perspective, B cells from p40 -/- IL-2Rα -/- mice downregulated IL-10 production and CTLA-4 expression, leading to loss of B cell regulatory function. We suggest that the dysfunction of B1a cells in the PC in this murine model of autoimmune cholangitis results in defective regulatory function. This highlights a new potential therapeutic target in PBC.

International audience; Abnormal overexpression of CXCL13 is observed in many inflamed tissues and in particular in autoimmune diseases. Myasthenia gravis (MG) is a neuromuscular disease mainly mediated by anti-acetylcholine receptor autoantibodies. Thymic hyperplasia characterized by ectopic germinal centers (GCs) is a common feature in MG and is correlated with high levels of anti-AChR antibodies. We previously showed that the B-cell chemoattractant, CXCL13 is overexpressed by thymic epithelial cells in MG patients. We hypothesized that abnormal CXCL13 expression by the thymic epithelium triggered B-cell recruitment in MG. We therefore created a novel transgenic (Tg) mouse with a keratin 5 driven CXCL13 expression. The thymus of Tg mice overexpressed CXCL13 but did not trigger B-cell recruitment. However, in inflammatory conditions, induced by Poly(I:C), B cells strongly migrated to the thymus. Tg mice were also more susceptible to experimental autoimmune MG (EAMG) with stronger clinical signs, higher titers of anti-AChR antibodies, increased thymic B cells, and the development of germinal center-like structures. Consequently, this mouse model finally mimics the thymic pathology observed in human MG. Our data also demonstrated that inflammation is mandatory to reveal CXCL13 ability to recruit B cells and to induce tertiary lymphoid organ development.

// Cheng-Hsun Ho 1, 2, * , Huai-Chia Chuang 3, * , I-Chin Wu 2 , Hung-Wen Tsai 4, 5 , Yih-Jyh Lin 6 , Hung-Yu Sun 7 , Kung-Chia Young 7 , Yen-Cheng Chiu 2 , Pin-Nan Cheng 2 , Wen-Chun Liu 2, 5 , Tse-Hua Tan 3, 8 , Ting-Tsung Chang 2, 5, 9 1 Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 2 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3 Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan 4 Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 5 Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan 6 Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 7 Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 8 Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA 9 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan * These authors have contributed equally to this work Correspondence to: Ting-Tsung Chang, email: ttchang@mail.ncku.edu.tw Tse-Hua Tan, email: ttan@nhri.org.tw Keywords: hepatocellular carcinoma, recurrence, GLK, NFκB Received: September 08, 2015 Accepted: June 04, 2016 Published: June 20, 2016 ABSTRACT Germinal center kinase-like kinase (GLK) is a key controller of autoimmunity. In this study, we assessed the clinical relevance and tumorigenic effects of GLK in hepatocellular carcinoma (HCC). Using immunohistochemistry, we showed that the GLK proportion score increased in both cancerous and adjacent non-cancerous liver tissue from patients with HCC recurrence. A Kaplan-Meier analysis revealed that patients with a wide distribution of GLK in non-cancerous liver tissue had a higher rate of HCC recurrence than those with very low or no GLK expression. Multivariate Cox regression analyses indicated that a high GLK proportion score in non-cancerous liver tissue was an independent predictor of early HCC recurrence after resection. Lentiviral vector-mediated overexpression of GLK activated the nuclear factor kappa B (NFκB) signaling cascade and accelerated cell cycle progression in primary human hepatocytes, thereby promoting proliferation. An increase in GLK expression coincided with NFκB activation and enhanced expression of proliferating cell nuclear antigen in HCC tissue. Our findings demonstrate a potential hepatocarcinogenic effect of GLK and the feasibility of using GLK to predict early HCC recurrence.

// Qing Zhu 1, 2 , Su-Xia Han 1 , Cong-Ya Zhou 1 , Meng-Jiao Cai 1 , Li-Ping Dai 2 , Jian-Ying Zhang 2 1 Department of Oncology, The First Affiliated Hospital of Xi’an Jiaotong University Medical Center, Xi’an, Shaanxi, P.R. China 2 Department of Biological Sciences, The University of Texas at El Paso, El Paso, Texas, USA Correspondence to: Qing Zhu, e-mail: newzhuqing1972@yahoo.com Jian-Ying Zhang, e-mail: jzhang@utep.edu Keywords: autoantibody, DNA repair enzyme poly (ADP-Ribose) polymerase 1 (PARP1)/BRCA1/BRCA2, synthetic lethality, tumor-associated antigen (TAA), autoimmune Received: January 05, 2015 Accepted: February 24, 2015 Published: March 24, 2015 ABSTRACT Purpose: To determine the role of autoantibodies to PARP1 and BRCA1/BRCA2 which were involved in the synthetic lethal interaction in cancer. Methods: Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect autoantibodies to PARP1 and BRCA1/BRCA2 in 618 serum samples including 131 from breast cancer, 94 from lung cancer, 34 from ovarian cancer, 107 from prostate cancer, 76 from liver cancer, 41 from pancreatic cancer and 135 from normal individuals. The positive sera with ELISA were confirmed by Western blot. Immunohistochemistry was used to examine the expression of PARP1 and BRCA1/BRCA2 in breast cancer. Results: Autoantibody frequency to PARP1, BRCA1, and BRCA2 in cancer varied from 0% to 50%. When the sera from cancer patients were tested for the presence of autoantibodies to PARP1 and BRCA1/BRCA2, the autoantibody responses slightly decreased and the positive autoantibody reactions varied from 0% to 50.0%. This was significantly higher autoantibody responses to PARP1 and BRCA1/BRCA2 (especially to PARP1 and BRCA1) in ovarian cancer and breast cancer compared to normal control sera (P < 0.001 and P < 0.01). Immunohistochemistry indicated that Pathology Grade at diagnosis to PARP1 expression in breast cancer was different (P < 0.05). Conclusions: Different cancers have different profiles of autoantibodies. The autoantibodies to proteins involving the synthetic lethal interactions would be novel serological biomarker in some selective cancers.

// Xin-guang Liu 1,* , Yu Liu 2,* and Feng Chen 1,3 1 Department of Hematology, Qilu Hospital, Shandong University, Jinan, P. R. China 2 School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, Jinan, P. R. China 3 Capital Medical University Cancer Center, Beijing Shijitan Hospital, Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing, China * These authors have contributed equally to this paper Correspondence to: Feng Chen, email: // Keywords : soluble fibrinogen-like protein 2; immunoregulation; transplantation; hepatitis; autoimmunity Received : July 25, 2016 Accepted : September 29, 2016 Published : October 08, 2016 Abstract Soluble fibrinogen-like protein 2 (sFGL2) is the soluble form of fibrinogen-like protein 2 belonging to the fibrinogen-related protein superfamily. It is now well characterized that sFGL2 is mainly secreted by regulatory T cell (Treg) populations, and exerts potently immunosuppressive activities. By repressing not only the differentiation and proliferation of T cells but also the maturation of dendritic cells (DCs), sFGL2 acts largely as an immunosuppressant. Moreover, sFGL2 also induces apoptosis of B cells, tubular epithelial cells (TECs), sinusoidal endothelial cells (SECs), and hepatocytes. This mini-review focuses primarily on the recent literature with respect to the signaling mechanism of sFGL2 in immunomodulation, and discusses the clinical implications of sFGL2 in transplantation, hepatitis, autoimmunity, and tumors.