bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ulcerative Colitis-associated E. coli pathobionts potentiate colitis in susceptible hosts
Authors: Yang Hyungjun , Mirsepasi-Lauridsen Hengameh Chloé , Struve Carsten , Allaire Joannie M. , Bosman Else , Sivignon Adeline , Vogl Wayne , Ma Caixia , Reid Gregor , Li Xiaoxia , Petersen Andreas Munk , Jacobson Kevan , Gouin Sébastien , Barnich Nicolas , Yu Hongbing , Krogfelt Karen Angeliki , Vallance Bruce A 
Published: January 2023

Abstract
Ulcerative colitis (UC) is chronic inflammatory condition linked to intestinal microbial dysbiosis, including the expansion of E. coli strains related to extra-intestinal E. coli. These “pathobionts” exhibit pathogenic properties, but their potential to promote UC is unclear due to the lack of suitable animal models. Here, we established a mouse model using a representative UC pathobiont strain (p19A), and mice lacking single immunoglobulin and toll-interleukin 1 receptor domain (SIGIRR), a deficiency increasing susceptibility to gut infections. p19A was found to adhere to the cecal mucosa of Sigirr−/− mice, causing modest inflammation. Moreover, it dramatically worsened DSS induced colitis, in concert with adherence to, and penetration of the inflamed mucosa. This pathogenicity was lost in a p19A strain lacking the adhesin FimH; following treatment with FimH antagonists, or was attenuated when using a p19A strain lacking a-hemolysin genes. Thus UC pathobionts can worsen the course of colitis in susceptible hosts.
Identification of novel loci controlling IBD susceptibility utilizing the genetic diversity of wild-derived mice
Authors: Lahue Karrie Godburn , Crothers Jessica , Lavoie Brigitte , Fang Qian , Mawe Gary , Krementsov Dimitry 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) is a complex disease that imposes a significant and growing health burden in industrialized nations. Recent genetic studies have identified multiple genetic associations with IBD, but the mechanisms underlying these associations are poorly understood. Animal models are needed to bridge this gap in knowledge, but conventional laboratory mouse strains lack the genetic diversity of human populations. To more accurately model human genetic diversity and to identify new genetic loci that control susceptibility to IBD, we utilized a panel of chromosome (Chr) substitution (consomic) strains, carrying chromosomes from the wild-derived and genetically divergent PWD/PhJ (PWD) strain on the commonly used C57BL/6J (B6) background. Two models of IBD were used, TNBS- and DSS-induced colitis. Multiple disease severity parameters were evaluated, including weight loss, disease activity, fecal Lipocalin-2 production, and histopathology. Strikingly, compared with B6 mice, wild-derived PWD mice were highly susceptible to TNBS-induced colitis, but resistant to DSS-induced colitis. Using consomic mice, we found several PWD-derived loci that exhibited significant effects on IBD susceptibility. Most pronounced was a locus on Chr2, which resulted in very high susceptibility to both DSS and TNBS colitis, while several other PWD-derived loci were protective. Altogether, our experiments identified novel IBD susceptibility loci, harboring genes that control susceptibility to various aspects of IBD pathogenesis, and underscoring the utility of wild-derived mouse genetics. Future studies will identify these genes and their functions, to generate new insights into IBD etiology and pathophysiology.
Persistent IL-1b Signaling Aggravates Murine Enteropathogen, Citrobacter rodentium Infection in Mice
Authors: Yeoh Beng San , Saha Piu , Golonka Rachel M , Vijay-Kumar Matam 
Published: January 2023

Abstract
The inflammasome cytokine IL-1b is an important mediator of the inflammatory responses against invading pathogens. However, it is not clear whether sustained IL-1b signaling following the loss of its endogenous inhibitor, secretory IL-1 receptor antagonist (sIL-1Ra), could improve mucosal immunity against the enteropathogen, Citrobacter rodentium (CR). In light of increased prescription of rec-sIL-1Ra (aka Anakinra) to treat inflammatory bowel disease, we undertook this study. At basal levels, sIL-1Ra-deficient (sIL-1RaKO) mice displayed leukocytosis and elevated inflammatory marker, i.e. serum and fecal lipocalin 2. Furthermore, bone marrow-derived macrophages and neutrophils from sIL-1RaKO mice generated higher levels of iNOS and nitrite, and ROS and NETs, respectively. These results collectively suggest sIL-1RaKO mice have low-grade chronic inflammation. Based on these results, we hypothesized that sIL-1RaKO mice with persistent IL1-b signaling could efficiently clear CR infection than their WT littermates. Oral challenge of CR (1×109 CFU/mouse) resulted in luminal colonization, which peaked at day 7 post-infection, in both groups; however, sIL-1RaKO mice displayed a higher CR burden and an exacerbated infection. The aggravated course of infection was further visualized by inoculating sIL-1RaKO mice with bioluminescent CR. Histologic analysis revealed that transmissible colonic hyperplasia was more pronounced in sIL-1RaKO mice. Interestingly, basal ileal Paneth’s cell-specific antimicrobial proteins (Ang4 and Reg3g) were significantly reduced in sIL-1RaKO mice. Collectively, our results demonstrate that a balanced mucosal IL-1b signaling is required to counter and clear enteropathogen infection.
AS101 ameliorates experimental autoimmune uveitis by regulating Th1 and Th17 responses and inducing Treg cells
Authors: Bing So Jin , Shemesh Itay , Chong Wai Po , Jittayasothorn Yingyos , Silver Phyllis B , Sredni Benjamin , Caspi Rachel R 
Published: January 2023

Abstract
AS101 is an organotellurium compound with multifaceted immunoregulatory properties that is remarkable for its lack of toxicity. We tested the therapeutic effect of AS101 in experimental autoimmune uveitis (EAU), a model for human autoimmune uveitis. Unexpectedly, treatment with AS101 elicited Treg generation in vivo in otherwise unmanipulated mice. Mice immunized for EAU with the retinal antigen IRBP and treated with AS101 developed attenuated disease, as did recipients of retina-specific T cells activated in vitro in the presence of AS101. In both settings, eye-infiltrating effector T cells were decreased, whereas regulatory T (Treg) cells in the spleen were increased. Mechanistic studies in vitro revealed that AS101 restricted polarization of retina-specific T cells towards Th1 or Th17 lineage by repressing activation of their respective lineage-specific transcription factors and downstream signals. Retina-specific T cells polarized in vitro towards Th1 or Th17 in the presence of AS101 had impaired ability to induce EAU in naïve recipients. Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-β. We conclude that AS101 modulates autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for autoimmune uveitis.
IL-22 and Reg3γ overexpression affects Experimental Autoimmune Encephalomyelitis Severity
Authors: Eken Ahmet , Yetkin Mehmet Fatih , Okus Fatma Zehra , Cakir Mustafa , Karayigit Mehmet Onder , Erdem Serife , Haliloglu Yesim , Oukka Mohamed , Altuntas Hamiyet Donmez , Mirza Meral , Canatan Halit 
Published: January 2023

Abstract
IL-22 belongs to IL-10 family cytokines and is produced by RORγt+ innate and adaptive lymphocytes, including ILC3, γδ, iNKT, Th17, and Th22 cells. IL-22 receptor, however, is expressed primarily by non-hematopoietic cells. IL-22 is critical for barrier immunity at the mucosal surfaces in the steady state and during infection. Although IL-22 knock out mice were previously shown to develop experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis (MS), how IL-22 manipulation in adult mice would affect EAE course has not been studied. In this study, we over-expressed IL-22 via hydrodynamic gene delivery or blocked it via neutralizing antibodies in C57BL/6 mice to assess the impact of IL-22 modulation on EAE course. IL-22 overexpression significantly but marginally decreased EAE scores, demyelination and reduced infiltration of IFNγ+IL-17A+ Th17 cells into central nervous system (CNS). In contrast, neutralization of IL-22 exacerbated EAE scores. Surprisingly, overexpression of Reg3γ, an epithelial cell-derived antimicrobial peptide induced by IL-22, significantly exacerbated EAE scores and infiltration of IFN-γ+IL-17A+ and IL-17A+GM-CSF+ Th17 cells to CNS. Our results provide novel insight into the role of IL-22 and IL-22-induced antimicrobial peptides in the pathogenesis of CNS inflammation in a murine model of MS.
Lactobacillus reuteri reduces the severity of experimental autoimmune encephalomyelitis in mice by modulating gut microbiota
Authors: Liu Yuying , He Baokun , Hoang Thomas K , Tian Xiangjun , Taylor Christopher M , Blanchard Eugene E , Luo Meng , Bhattacharjee Meenakshi B , Freeborn Jasmin , Park Sinyoung , Couturier Jacob , Lindsey J William , Tran Dat Q , Rhoads J Marc 
Published: January 2023

Abstract
The gut microbiome plays an important role in immune function and has been implicated in multiple sclerosis (MS). However, how to modulate microbiota to prevent or treat MS remain largely unknown. Probiotic Lactobacillus reuteri DSM 17938 (L. reuteri) has anti-inflammatory effects in mouse models of neonatal necrotizing enterocolitis and Treg-deficiency-induced autoimmune disease. L. reuteri in these models modulated gut microbiota and microbiota-associated metabolites to inhibit TH1 and TH2 differentiation and their-associated cytokines, significantly ameliorating the severity of these diseases. An in vitro study indicated that L. reuteri inhibits the differentiation of naïve CD4+T cells into TH17 and TH1 cells. We determined the effect of L. reuteri on experimental autoimmune encephalomyelitis (EAE) mouse model, a widely used animal model of MS, a model which is primarily mediated by TH17 and TH1 cells. We discovered that L. reuteri treatment reduced TH1/TH17 cells and their associated cytokines IFN-γ/IL-17 in EAE, inhibiting the development of EAE. We also showed that the loss of diversity in gut microbiota induced by EAE was largely restored by L. reuteri treatment. Taxonomy-based analysis of gut microbiota showed that the “beneficial” genera Bifidobacterium, Prevotella, and Lactobacillus were negatively correlated with EAE clinical severity scores, whereas the genera Anaeroplasma, Rikenellaceae, and Clostridium were positively correlated. Notably, L. reuteri treatment altered the relative abundances of these EAE-associated taxa in mice. In conclusion, probiotic L. reuteri changed gut microbiota to modulate immune responses in EAE, making it a novel candidate in future studies to modify the severity of MS.
The cytoplasmic domain of CTLA-4 control autoimmunity via inducing regulatory T cells
Authors: Kim Gil-Ran , Lim Sangho , Lee Jae-Ung , Choi Je-Min 
Published: January 2023

Abstract
Regulatory T cells (Tregs) have critical roles for maintaining immune tolerance and homeostasis. Recently, it is revealed that CTLA-4 is an essential membrane protein for the suppressive function of Treg. However, the molecular mechanism of cytoplasmic domain of CTLA-4 (ctCTLA-4) and its role in Treg function and differentiation is not clearly understood. In this study, we utilized ctCTLA-4 peptide and its various mutant forms conjugated with dNP2, a cell-permeable peptide, to investigate the mechanism of ctCTLA-4 in Treg function and differentiation. We found that the ctCTLA-4 convert naïve T cells to Foxp3-positive cells in T helper 17 cell differentiation condition in vitro, while the lysine-rich motif mutant form could not. The dNP2-ctCTLA-4 also significantly inhibits experimental autoimmune encephalomyelitis (EAE) in vivo, by reducing CNS-infiltrating Th17 cells with significantly increased Treg proportion. As similar with in vitroresults, lysine-rich motif mutant form could not increase Treg proportion and inhibit EAE. To elucidate its molecular mechanisms, we conducted HuProt protein microarray to identify lysine-rich motif dependent binding partner of ctCTLA-4 related with increasing Tregs. With the results, we found that ctCTLA-4 decreased a phosphorylation of MAPK in T cell stimulation conditions resulting enhanced nuclear localization of Smad2/3, a key transcription factor for Foxp3 expression. These results suggest that ctCTLA-4 has a critical molecular mechanism of inducing Tregs to maintain peripheral immune tolerance to control autoimmunity.
The effect of Chinese herbal medicine compound, CS029, in suppression of dendritic cells and its therapeutic application in experimental autoimmune encephalomyelitis
Authors: Song Ying-Chyi , Yen Hung-Rong 
Published: January 2023

Abstract
Dendritic cell (DC) is a kind of professional antigen-presenting cells that play a crucial role in the activation of naive T cell response. Previous studies have demonstrated that controlling DCs can affect the development of autoimmune diseases. Multiple sclerosis (MS) is an inflammatory autoimmune disease, in which the immune system attacks myelinated axons in the central nervous system (CNS). Although several immunomodulatory drugs have been developed to treat MS, the current drugs have no satisfactory efficacy. Therefore, it is necessary to develop new drugs to improve the treatment of MS. We aimed to develop new immunomodulatory agents for the treatment of MS from Chinese herbal medicine (CHM). Among the CHM, we identified an alkaloid CHM compound (CS029), which could reduce inflammatory cytokine production through the TLR-dependent and -independent activation of DC. Moreover, we demonstrated that CS029 could inhibit antigen presentation ability of DC in vitro. In a murine experimental autoimmune encephalomyelitis (EAE) model, we demonstrated that the mean clinical score decreased 6-fold by CS029 treatment (50 mg/kg) compared with the vehicle control. Furthermore, we identified that CS029 treatment could significantly decrease the infiltration of DCs, T cells and total immune cells into the CNS. Therefore, we suggested that CS029 treatment can be used as an immunosuppressive agent to inhibit DC functional maturation and then lead to the suppression of autoreactive T cell response, blockade of immune cells trafficking into CNS, and further mitigation of the symptoms of MS. This study elucidated the role of DCs in multiple sclerosis by CHM treatment, which may shed light on the development of new therapeutic approaches.
Efficacies of anti-CD20 antibody and Atacicept are differentially impacted by B Cell Maturation Antigen in neuro-autoimmunity
Authors: Kumar Gaurav , Ko Rose M , Axtell Robert C. 
Published: January 2023

Abstract
B cells have emerged as a therapeutic target for multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies are effective in treating MS. Yet, TACI-Ig treatment, which blocks BAFF and APRIL (two cytokines important for B cell development and function), paradoxically increased disease activity in MS patients. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and regulatory effects in MS. B cell Maturation Antigen (BCMA), a receptor that binds BAFF and APRIL, plays a prominent role in B cell function. The role BCMA plays in MS remains enigmatic and therefore we explored the impact BCMA deficiency has on the development and progression of the experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. We found that EAE induced with MOG35–55 was severe in BCMA−/− mice compared to BCMA+/+ mice. The increased disease was associated with increased CNS inflammation and a skewing of B-cells toward a mature/inflammatory phenotype. Also, for the first time, we observed that BCMA deficiency directly affects the infiltration of inflammatory myeloid cells during EAE. We found that anti-CD20 treatment significantly reduced EAE in BCMA−/− mice but had no effect on BCMA+/+ mice. Conversely, we found that TACI-Ig treatment had no effect on BCMA−/− mice but did reduce EAE in BCMA+/+ mice. Our study demonstrates that BAFF and APRIL constrain the development and function of inflammatory B-cells through BCMA. We further demonstrate that BCMA inhibits inflammatory B cell responses, yet promotes inflammatory responses in macrophages. Finally, our data provide clues into the paradoxical results of clinical trials with anti-CD20 and TACI-Ig in MS patients.
The significance of spontaneously immortalized B lymphocytes from patients with AIDS-related non-Hodgkin’s lymphoma and HIV-infected individuals
Authors: Zhuang Ke , Zhang Yongxi , Zhou Li , Qi Xiaoying , Xu Xiqiu , Meng Fengzhen , Xu Zhigao , Liu Jinbiao , Shao Liang , Xiong Yong , Ke Hengning , Gui Xien 
Published: January 2023

Abstract
Reliable tumor biomarkers for risk assessment, screening, detection, diagnosis, and prognosis remain an unmet need for patients with AIDS-Related Non-Hodgkin’s Lymphoma (AIDS-NHL) and its high risk population–HIV/AIDS patients. In this study, we generated spontaneously immortalized B lymphocyte cell (SIBC) lines by culturing peripheral blood mononuclear cells (PBMCs) derived from AIDS-NHL and HIV/AIDS patients, then evaluated their clinical significance for detection, diagnosis, and prognosis. From 34 AIDS-NHL and 71 HIV/AIDS patients, we generated 14 AIDS-NHL-SIBC and 6 HIV-SIBC lines, respectively. Among 14 AIDS-NHL-SIBC lines, 12 SIBCs were derived from patients with poor prognoses. All SIBCs presented main markers typical of memory B-cells (CD3−CD20+CD27+) and the majority of cells expressed NHL related immunologic proteins (BCL-2, MUM-1. Ki67, etc.). AIDS-NHL-SIBCs exhibited the typical biological characteristics of tumor cells, including monoclonal Ig gene rearrangement, abnormal chromosome, and growth of xenograft tumors in NOD/SCID mice, while HIV-SIBCs possessed partial tumor cell properties, but no xenograft tumors. These findings suggest that the AIDS-NHL-SIBC lines are representative of the malignant B-lymphocytes circulating in AIDS-NHL patients (CTC), while HIV-SIBC might be a CTC precursor in HIV/AIDS patients. These data provide evidence of a potentially valuable diagnostic and prognostic biomarker for AIDS-NHL patients, and present a basis for early screening of NHL among HIV/AIDS patients.
Low-dose neoadjuvant chemotherapy dominates Ki67− quiescent tumor dormancy for an effective immunotherapy of breast cancer
Authors: Aqbi Hussein , Coleman Cara , Idowu Michael , Manjili Masoud 
Published: January 2023

Abstract
Breast cancer mortality is mainly due to distant recurrence of the disease. The disease recurrence is usually because of the establishment of tumor dormancy following successful treatment of early stage breast cancer. In current clinical practice, dormant tumor cells are not actively treated, because they do not respond to chemotherapy or radiation therapies. Immunotherapeutic targeting of tumor dormancy is also challenging because of the induction of tumor immunoediting, leading to tumor escape and relapse. Recently, we have characterized Ki67− quiescent and Ki67low indolent types of tumor dormancy. We demonstrated that quiescent, but not indolent, dormant tumor cells fail to undergo immunoediting and remain highly susceptible to immunotherapy. Here, we sought to develop neoadjuvant therapies for dominating a quiescent type of tumor dormancy as the best target for immunotherapy. We showed that a low dose 5-FU+Adriamycin+Cyclophosphamide (FAC) dominated Ki67− quiescent type of tumor dormancy in the neu-overexpression mouse mammary carcinoma (MMC) tumor cells. These dormant cells were effectively controlled by immunotherapy in FVBN202 transgenic mouse model of spontaneous breast cancer. Since the antibiotic azithromycin has been shown to effectively eliminate senescent cells, we also sought to determine its efficacy against dormant tumor cells. We demonstrated that azithromycin specifically induced apoptosis in FAC-induced dormant tumor cells. All together, the results suggest that use of less toxic, low dose chemotherapy combined with azithromycin in a neoadjuvant setting could lead to the elimination of dormant tumor cells by immunotherapy.
PD-1 expressions on monocytes from patients with hepatocellular carcinoma differs depending on the progression of the cancer
Authors: OHAMA Hideko , Asai Akira , Tsuchimoto Yusuke , Fukunishi Shinya , Higuchi Kazuhide 
Published: January 2023

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world. Multifocal HCC often arise synchronously or metachronously, leading high mortality rates in HCC patients. Therefore, it is necessary to diagnose the progression for HCC and to appropriately treat it accordingly. In this study, we tried to analyze for immunological characters of monocytes isolated from several stages of HCC patients and examined whether these characters can be used as a new tumor marker for HCC.
From 2017 August to 2018 December, 35 patients of advanced-stage HCC and 33 patients of early-stage HCC were enrolled. Monocytes from peripheral blood of these patients were stained for anti-PD-1 antibody, anti-PD-L1 antibody and anti-PD-L2 antibody. These cells were analyzed for flow cytometry. Five healthy donors were used for the control groups.
In the results, monocytes from early-stage HCC patients were not express PD-L1 (2.9 ± 1.1%), and express few PD-L2 (43.4 ± 13.5%) and PD-1 (45.2 ± 15.1%). However, monocytes from advanced-stage HCC patients were expressed PD-L1 (75.3 ± 20.7%) and PD-L2 (74.7 ± 15.8%), but not PD-1(1.4 ± 1.1%). As the controls, monocytes from healthy donors were not expressed PD-L1 (21.7 ± 5.5%), PD-L2 (31.7 ± 23.8%) and PD-1 (11.6 ± 6.4%). When CD8− cells from advanced-stage HCC patients were co-cultured with monocytes from syngeneic patients, the turmoricidal activities of these cells were suppressed(15.7±7.5%). In contrast, CD8− cells from early-stage HCC, were co-cultured with syngeneic monocytes, kept turmoricidal activities.
In conclusions, PD-L1 expression in monocytes was increased, as HCC progressed and may be using a new marker of the classification for the progression in hepatocellular carcinoma.
Repression of osteopontin by IRF8 regulates a novel immunosuppressive checkpoint
Authors: Klement John David , Paschall Amy V , Redd Priscilla S. , Ibrahim Mohammed L. , Lu Chunwan , Yang Dafeng , Celis Esteban , Abrams Scott I , Ozato Keiko , Liu Kebin 
Published: January 2023

Abstract
While current immune checkpoint inhibitors (ICIs) have shown efficacy in a wide variety of human cancers, many patients and cancer types fail to respond to ICI immunotherapy, suggesting the presence of other immunoinhibitory checkpoints. We report here that a deficiency in the transcription factor interferon regulatory factor 8 (IRF8) led to a loss of function of cytotoxic T lymphocytes (CTLs) in both an allograft tumor and a peptide vaccine model. However, a T cell-specific knockout and a mixed chimera model demonstrated that IRF8 suppressed CTL activation through a CTL-extrinsic mechanism. This was found to be through IRF8-dependent suppression of the matricellular protein osteopontin (OPN). During colorectal cancer (CRC) development, IRF8 is downregulated in both tumor-associated CD11b+Ly6CloLy6Ghi myeloid cells and colon epithelial cells, where it represses OPN expression by binding to its promoter. Accordingly, in both mouse CRC models and human CRC patients, transcriptional downregulation of IRF8 was accompanied by an upregulation of OPN at the transcriptional and protein level. Enhanced levels of OPN were found to negatively correlate with patient survival. In vitro stimulation of mouse and human CTLs in the presence of OPN led to decreased activation and interferon gamma secretion. Similarly, deletion of spp1, which encodes for OPN, from murine CT26 colon adenocarcinoma cells caused increased susceptibility to CTL-mediated lysis and enhanced CTL activation. As such, tumor and myeloid-derived OPN may function as a novel immune checkpoint to restrain host CTL activation.