bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contrasting roles for IL-22 in DSS-induced colitis (38.7)
Authors: Smith Carole L , Rottman James B , Maxwell Joseph R 
Published: January 2023

Abstract
Interleukin (IL)-22 is a multifunctional cytokine with diverse biological activities which include involvement in the inflammatory response, tissue repair and pathogen defense. Recently, IL-22 was shown to be protective in two models of inflammatory bowel disease (IBD) in mice. In order to confirm those results and develop a reagent that could serve as a therapy, we generated IL-22-Fc which had an increased half-life relative to recombinant IL-22 (rIL-22). The effects of rIL-22 versus IL-22-Fc were compared in dextran sulphate sodium (DSS)-induced colitis. Prophylactic, but not therapeutic, administration of either rIL-22 or IL-22-Fc prevented disease and was significantly more efficacious than granulocyte macrophage colony stimulating factor (GM-CSF), a cytokine that has been used clinically in human IBD patients. The mechanism of the protective effect of IL-22 was in part driven by reduced circulating levels of inflammatory cytokines and enhanced proliferation/regeneration of the colonic epithelium. However, IL-22-Fc exacerbated weight loss and induced anemia. Thus, although prophylactic IL-22R stimulation protected animals from DSS-induced colitis, metabolic effects such as iron deficiency and weight loss complicate the benefit received. These data demonstrate that IL-22 can simultaneously play beneficial and detrimental roles in inflammatory diseases.
Lung Th17 inflammatory responses augment polymeric immunoglobulin receptor expression by the airway epithelium and promote B cell recruitment and increase in secretory IgA levels (39.10)
Authors: Jaffar Zeina , Ferrini Maria , Herritt Lou A. , Roberts Kevan 
Published: January 2023

Abstract
Polymeric immunoglobulin receptor (pIgR) is a central player in mucosal immunity that mediates delivery of polymeric IgA and IgM to the apical surface via transcytosis across the type I mucosal epithelium. Emerging evidence suggests that Th17 cells, characterized by their production of IL-17, not only mediate autoimmunity but also play key roles in mucosal host defense against extracellular microbes. We demonstrate that adoptive transfer of OVA-specific CD4+ Th17 cells into BALB/c mice, in addition to causing neutrophilic inflammation, mediated a pronounced influx of CD19+ B cells into the lungs following OVA inhalation. Coincident with the cellular recruitment, were the striking elevation in pIgR expression by the airway epithelium and the subsequent increase in IgM and secretory IgA levels. Intranasal administration of IL-17 revealed a key role for this cytokine in the upregulation of pIgR expression by the epithelium. Lung mucosal Th17 responses were markedly regulated by the transfer of antigen-specific CD4+CD25+Foxp3+ regulatory T cells whose suppressive function was restricted to the site of inflammation. These findings support a key role for IL-17-producing Th17 cells in mediating pulmonary immune defense against respiratory pathogens by promoting the expression of pIgR and subsequent transport of mucosal IgA and IgM into the airway lumen.
The impact of obesity on intestinal γδ T cell function (166.17)
Authors: Cheung Kitty , Jameson Julie 
Published: January 2023

Abstract
Populations of people struggling with obesity are reaching critical levels, spanning across the age and economic spectrum. Deterioration of the gut has been implicated in the exacerbation of obesity and metabolic diseases due to its role as the major tissue responsible for the absorption of nutrients. γδ T cells serve an important role in intestinal maintenance by repairing the gut epithelium through production of keratinocyte growth factor and regulating inflammation. We want to investigate the role of γδ IELs in the gut homeostasis and how their functions are altered due to obesity and chronic inflammation. Various obesity models were utilized including leptin receptor deficient mice (db/db), mice fed on a high fat diet (HFD), and γδ T cell deficient mice. Both FACs analysis and CD3 immunofluorescent staining show an overall decrease in T cell numbers in the gut of HFD mice. Surprisingly, αβ and γδ T cell populations are differentially susceptible to the effects of obesity. Through BrdU incorporation, we found that γδ T cells are better able to maintain homeostatic proliferation than αβ T cells. Phenotypic analysis of these IEL subsets may hint at further differences. These data confirm that obesity adversely affects T cell populations in the gut. We are currently investigating how IEL function is impacted by the chronic inflammatory environment and how dysfunctional IELs exacerbate the diabetic condition.
Novel method for the development of regulatory T cells (166.22)
Authors: Ebeling Cory , Ilarraza Ramses , Adamko Darryl 
Published: January 2023

Abstract
Background: Regulatory T cells (Treg) are important in the inhibition of inflammatory disorders, like asthma. Unfortunately, current protocols used to develop them in vitro for study rely on complicated cloning methods that may not represent biologically relevant Treg. LPS-free ovalbumin (OVA) given intranasal (i.n.) can induce mucosal tolerance in mice. Therefore, we hypothesized that Dendritic cells (DCs) taken from the draining lymph nodes (LNs) of mice given LPS-free OVA would induce Treg in vitro. Methods: Mice were given i.n. LPS-free OVA. 24 h later cervical and bronchial LNs were excised and DCs were isolated (~98% purity). DCs were cultured in vitro with transgenic OVA-specific T cells for four days. The development of Treg was assessed by flowcytometry (Foxp3 expression), ELISA (IL-10 production), and inhibition of T cell proliferation (CFSE staining/BrdU uptake). Finally, we studied the effectiveness of these cells to inhibit the development of AHR in a mouse model of asthma. Results: T cells from mice treated with LPS-free OVA showed high levels of Foxp3 expression, high IL-10 production, and the ability to inhibit OVA specific T cells in vitro. compared to control mice. Furthermore, T cells from LPS-free OVA treated mice prevented the development of AHR when given to mice before OVA challenge (i.n.). Conclusion: We believe our protocol could represent an alternative method to develop Treg cells for study.
Unique pathways of purinergic P2X7 receptor-mediated colonic mast cell activation in the intestinal inflammation (166.9)
Authors: Kurashima Yosuke , Amiya Takeaki , Kunisawa Jun , Kiyono Hiroshi 
Published: January 2023

Abstract
Accumulating evidence has demonstrated that purinergic signals by ATP and ADP induced the activation of immune cells through a wide variety of purinergic receptors and purine-metabolic ecto-enzymes. Here we show the P2X7 receptor-mediated activation of colonic mast cells in the induction of mast cell-mediated intestinal inflammation. Intestinal inflammation was ameliorated in MC-deficient KitW-sh/W-sh mice, and reconstitution with wild-type, but not P2x7-/-, MCs resulted in recovered susceptibility to inflammation. Intriguingly, colonic mast cells expressed both ATP-reactive P2X7 receptor and ADP-reactive P2Y receptors, but inhibition of P2Y receptors did not suppress ADP-mediated mast cell activation. Besides, inhibition of P2X7 receptor as well as adenylate kinase, an ecto-enzyme to convert ADP to ATP, reduced ADP-induced mast cell activation. These results suggest that mast cells have potential to produce ATP from ADP by adenylate kinase to enhance P2X7 receptor-mediated inflammatory response in the gut.
Implications of gut bacteria/dendritic cells interactions in development of Th17 lymphocytes and Type 1 Diabetes resistance (167.12)
Authors: Lau Kenneth , Ardissone Alexandria , Wilson Tenisha , Collins Erin , Lorca Graciela , Wasserfall Clive , Neu Josef , Atkinson Mark , Shatz Desmond , Triplett Eric , Larkin, III Joseph 
Published: January 2023

Abstract
Recent literature has suggested that Type 1 Diabetes (T1D) onset is negatively correlated to the presence of TH17 cells. Consistent with this notion, we observed that total lymph nodes isolated from NOD mice (which spontaneously develop T1D) produced lower levels of IL17 in vitro than from diabetes resistant NOR or C57BL/6 mice. Significantly, increasing evidence shows that gut bacteria are vital in the proper development of TH17 cells. Oral feedings of Lactobacillus johnsonii (LjN6.2), a strain isolated from the gut, has been shown to mediate T1D resistance and a TH17 bias. We used LjN6.2 to stimulate diabetes prone and resistant strains, measuring cytokine production and cell populations via flow cytometry. When equal numbers of T cells and antigen presenting cells (APCs) were incubated with LjN6.2, it was observed that NOD T cells were capable of producing abundant IL17. Because APCs in NOD mice are reduced in number and defective, we next analyzed whether this IL17 production was due to restored APC function by LjN6.2. APCs responded to LjN6.2 by producing extensive IL6 and upregulated MHCI, CD86, and CD80. We next tested if a footpad injected vaccine of LjN6.2 pulsed BMDCs could cause a TH17 bias in vitro. Indeed, splenocytes isolated from treated NOD mice showed increased production of IL6 and IL17. These studies present a possible role for gut flora in biasing T lymphocyte effector functions away from autoimmune diseases like T1D through dendritic cell modulation.
Role of myeloid-derived suppressor cells in type 1 diabetes (167.16)
Authors: Yen Chun-Yu , Chen Shu-Hsia , Pan Ping-Ying , Pan Chien-Yuan , Yang Wen-Chin 
Published: January 2023

Abstract
Type 1 diabetes is an autoimmune disease which are mainly caused by the autoimmune destruction of pancreatic islets. One of the most effective immunotherapy for type 1 diabetes (T1D) relies on the induction of peripheral tolerance. Accumulating data show that myeloid-derived suppressor cells (MDSCs) can suppress immune response through multiple strategies. In the study, we first showed MHC-dependent Ag presentation is required in MDSC-mediated Treg induction or T-cells suppression. The mechanism of action of MDSCs included the secretion of anti-inflammation cytokines, induction of CD4+CD25+Foxp3+ Treg and suppression of T-cell proliferation to create immune tolerance. Next, we examined the role of MDSCs in murine models. Adoptive transfer of MDSCs reduced diabetes by 75% compared with control group in RIP-HA/Rag2-/- mice. We further confirmed the protective role of MDSCs in NOD/scid mice. NOD/scid mice were injected with inflammatory T cells from diabetic NOD mice in the presence of MDSCs. Consistently, single-dose treatment of MDSCs showed significant long-term protection (60% remained diabetes free) and the protection effect is dose-dependent. Overall, the data suggest that MDSCs can suppress T1D via regulation of T cell-mediated tolerance. MDSCs have great potential to treat T1D and other autoimmune diseases.
B-cells are a therapeutic target for IFNβ in relapsing-remitting multiple sclerosis (167.17)
Authors: Marcus Karen , Ramgolam Vinod , Sha Yonggang , Choudhary Neelima , Troiani Luigi , Chopra Manisha , Markovic-Plese Silva 
Published: January 2023

Abstract
Background: IFNβ-1b is a first-line immunomodulatory therapy for relapsing remitting multiple sclerosis (RRMS), however its effects on B-cells have not been characterized. Methods: We have characterized the effect of the IFNβ-1b administered to RRMS patients on the B-cells’ antigen presenting capacity using allogenic MLR and cytokine secretion using ELISA. B-cells were derived from 7 treated and 7 untreated RRMS patients Results: B-cells derived from RRMS patients treated with recombinant subcutaneously injected IFNβ-1b revealed that they induced a significantly lower proliferative response in allogenic mixed lymphocyte reaction (MLR) than the B-cells from untreated patients (p=0.018). Further confirming the IFNβ-1b in-vitro induced changes in B-cell cytokine secretion that collectively inhibit Th17 cell differentiation, B-cells derived from the IFNβ-1b-treated patients secreted significantly lower levels of IL-1β(p=0.046) and IL-23(p=0.028), and higher levels of IL-12(p=0.046) and IL-27(p=0.028) in comparison to the B-cells derived from untreated RRMS patients.Conclusion: IFNβ-1b exerts its therapeutic effects in part by inhibiting B-cells’ antigen presenting capacity and by modifying their secretion of Th17-regulatory cytokines, which contribute to the autoimmune pathogenesis of RRMS.
CRP-mediated reduction of EAE severity is FcγRIIb dependent (167.18)
Authors: Wright Tyler , Jones Nicholas , Ramos Theresa , McCrory Mark , Szalai Alexander 
Published: January 2023

Abstract
Blood levels of human C-reactive protein (CRP), the prototypical acute phase protein, elevate in response to inflammatory stimuli. Previously, our lab has shown that elevation of transgene-expressed human CRP is protective in mice with experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). Specifically, EAE onset is delayed and its clinical severity reduced in human CRP transgenic mice (CRPTg) compared to wildtype mice. Since human CRP is known to bind human and mouse Fc receptors (FcR), we sought to determine which FcRs, if any, might be required for human CRP-mediated protection from EAE. To do so, we induced EAE in CRPTg mice with normal FcR expression versus CRPTg mice deficient in expression of FcγRI, FcγRIIb, or FcγRIII. Time of EAE onset and clinical severity of disease were monitored for 30 days. We observed that in CRPTg mice deficient in the excitatory Fc receptors, FcγRI and FcγRIII, CRP’s full protective effect was still manifest. In stark contrast, for CRPTg mice deficient in the inhibitory Fc receptor, FcγRIIb, no human CRP dependent protection was evident. Furthermore, in wildtype mice with established EAE subcutaneous administration of purified human CRP stalled disease progression, whereas the same treatment did not impede EAE progression in FcγRIIB deficient mice. These results suggest that a human CRP→mouse FcγRIIB axis is responsible for the observed protection of human in the CRPTg model.
Indispensable role of B cells in mediating protective effects of estrogen against EAE (167.20)
Authors: Bodhankar Sheetal , Wang Chunhe , Vandenbark Arthur , Offner Halina 
Published: January 2023

Abstract
Increased remissions in multiple sclerosis (MS) during pregnancy suggest elevated levels of sex steroids exert immunoregulatory activity. Estrogen (E2) protects against experimental autoimmune encephalomyelitis (EAE), but its mechanism is unclear. Depletion of B cells prior to induction of EAE exacerbates disease severity. The purpose of this study was to evaluate role of B cells in E2-induced protection against EAE. B cell deficient (μMT-/-) mice were used to study whether absence of B cells abrogated E2-mediated protection against EAE. Mice were sham-treated or implanted with E2 pellets, 8 days prior to immunization with mMOG35-55 peptide with CFA/Ptx and the disease course was followed. EAE-protective effects of E2 were totally lost in μMT-/- mice, with no reduction in disease severity, cellular infiltration or pro-inflammatory factors in CNS compared to controls. E2 treatment of WT mice selectively increased percentage expression of PD-L1 on B cells and IL-10-producing CD1dhighCD5+ regulatory B cells. Direct treatment of B cells with E2 significantly reduced proliferation of MOG35-55-specific T cells that required ERα. Thus, B cells play an indispensable role in E2-mediated protection involving direct E2 effects on regulatory B cells. E2-primed B cells may play a crucial regulatory role in MS and have strong implications in current MS therapies that cause B cell-depletion.
Adipose tissue-derived mesenchymal stem cells ameliorate experimental autoimmune hearing loss (167.23)
Authors: Zhou Bin , Yuan Jingdong , Zhou Yixuan , Ghawji Maher , Yoo Tai 
Published: January 2023

Abstract
Objective Autoimmune inner ear disease (AIED) is characterized by progressive, bilateral although asymmetric, and sensorineural hearing loss; there are no specific therapeutic strategies to treat AIED. However, human adipose-derived mesenchymal stem cells (hASCs) are a promising approach for the treatment of autoimmune diseases due to their immune modulatory effects and regenerative potential. Methods BALB/c mice underwent β-tubulin immunization to develop EAHL; and then administered hASCs or PBS intraperitoneally once a week for 6 consecutive weeks. Results Systemic infusion of hASCs significantly improved hearing function in established EAHL. hASCs decreased the proliferation of antigen-specific Th1/Th17 cells and induced the production of anti-inflammatory cytokine IL-10. hASCs also induced the generation of antigen-specific CD4+CD25+Foxp3+ Treg cells, with the capacity to suppress autoantigen-specific T cell responses. Moreover, we tested the presence of HLA-ABC by confocal analysis found that hASCs migrated to inner ear including the stris vascularis and spiral ligament. By histology, we confirmed that hASCs treatment correlated with the repair process of morphological recovery in the inner ear, while the cochlea of control mice remained seriously damaged. Conclusion We show that hASCs have therapeutic potential by a bimodal mechanism, by suppressing the autoimmune response of EAHL as well as by inducing repair of cochlea in animals with established disease.
Programmed death-1 promotes tolerance by blocking the T cell receptor-induced stop signal. (167.26)
Authors: Fife Brian , Pauken Kristen , Obu Takashi 
Published: January 2023

Abstract
Programmed death-1 (PD-1) and CTLA-4 are inhibitory receptors expressed on activated T cells that are critical for preventing autoimmunity. However, the biological context in which PD-1 and CTLA-4 control T cell tolerance is not fully understood. In this study we used an antigen specific diabetes model and T cell dynamic motility during the induction and maintenance of tolerance in vivo by two-photon imaging. Using this system we demonstrate that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. However, blocking interactions between PD-1 and PD-L1 altered the dynamic T cell motility and caused the breakdown in peripheral tolerance resulting in autoimmune diabetes. Neutralizing CTLA-4, on the other hand, did not impact tolerized T cell motility in vivo or clinical disease. The ability of PD-1 to influence the T-cell stop signal was antigen dependent, since T cell motility and T cell-DC contact times were unaffected by PD-L1 neutralization in non-draining (inguinal) LNs. These data provide in vivo evidence that PD-1 -PD-L1 interactions are critical for the maintenance of peripheral tolerance and prevention of autoimmunity. Further, the effects of PD-1 are fundamentally distinct from those of CTLA-4 and suggest unique mechanisms of action for these two inhibitory receptors.
miRNA modulation of T cell phenotype in Multiple Sclerosis (167.3)
Authors: Guerau-de-Arellano Mireia , Smith Kristen Marie , Godlewski Jakub , Lawler Sean , Whitacre Caroline , Racke Michael K. , Lovett-Racke Amy E. 
Published: January 2023

Abstract
Pro-inflammatory T cells mediate autoimmune demyelination in Multiple Sclerosis (MS). However, the factors driving their development and MS susceptibility are obscure. We investigated how miRNAs, newly described as post-transcriptional regulators of gene expression, contribute to pathogenic T cell differentiation in MS. We profiled miRNA expression in naïve CD4+ T cells of healthy (n=8) and untreated MS (n=22) donors. miR-128, miR-27a/b and miR-340 were increased in naïve CD4+ T cells from MS patients. miR-128, -27a/b and -340 directly suppressed the pro-Th2 factor Bmi1, resulting in decreased GATA-3 expression. miR-340 additionally suppressed the Th2 cytokine IL-4. Overall, these miRNAs suppressed Th2 and enhanced pro-inflammatory Th1 responses. In addition, transfection of myelin-specific T cells with these miRNAs worsened EAE while treatment of MS patient cells with miRNA inhibitors led to the restoration of Th2 responses. These findings link miR-128, -27ab and -340 overexpression in MS patients’ naïve CD4+ T cells to the pro-inflammatory T cell differentiation observed in MS and illustrate the biological significance and therapeutic potential of these miRNAs.
Altered miRNA expression in splenic lymphocytes in autoimmune-prone murine models with active lupus disease (167.9)
Authors: Dai Rujuan , Heid Bettina , Khan Deena , Ahmed S. Ansar 
Published: January 2023

Abstract
There is markedly increased recognition of physiological and pathological roles of miRNAs in immune system that impacts health and disease. While numerous dysregulated miRNAs were identified in autoimmune diseases, the significance of most disease-related miRNAs remains elusive. We have recently reported that selective miRNAs including the miR-182-96-183 cluster were commonly dysregulated in splenocytes from MRL-lpr, C57BL/6-lpr and NZB/WF1 mice when compared to control mice. Also, we have shown that the dysregulation of these miRNAs was associated with lupus disease development. In current study, we investigated the potential pathogenic contribution of lupus-associated miRNAs. The previous reports have shown that miR-182 and miR-96 target Foxo1 and Foxo3a, which play critical roles in controlling T lymphocyte homeostasis and tolerance. Consistent with the upregulation of miR-182-96-183, we found that Foxo3a and Foxo1 protein levels were inhibited in splenocytes from MRL-lpr mice when compared to MRL mice. However, the Real-time RT-PCR revealed that only Foxo1 mRNA, but not Foxo3a mRNA level was decreased in splenocytes from MRL-lpr mice, suggesting a post-transcriptional regulation of Foxo3a in splenocytes from lpr mice. Together, our data suggested a potential pathogenic contribution of miR-182 to lupus by targeting Foxo1 and Foxo3a, which could conceivably lead to the abnormal lymphocytes activation and autoimmunity development.
Immune regulatory mechanism in mouse IBD model (168.26)
Authors: Cho Kyung-Ah , Suh Jee Won , Woo So-Youn 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) in humans, such as Crohn’s disease and ulcerative colitis, is characterized by chronic inflammation with dysregulated mucosal immune tolerance. Some reported that immune responses to intestinal microbiota are critical to develop IBD and NOD-like receptor-mediated inflammasome is related to epithelial integrity. In order to investigate dysregulated mechanism focusing on the relationship between inflammasome and regulatory cells in IBD, we used a 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model in WT-C57BL/6 mice and caspase-1-/- mice. In addition, to observe Th2-dependent immune responses in IBD mouse, we also used WT-Balb/c mice and eosinophil-deficient ΔdblGATA mice. As a result, mice treated TNBS had significant changes in clinical parameters, weight loss, and colonic weights compared with those of sham control mice. Histologic analysis also showed severe inflammation in intestines of TNBS treated mice. We found that deficiency of eosinophil or IL-1β had resistance in initial stage of disease progression, represented by survival score and body weight loss and we also noted that proportion of Foxp3+ cells and myeloid-derived suppressor cells (MDSCs) increased in above TNBS-treated ΔdblGATA and caspase-1-/- mice. These results provide us another mechanism of immune modulation in the pathogenesis of intestinal inflammation.