356 results on '"Blumberg RS"'
Search Results
2. 'ER stress(ed out)!': Paneth cells and ischemia-reperfusion injury of the small intestine
- Author
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Kaser A, Tomczak M, and Blumberg RS
- Published
- 2011
3. Endoplasmic reticulum stress: implications for inflammatory bowel disease pathogenesis.
- Author
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Kaser A, Martínez-Naves E, Blumberg RS, Kaser, Arthur, Martínez-Naves, Eduardo, and Blumberg, Richard S
- Published
- 2010
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4. Adaptive immunity in inflammatory bowel disease: state of the art.
- Author
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Kaser A and Blumberg RS
- Published
- 2008
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5. Immunolocalization of CD1d in human intestinal epithelial cells and identification of a β2-microglobulin-associated form.
- Author
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Somnay-Wadgaonkar, K, Nusrat, A, Kim, HS, Canchis, WP, Balk, SP, Colgan, SP, and Blumberg, RS
- Abstract
In order to better understand the role of intestinal CD1d, we sought to define the cellular localization and further characterize the biochemical structure of CD1d in human intestinal epithelial cells (IEC). Using a CD1d-specific rabbit anti-gst-CD1d antibody, immunoprecipitation of radiolabeled cell surface proteins detected a previously identified 37 kDa protein as well as a 48-50 kDa protein which were confirmed by Western blotting with a CD1d-specific mAb, D5. Immunoprecipitation of protein lysates with the CD1d-specific mAb, D5 and 51.1.3, and the β2-microglobulin (β2m)-specific mAb, BBM.1, followed by N-glycanase digestion and Eastern blotting with the D5 mAb showed that the 48-50 kDa protein was a β2m-associated, CD1d glycoprotein. CD1d was immunolocalized to the apical and lateral regions of native small and large intestinal IEC as defined by confocal laser microscopy using the D5 mAb and the rabbit anti-gst-CD1d antibody. In addition, a large apical intracellular pool of CD1d was identified. Identical observations were made with polarized T84 cells. Selective biotin labeling of apical and basolateral cell surfaces followed by immunoprecipitation with the D5 mAb, N-glycanase digestion and avidin blotting confirmed the presence of glycosylated CD1d on both cell surfaces and immunolocalization of the 37 kDa non-glycosylated form of CD1d to the apical cell surface. These studies show that CD1d is located in an ideal position for luminal antigen sampling and presentation to subjacent intraepithelial lymphocytes. [ABSTRACT FROM PUBLISHER]
- Published
- 1999
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6. Biliary glycoprotein (BGP;CD66a) functions as an inhibitory coreceptor for activation of human intestinal intraepithelial lymphocytes (iIEL)
- Author
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Morales, V, Christ, A, Watt, S, Russell, G, Bahn, AK, Mizoguchi, A, Freeman, G, and Blumberg, RS
- Published
- 1998
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7. Paneth cell TNF signaling induces gut bacterial translocation and sepsis.
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Wallaeys C, Garcia-Gonzalez N, Timmermans S, Vandewalle J, Vanderhaeghen T, De Beul S, Dufoor H, Eggermont M, Moens E, Bosteels V, De Rycke R, Thery F, Impens F, Verbanck S, Lienenklaus S, Janssens S, Blumberg RS, Iwawaki T, and Libert C
- Abstract
The cytokine tumor necrosis factor (TNF) plays important roles in limiting infection but is also linked to sepsis. The mechanisms underlying these paradoxical roles are unclear. Here, we show that TNF limits the antimicrobial activity of Paneth cells (PCs), causing bacterial translocation from the gut to various organs. This TNF-induced lethality does not occur in mice with a PC-specific deletion in the TNF receptor, P55. In PCs, TNF stimulates the IFN pathway and ablates the steady-state unfolded protein response (UPR), effects not observed in mice lacking P55 or IFNAR1. TNF triggers the transcriptional downregulation of IRE1 key genes Ern1 and Ern2, which are key mediators of the UPR. This UPR deficiency causes a significant reduction in antimicrobial peptide production and PC antimicrobial activity, causing bacterial translocation to organs and subsequent polymicrobial sepsis, organ failure, and death. This study highlights the roles of PCs in bacterial control and therapeutic targets for sepsis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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8. IL-22 promotes mucin-type O-glycosylation and MATH1 + cell-mediated amelioration of intestinal inflammation.
- Author
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Singh A, Beaupre M, Villegas-Novoa C, Shiomitsu K, Gaudino SJ, Tawch S, Damle R, Kempen C, Choudhury B, McAleer JP, Sheridan BS, Denoya P, Blumberg RS, Hearing P, Allbritton NL, and Kumar P
- Published
- 2024
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9. The fate of secretory cells during intestinal homeostasis, regeneration, and tumor formation is regulated by Tcf4.
- Author
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Janeckova L, Stastna M, Hrckulak D, Berkova L, Kubovciak J, Onhajzer J, Kriz V, Dostalikova S, Mullerova T, Vecerkova K, Tenglerova M, Coufal S, Kostovcikova K, Blumberg RS, Filipp D, Basler K, Valenta T, Kolar M, and Korinek V
- Abstract
The single-layer epithelium of the gastrointestinal tract is a dynamically renewing tissue that ensures nutrient absorption, secretory and barrier functions and is involved in immune responses. The basis for this homeostatic renewal is the Wnt signaling pathway. Blocking this pathway can lead to epithelial damage, while its abnormal activation can result in the development of intestinal tumors. In this study, we investigated the dynamics of intestinal epithelial cells and tumorigenesis using a conditional mouse model. Using single-cell and bulk RNA sequencing and histological analysis, we elucidated the cellular responses following the loss of specific cell types. We focused on the fate of cells in the lower parts of the intestinal crypts and the development of colon adenomas. By partially inactivating the transcription factor Tcf4, a key effector of the Wnt signaling pathway, we analyzed the regeneration of isolated hyperproliferative foci (crypts). Our results suggest that the damaged epithelium is not restored by a specific regeneration program associated with oncofetal gene production, but rather by a standard homeostatic renewal pathway. Moreover, disruption of Tcf4 in secretory progenitors resulted in a significant shift in the cell lineage from Paneth cells to goblet cells, characterized by morphological changes and loss of Paneth cell-specific genes. We also found that hyperactivation of the Wnt signaling pathway in colonic adenomas correlated with the upregulation of genes typical of Paneth cells in the intestine, followed by the emergence of secretory tumor cells producing the Wnt3 ligand. The absence of Tcf4 led to a phenotypic shift of the tumor cells towards goblet cells. Our study presents a new model of epithelial regeneration based on the genetically driven partial elimination of intestinal crypts. We highlight the critical role of Tcf4 in the control of cell lineage decisions in the intestinal epithelium and colon tumors.
- Published
- 2024
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10. High-dimensional mapping of human CEACAM1 expression on immune cells and association with melanoma drug resistance.
- Author
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Huang YH, Yoon CH, Gandhi A, Hanley T, Castrillon C, Kondo Y, Lin X, Kim W, Yang C, Driouchi A, Carroll M, Gray-Owen SD, Wesemann DR, Drake CG, Bertagnolli MM, Beauchemin N, and Blumberg RS
- Abstract
Background: Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood., Methods: An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with
159 Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed., Results: CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells., Conclusions: To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies., (© 2024. The Author(s).)- Published
- 2024
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11. Author Correction: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.
- Author
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Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A, Dougan SK, Petersen BS, Melum E, Pertel T, Clayton KL, Raab M, Chen Q, Beauchemin N, Yazaki PJ, Pyzik M, Ostrowski MA, Glickman JN, Rudd CE, Ploegh HL, Franke A, Petsko GA, Kuchroo VK, and Blumberg RS
- Published
- 2024
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12. IgG exacerbates genital chlamydial pathology in females by enhancing pathogenic CD8 + T cell responses.
- Author
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Armitage CW, O'Meara CP, Bryan ER, Kollipara A, Trim LK, Hickey D, Carey AJ, Huston WM, Donnelly G, Yazdani A, Blumberg RS, and Beagley KW
- Subjects
- Humans, Female, Male, Animals, Mice, CD8-Positive T-Lymphocytes, Immunoglobulin G, Genitalia, Chlamydia, Infertility
- Abstract
Chlamydia trachomatis infections are an important sexually transmitted infection that can lead to inflammation, scarring and hydrosalpinx/infertility. However, infections are commonly clinically asymptomatic and do not receive treatment. The underlying cause of asymptomatic immunopathology remains unknown. Here, we demonstrate that IgG produced during male infection enhanced the incidence of immunopathology and infertility in females. Human endocervical cells expressing the neonatal Fc Receptor (FcRn) increased translocation of human IgG-opsonized C. trachomatis. Using total IgG purified from infected male mice, we opsonized C. muridarum and then infected female mice, mimicking sexual transmission. Following infection, IgG-opsonized Chlamydia was found to transcytose the epithelial barrier in the uterus, where it was phagocytosed by antigen-presenting cells (APCs) and trafficked to the draining lymph nodes. APCs then expanded both CD4
+ and CD8+ T cell populations and caused significantly more infertility in female mice infected with non-opsonized Chlamydia. Enhanced phagocytosis of IgG-opsonized Chlamydia significantly increased pro-inflammatory signalling and T cell proliferation. As IgG is transcytosed by FcRn, we utilized FcRn-/- mice and observed that shedding kinetics of Chlamydia were only affected in FcRn-/- mice infected with IgG-opsonized Chlamydia. Depletion of CD8+ T cells in FcRn-/- mice lead to a significant reduction in the incidence of infertility. Taken together, these data demonstrate that IgG seroconversion during male infection can amplify female immunopathology, dependent on FcRn transcytosis, APC differentiation and enhanced CD8 T cell responses., (© 2023 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)- Published
- 2024
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13. Interplay of gut microbiota and host epithelial mitochondrial dysfunction is necessary for the development of spontaneous intestinal inflammation in mice.
- Author
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Alula KM, Dowdell AS, LeBere B, Lee JS, Levens CL, Kuhn KA, Kaipparettu BA, Thompson WE, Blumberg RS, Colgan SP, and Theiss AL
- Subjects
- Humans, Animals, Mice, Inflammation metabolism, Paneth Cells, Butyrates metabolism, Mitochondria metabolism, Intestinal Mucosa metabolism, Crohn Disease, Gastrointestinal Microbiome, Ileitis metabolism, Inflammatory Bowel Diseases metabolism
- Abstract
Background: Intestinal epithelial cell (IEC) mitochondrial dysfunction involvement in inflammatory bowel diseases (IBD), including Crohn's disease affecting the small intestine, is emerging in recent studies. As the interface between the self and the gut microbiota, IECs serve as hubs of bidirectional cross-talk between host and luminal microbiota. However, the role of mitochondrial-microbiota interaction in the ileum is largely unexplored. Prohibitin 1 (PHB1), a chaperone protein of the inner mitochondrial membrane required for optimal electron transport chain function, is decreased during IBD. We previously demonstrated that mice deficient in PHB1 specifically in IECs (Phb1
i∆IEC ) exhibited mitochondrial impairment, Paneth cell defects, gut microbiota dysbiosis, and spontaneous inflammation in the ileum (ileitis). Mice deficient in PHB1 in Paneth cells (epithelial secretory cells of the small intestine; Phb1∆PC ) also exhibited mitochondrial impairment, Paneth cell defects, and spontaneous ileitis. Here, we determined whether this phenotype is driven by Phb1 deficiency-associated ileal microbiota alterations or direct effects of loss of PHB1 in host IECs., Results: Depletion of gut microbiota by broad-spectrum antibiotic treatment in Phb1∆PC or Phb1i∆IEC mice revealed a necessary role of microbiota to cause ileitis. Using germ-free mice colonized with ileal microbiota from Phb1-deficient mice, we show that this microbiota could not independently induce ileitis without host mitochondrial dysfunction. The luminal microbiota phenotype of Phb1i∆IEC mice included a loss of the short-chain fatty acid butyrate. Supplementation of butyrate in Phb1-deficient mice ameliorated Paneth cell abnormalities and ileitis. Phb1-deficient ileal enteroid models suggest deleterious epithelial-intrinsic responses to ileal microbiota that were protected by butyrate., Conclusions: These results suggest a mutual and essential reinforcing interplay of gut microbiota and host IEC, including Paneth cell, mitochondrial health in influencing ileitis. Restoration of butyrate is a potential therapeutic option in Crohn's disease patients harboring epithelial cell mitochondrial dysfunction. Video Abstract., (© 2023. The Author(s).)- Published
- 2023
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14. IL-22: Immunity's bittersweet symphony.
- Author
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Duan J, Matute JD, and Blumberg RS
- Subjects
- Genes, MHC Class II, Interleukin-22, Interleukins, Epithelial Cells
- Abstract
Epithelial cells play a crucial role in barrier defense. Here, Moniruzzaman et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230106) discovered that interleukin-22 (IL-22) represses MHC class II expression by epithelial cells with an opposite impact on chronic inflammatory disease and viral infection., (© 2023 Duan et al.)
- Published
- 2023
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15. T Cell CEACAM1-TIM-3 Crosstalk Alleviates Liver Transplant Injury in Mice and Humans.
- Author
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Kojima H, Kadono K, Hirao H, Dery KJ, Torgerson T, Yao S, Kaldas FM, Farmer DG, Blumberg RS, and Kupiec-Weglinski JW
- Subjects
- Humans, Mice, Animals, Hepatitis A Virus Cellular Receptor 2 genetics, Hepatitis A Virus Cellular Receptor 2 metabolism, T-Lymphocytes, NF-kappa B metabolism, Living Donors, Liver metabolism, Mice, Knockout, Transcription Factors metabolism, Mice, Inbred C57BL, Liver Transplantation, Liver Diseases
- Abstract
Background & Aims: Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) acts through homophilic and heterophilic interactions with T cell immunoglobulin domain and mucin domain-containing protein 3 (TIM-3), which regulates innate immune activation in orthotopic liver transplantation (OLT). We investigated whether cluster of differentiation (CD) 4
+ T cell-dependent CC1-TIM-3 crosstalk may affect OLT outcomes in mice and humans., Methods: Wild-type (WT) and CC1-deficient (CC1 knock-out [KO]) mouse livers were transplanted into WT, CC1KO, or T-cell TIM-3 transgenic (TIM-3Tg)/CC1KO double-mutant recipients. CD4+ T cells were adoptively transferred into T/B cell-deficient recombination activating gene 2 protein (Rag2) KO recipients, followed by OLT. The perioperative liver-associated CC1 increase was analyzed in 50 OLT patients., Results: OLT injury in WT livers deteriorated in CC1KO compared with CC1-proficient (WT) recipients. The frequency of TIM-3+ CD4+ T cells was higher in WT than CC1KO hosts. Reconstitution of Rag2KO mice with CC1KO-T cells increased nuclear factor (NF)-κB phosphorylation and OLT damage compared with recipients repopulated with WT T cells. T-cell TIM-3 enhancement in CC1KO recipients (WT → TIM3Tg/CC1KO) suppressed NF-κB phosphorylation in Kupffer cells and mitigated OLT injury. However, TIM-3-mediated protection was lost by pharmacologic TIM-3 blockade or an absence of CC1 in the donor liver (CC1KO → TIM-3Tg/CC1KO). The perioperative CC1 increase in human OLT reduced hepatocellular injury, early allograft dysfunction, and the cumulative rejection rate., Conclusions: This translational study identifies T cell-specific CC1 signaling as a therapeutic means to alleviate OLT injury by promoting T cell-intrinsic TIM-3, which in turn interacts with liver-associated CC1 to suppress NF-κB in Kupffer cells. By suppressing peritransplant liver damage, promoting T-cell homeostasis, and improving OLT outcomes, recipient CC1 signaling serves as a novel cytoprotective sentinel., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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16. Characterizing CD4 T cell differentiation in mouse small intestine using T cell transfer, lamina propria preparation, and flow cytometry.
- Author
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Duan J, Sun Y, Matute JD, and Blumberg RS
- Subjects
- Animals, Mice, Flow Cytometry, Cell Differentiation, Intestine, Small, CD4-Positive T-Lymphocytes, Mucous Membrane
- Abstract
Studying gene function in T cells is crucial for understanding physiology and disease pathogenesis. Here, we provide a protocol to examine the role of specific genes in CD4
+ T cell differentiation in the intestine. We describe steps for isolating naïve CD4+ T cells from mouse spleens and transferring them to recipient mice. We detail procedures to isolate lamina propria cells and analyze CD4+ T subsets using flow cytometry. This protocol is useful in the study of mucosal immune functions. For complete details on the use and execution of this protocol, please refer to Duan et al.1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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17. The therapeutic age of the neonatal Fc receptor.
- Author
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Pyzik M, Kozicky LK, Gandhi AK, and Blumberg RS
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- Infant, Newborn, Humans, Histocompatibility Antigens Class I, Antigens, Immunoglobulin G, Receptors, Fc metabolism
- Abstract
IgGs are essential soluble components of the adaptive immune response that evolved to protect the body from infection. Compared with other immunoglobulins, the role of IgGs is distinguished and enhanced by their high circulating levels, long half-life and ability to transfer from mother to offspring, properties that are conferred by interactions with neonatal Fc receptor (FcRn). FcRn binds to the Fc portion of IgGs in a pH-dependent manner and protects them from intracellular degradation. It also allows their transport across polarized cells that separate tissue compartments, such as the endothelium and epithelium. Further, it is becoming apparent that FcRn functions to potentiate cellular immune responses when IgGs, bound to their antigens, form IgG immune complexes. Besides the protective role of IgG, IgG autoantibodies are associated with numerous pathological conditions. As such, FcRn blockade is a novel and effective strategy to reduce circulating levels of pathogenic IgG autoantibodies and curtail IgG-mediated diseases, with several FcRn-blocking strategies on the path to therapeutic use. Here, we describe the current state of knowledge of FcRn-IgG immunobiology, with an emphasis on the functional and pathological aspects, and an overview of FcRn-targeted therapy development., (© 2023. Springer Nature Limited.)
- Published
- 2023
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18. Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress.
- Author
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Martín-Adrados B, Wculek SK, Fernández-Bravo S, Torres-Ruiz R, Valle-Noguera A, Gomez-Sánchez MJ, Hernández-Walias JC, Ferreira FM, Corraliza AM, Sancho D, Esteban V, Rodriguez-Perales S, Cruz-Adalia A, Nakaya HI, Salas A, Bernardo D, Campos-Martín Y, Martínez-Zamorano E, Muñoz-López D, Gómez Del Moral M, Cubero FJ, Blumberg RS, and Martínez-Naves E
- Subjects
- Humans, Caco-2 Cells, Thapsigargin, Endoplasmic Reticulum Stress genetics, Epithelial Cells metabolism, Hydroxymethylglutaryl-CoA Synthase, Colitis, Ulcerative pathology, Inflammatory Bowel Diseases metabolism
- Abstract
Introduction: The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease., Methods: We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells., Results: Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines., Conclusion: We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2 , a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Martín-Adrados, Wculek, Fernández-Bravo, Torres-Ruiz, Valle-Noguera, Gomez-Sánchez, Hernández-Walias, Ferreira, Corraliza, Sancho, Esteban, Rodriguez-Perales, Cruz-Adalia, Nakaya, Salas, Bernardo, Campos-Martín, Martínez-Zamorano, Muñoz-López, Gómez del Moral, Cubero, Blumberg and Martínez-Naves.)
- Published
- 2023
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19. Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.
- Author
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Duan J, Matute JD, Unger LW, Hanley T, Schnell A, Lin X, Krupka N, Griebel P, Lambden C, Sit B, Grootjans J, Pyzik M, Sommer F, Kaiser S, Falk-Paulsen M, Grasberger H, Kao JY, Fuhrer T, Li H, Paik D, Lee Y, Refetoff S, Glickman JN, Paton AW, Bry L, Paton JC, Sauer U, Macpherson AJ, Rosenstiel P, Kuchroo VK, Waldor MK, Huh JR, Kaser A, and Blumberg RS
- Subjects
- Cell Differentiation, Humans, Animals, Mice, Mice, Transgenic, Anti-Bacterial Agents pharmacology, Endoplasmic Reticulum Stress drug effects, Intestinal Mucosa drug effects, Intestinal Mucosa metabolism, Th17 Cells cytology, Th17 Cells metabolism
- Abstract
Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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20. Intelectin-1 binds and alters the localization of the mucus barrier-modifying bacterium Akkermansia muciniphila.
- Author
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Matute JD, Duan J, Flak MB, Griebel P, Tascon-Arcila JA, Doms S, Hanley T, Antanaviciute A, Gundrum J, Mark Welch JL, Sit B, Abtahi S, Fuhler GM, Grootjans J, Tran F, Stengel ST, White JR, Krupka N, Haller D, Clare S, Lawley TD, Kaser A, Simmons A, Glickman JN, Bry L, Rosenstiel P, Borisy G, Waldor MK, Baines JF, Turner JR, and Blumberg RS
- Subjects
- Humans, Mice, Animals, Mucus metabolism, Lectins, Verrucomicrobia metabolism, Colitis, Ulcerative metabolism, Colitis, Ulcerative microbiology, Colitis, Ulcerative pathology
- Abstract
Intelectin-1 (ITLN1) is a lectin secreted by intestinal epithelial cells (IECs) and upregulated in human ulcerative colitis (UC). We investigated how ITLN1 production is regulated in IECs and the biological effects of ITLN1 at the host-microbiota interface using mouse models. Our data show that ITLN1 upregulation in IECs from UC patients is a consequence of activating the unfolded protein response. Analysis of microbes coated by ITLN1 in vivo revealed a restricted subset of microorganisms, including the mucolytic bacterium Akkermansia muciniphila. Mice overexpressing intestinal ITLN1 exhibited decreased inner colonic mucus layer thickness and closer apposition of A. muciniphila to the epithelial cell surface, similar to alterations reported in UC. The changes in the inner mucus layer were microbiota and A. muciniphila dependent and associated with enhanced sensitivity to chemically induced and T cell-mediated colitis. We conclude that by determining the localization of a select group of bacteria to the mucus layer, ITLN1 modifies this critical barrier. Together, these findings may explain the impact of ITLN1 dysregulation on UC pathogenesis., (© 2022 Matute et al.)
- Published
- 2023
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21. The γδ IEL effector API5 masks genetic susceptibility to Paneth cell death.
- Author
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Matsuzawa-Ishimoto Y, Yao X, Koide A, Ueberheide BM, Axelrad JE, Reis BS, Parsa R, Neil JA, Devlin JC, Rudensky E, Dewan MZ, Cammer M, Blumberg RS, Ding Y, Ruggles KV, Mucida D, Koide S, and Cadwell K
- Subjects
- Animals, Humans, Mice, Cell Death, Intestinal Mucosa pathology, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, Cell Survival, Organoids, Alleles, Apoptosis Regulatory Proteins metabolism, Crohn Disease genetics, Crohn Disease metabolism, Crohn Disease pathology, Genetic Predisposition to Disease genetics, Nuclear Proteins metabolism, Paneth Cells pathology, Intraepithelial Lymphocytes immunology, Intraepithelial Lymphocytes metabolism
- Abstract
Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn's disease, a major type of inflammatory bowel disease
1-7 . Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium8,9 . This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn's disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte-epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1 risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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22. Structural analysis of human CEACAM1 oligomerization.
- Author
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Gandhi AK, Sun ZJ, Huang YH, Kim WM, Yang C, Petsko GA, Beauchemin N, and Blumberg RS
- Subjects
- Binding Sites, Carbohydrates, Humans, Antigens, CD metabolism, Cell Adhesion Molecules metabolism
- Abstract
The human (h) CEACAM1 GFCC' face serves as a binding site for homophilic and heterophilic interactions with various microbial and host ligands. hCEACAM1 has also been observed to form oligomers and micro-clusters on the cell surface which are thought to regulate hCEACAM1-mediated signaling. However, the structural basis for hCEACAM1 higher-order oligomerization is currently unknown. To understand this, we report a hCEACAM1 IgV oligomer crystal structure which shows how GFCC' face-mediated homodimerization enables highly flexible ABED face interactions to arise. Structural modeling and nuclear magnetic resonance (NMR) studies predict that such oligomerization is not impeded by the presence of carbohydrate side-chain modifications. In addition, using UV spectroscopy and NMR studies, we show that oligomerization is further facilitated by the presence of a conserved metal ion (Zn
++ or Ni++ ) binding site on the G strand of the FG loop. Together these studies provide biophysical insights on how GFCC' and ABED face interactions together with metal ion binding may facilitate hCEACAM1 oligomerization beyond dimerization., (© 2022. The Author(s).)- Published
- 2022
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23. PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease.
- Author
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Schwärzler J, Mayr L, Vich Vila A, Grabherr F, Niederreiter L, Philipp M, Grander C, Meyer M, Jukic A, Tröger S, Enrich B, Przysiecki N, Tschurtschenthaler M, Sommer F, Kronberger I, Koch J, Hilbe R, Hess MW, Oberhuber G, Sprung S, Ran Q, Koch R, Effenberger M, Kaneider NC, Wieser V, Keller MA, Weersma RK, Aden K, Rosenstiel P, Blumberg RS, Kaser A, Tilg H, and Adolph TE
- Subjects
- Animals, Endoribonucleases, Fatty Acids, Unsaturated, Humans, Inflammation drug therapy, Mice, Protein Serine-Threonine Kinases, Toll-Like Receptor 2, Crohn Disease drug therapy, Enteritis chemically induced, Enteritis drug therapy, Fatty Acids, Omega-3
- Abstract
Background & Aims: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs., Methods: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts., Results: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1
-/-IEC and Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients., Conclusions: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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24. Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation.
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Mead BE, Hattori K, Levy L, Imada S, Goto N, Vukovic M, Sze D, Kummerlowe C, Matute JD, Duan J, Langer R, Blumberg RS, Ordovas-Montanes J, Yilmaz ÖH, Karp JM, and Shalek AK
- Subjects
- Animals, Cell Differentiation, Intestines, Mice, Stem Cells, Organoids, Paneth Cells physiology
- Abstract
The cellular composition of barrier epithelia is essential to organismal homoeostasis. In particular, within the small intestine, adult stem cells establish tissue cellularity, and may provide a means to control the abundance and quality of specialized epithelial cells. Yet, methods for the identification of biological targets regulating epithelial composition and function, and of small molecules modulating them, are lacking. Here we show that druggable biological targets and small-molecule regulators of intestinal stem cell differentiation can be identified via multiplexed phenotypic screening using thousands of miniaturized organoid models of intestinal stem cell differentiation into Paneth cells, and validated via longitudinal single-cell RNA-sequencing. We found that inhibitors of the nuclear exporter Exportin 1 modulate the fate of intestinal stem cells, independently of known differentiation cues, significantly increasing the abundance of Paneth cells in the organoids and in wild-type mice. Physiological organoid models of the differentiation of intestinal stem cells could find broader utility for the screening of biological targets and small molecules that can modulate the composition and function of other barrier epithelia., (© 2022. The Author(s).)
- Published
- 2022
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25. Immunoglobulin A-specific deficiency induces spontaneous inflammation specifically in the ileum.
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Nagaishi T, Watabe T, Kotake K, Kumazawa T, Aida T, Tanaka K, Ono R, Ishino F, Usami T, Miura T, Hirakata S, Kawasaki H, Tsugawa N, Yamada D, Hirayama K, Yoshikawa S, Karasuyama H, Okamoto R, Watanabe M, Blumberg RS, and Adachi T
- Subjects
- Animals, B-Lymphocytes physiology, Cytokines metabolism, Disease Models, Animal, Female, Gastrointestinal Microbiome, Homeostasis, Ileitis metabolism, Ileitis pathology, Ileum metabolism, Ileum ultrastructure, Inflammation etiology, Inflammation metabolism, Inflammation pathology, Intravital Microscopy, Male, Mice, Mice, Mutant Strains, T-Lymphocytes physiology, Ileitis etiology, Ileum pathology, Immunoglobulin A physiology
- Abstract
Objective: Although immunoglobulin A (IgA) is abundantly expressed in the gut and known to be an important component of mucosal barriers against luminal pathogens, its precise function remains unclear. Therefore, we tried to elucidate the effect of IgA on gut homeostasis maintenance and its mechanism., Design: We generated various IgA mutant mouse lines using the CRISPR/Cas9 genome editing system. Then, we evaluated the effect on the small intestinal homeostasis, pathology, intestinal microbiota, cytokine production, and immune cell activation using intravital imaging., Results: We obtained two lines, with one that contained a <50 base pair deletion in the cytoplasmic region of the IgA allele (IgA tail-mutant; IgA
tm/tm ) and the other that lacked the most constant region of the IgH α chain, which resulted in the deficiency of IgA production (IgA-/- ). IgA-/- exhibited spontaneous inflammation in the ileum but not the other parts of the gastrointestinal tract. Associated with this, there were significantly increased lamina propria CD4+ T cells, elevated productions of IFN-γ and IL-17, increased ileal segmented filamentous bacteria and skewed intestinal microflora composition. Intravital imaging using Ca2+ biosensor showed that IgA-/- had elevated Ca2+ signalling in Peyer's patch B cells. On the other hand, IgAtm/tm seemed to be normal, suggesting that the IgA cytoplasmic tail is dispensable for the prevention of the intestinal disorder., Conclusion: IgA plays an important role in the mucosal homeostasis associated with the regulation of intestinal microbiota and protection against mucosal inflammation especially in the ileum., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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26. Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
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Ye H, Chen C, Wu H, Zheng K, Martín-Adrados B, Caparros E, Francés R, Nelson LJ, Gómez Del Moral M, Asensio I, Vaquero J, Bañares R, Ávila MA, Andrade RJ, Isabel Lucena M, Martínez-Chantar ML, Reeves HL, Masson S, Blumberg RS, Gracia-Sancho J, Nevzorova YA, Martínez-Naves E, and Cubero FJ
- Subjects
- Animals, Autophagy, Cytochrome P-450 CYP2E1 metabolism, Hepatocytes metabolism, Humans, Liver pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Acetaminophen toxicity, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury prevention & control, X-Box Binding Protein 1 antagonists & inhibitors, X-Box Binding Protein 1 genetics
- Abstract
Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1
f/f ) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa ) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury., (© 2022. The Author(s).)- Published
- 2022
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27. A model of preferential pairing between epithelial and dendritic cells in thymic antigen transfer.
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Vobořil M, Březina J, Brabec T, Dobeš J, Ballek O, Dobešová M, Manning J, Blumberg RS, and Filipp D
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- Animals, Dendritic Cells immunology, Dendritic Cells metabolism, Epithelial Cells immunology, Epithelial Cells metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Thymus Gland cytology, Antigen Presentation immunology, Autoantigens metabolism, Immune Tolerance, Thymus Gland immunology
- Abstract
Medullary thymic epithelial cells (mTECs), which produce and present self-antigens, are essential for the establishment of central tolerance. Since mTEC numbers are limited, their function is complemented by thymic dendritic cells (DCs), which transfer mTEC-produced self-antigens via cooperative antigen transfer (CAT). While CAT is required for effective T cell selection, many aspects remain enigmatic. Given the recently described heterogeneity of mTECs and DCs, it is unclear whether the antigen acquisition from a particular TEC subset is mediated by preferential pairing with a specific subset of DCs. Using several relevant Cre -based mouse models that control for the expression of fluorescent proteins, we have found that, in regards to CAT, each subset of thymic DCs preferentially targets a distinct mTEC subset(s). Importantly, XCR1
+ -activated DC subset represented the most potent subset in CAT. Interestingly, thymic DCs can also acquire antigens from more than one mTEC, and of these, monocyte-derived dendritic cells (moDCs) were determined to be the most efficient. moDCs also represented the most potent DC subset in the acquisition of antigen from other DCs. These findings suggest a preferential pairing model for the distribution of mTEC-derived antigens among distinct populations of thymic DCs., Competing Interests: MV, JB, TB, JD, OB, MD, JM, RB, DF No competing interests declared, (© 2022, Vobořil et al.)- Published
- 2022
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28. A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.
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Saveljeva S, Sewell GW, Ramshorn K, Cader MZ, West JA, Clare S, Haag LM, de Almeida Rodrigues RP, Unger LW, Iglesias-Romero AB, Holland LM, Bourges C, Md-Ibrahim MN, Jones JO, Blumberg RS, Lee JC, Kaneider NC, Lawley TD, Bradley A, Dougan G, and Kaser A
- Subjects
- CD8-Positive T-Lymphocytes, Dendritic Cells, Lymphocyte Activation, Autoimmunity, Purines metabolism
- Abstract
Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4
+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+ -dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation., Competing Interests: Declaration of interests The University of Cambridge has filed patent applications relating to this work. The authors declare no other competing financial interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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29. Publisher Correction: Host immunomodulatory lipids created by symbionts from dietary amino acids.
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Oh SF, Praveena T, Song H, Yoo JS, Jung DJ, Erturk-Hasdemir D, Hwang YS, Lee CC, Le Nours J, Kim H, Lee J, Blumberg RS, Rossjohn J, Park SB, and Kasper DL
- Published
- 2022
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30. Host immunomodulatory lipids created by symbionts from dietary amino acids.
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Oh SF, Praveena T, Song H, Yoo JS, Jung DJ, Erturk-Hasdemir D, Hwang YS, Lee CC, Le Nours J, Kim H, Lee J, Blumberg RS, Rossjohn J, Park SB, and Kasper DL
- Subjects
- Amino Acids, Branched-Chain chemistry, Animals, Antigens, CD1d immunology, Bacteroides fragilis genetics, Humans, Mice, Models, Animal, Models, Molecular, Natural Killer T-Cells cytology, Natural Killer T-Cells immunology, Receptors, Antigen, T-Cell immunology, Signal Transduction immunology, Amino Acids, Branched-Chain immunology, Amino Acids, Branched-Chain metabolism, Bacteroides fragilis metabolism, Galactosylceramides immunology, Galactosylceramides metabolism, Gastrointestinal Microbiome immunology, Symbiosis immunology
- Abstract
Small molecules derived from symbiotic microbiota critically contribute to intestinal immune maturation and regulation
1 . However, little is known about the molecular mechanisms that control immune development in the host-microbiota environment. Here, using a targeted lipidomic analysis and synthetic approach, we carried out a multifaceted investigation of immunomodulatory α-galactosylceramides from the human symbiont Bacteroides fragilis (BfaGCs). The characteristic terminal branching of BfaGCs is the result of incorporation of branched-chain amino acids taken up in the host gut by B. fragilis. A B. fragilis knockout strain that cannot metabolize branched-chain amino acids showed reduced branching in BfaGCs, and mice monocolonized with this mutant strain had impaired colonic natural killer T (NKT) cell regulation, implying structure-specific immunomodulatory activity. The sphinganine chain branching of BfaGCs is a critical determinant of NKT cell activation, which induces specific immunomodulatory gene expression signatures and effector functions. Co-crystal structure and affinity analyses of CD1d-BfaGC-NKT cell receptor complexes confirmed the interaction of BfaGCs as CD1d-restricted ligands. We present a structural and molecular-level paradigm of immunomodulatory control by interactions of endobiotic metabolites with diet, microbiota and the immune system., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
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31. Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus.
- Author
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Werth VP, Culton DA, Concha JSS, Graydon JS, Blumberg LJ, Okawa J, Pyzik M, Blumberg RS, and Hall RP 3rd
- Subjects
- Adolescent, Adult, Aged, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Autoantibodies blood, Chronic Disease, Female, Histocompatibility Antigens Class I, Humans, Immunoglobulin G adverse effects, Male, Middle Aged, Pemphigus immunology, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Immunoglobulin G therapeutic use, Pemphigus drug therapy, Receptors, Fc antagonists & inhibitors
- Abstract
Pemphigus is a debilitating IgG-mediated autoimmune disease requiring better tolerated, more targeted, and rapid onset therapies. ALXN1830 is a humanized IgG4 antibody that blocks neonatal Fc receptor interactions with IgG. A multicenter, open-label safety and tolerability phase 1b/2 trial (NCT03075904) was conducted in North America from July 2017 to January 2019 and included patients aged ≥18 years with a confirmed diagnosis of pemphigus (vulgaris or foliaceus) and active disease. Dosing included five weekly intravenous doses of ALXN1830 (10 mg/kg) and follow-up through day 112 (study termination). Pharmacokinetics, pharmacodynamics, safety, and efficacy, as evaluated by determining the change in the median pemphigus disease area index, were determined. In this pilot study of eight patients, five weekly infusions of ALXN1830 produced a rapid improvement in the pemphigus disease area index score within 14 days of the first dose. Pemphigus disease area index improvement increased further together with reductions in IgG, circulating immune complexes of IgG, and anti-desmoglein antibodies without affecting albumin, IgM, IgA, or C-reactive protein levels. ALXN1830 was well-tolerated, with headache as the most common adverse event. This study reveals the importance of neonatal Fc receptor in the biology of pemphigus and the potential for use of ALXN1830 in pemphigus treatment., (Published by Elsevier Inc.)
- Published
- 2021
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32. Foxo1 controls gut homeostasis and commensalism by regulating mucus secretion.
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Chen Z, Luo J, Li J, Kim G, Chen ES, Xiao S, Snapper SB, Bao B, An D, Blumberg RS, Lin CH, Wang S, Zhong J, Liu K, Li Q, Wu C, and Kuchroo VK
- Subjects
- Animals, Autophagy physiology, Colitis chemically induced, Colitis metabolism, Colitis microbiology, Dysbiosis genetics, Fatty Acids, Volatile metabolism, Female, Forkhead Box Protein O1 genetics, Goblet Cells pathology, Intestinal Mucosa cytology, Intestinal Mucosa metabolism, Intestinal Mucosa microbiology, Male, Mice, Inbred C57BL, Mucin-2 metabolism, Symbiosis physiology, Mice, Forkhead Box Protein O1 metabolism, Gastrointestinal Microbiome physiology, Gastrointestinal Tract physiology, Mucus metabolism
- Abstract
Mucus produced by goblet cells in the gastrointestinal tract forms a biological barrier that protects the intestine from invasion by commensals and pathogens. However, the host-derived regulatory network that controls mucus secretion and thereby changes gut microbiota has not been well studied. Here, we identify that Forkhead box protein O1 (Foxo1) regulates mucus secretion by goblet cells and determines intestinal homeostasis. Loss of Foxo1 in intestinal epithelial cells (IECs) results in defects in goblet cell autophagy and mucus secretion, leading to an impaired gut microenvironment and dysbiosis. Subsequently, due to changes in microbiota and disruption in microbiome metabolites of short-chain fatty acids, Foxo1 deficiency results in altered organization of tight junction proteins and enhanced susceptibility to intestinal inflammation. Our study demonstrates that Foxo1 is crucial for IECs to establish commensalism and maintain intestinal barrier integrity by regulating goblet cell function., Competing Interests: Disclosures: S.B. Snapper reported personal fees from Pandion, IFM Therapeutics, Hoffman La Roche, Amgen, Lilly, Takeda, Kyverna, Pfizer, Merck, and Third Rock outside the submitted work. S. Xiao is an employee of Celsius Therapeutics. V.K. Kuchroo has an ownership interest in and is a member of the scientific advisory board for Tizona Therapeutics, Bicara Therapeutics, Compass Therapeutics, Larkspur Biosciences, and Trishula Therapeutics. The interests of V.K. Kuchroo were reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict-of-interest policies. No other disclosures were reported., (© 2021 Chen et al.)
- Published
- 2021
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33. Corrigendum to "CEACAM1 specifically suppresses B cell receptor signaling-mediated activation".
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Tsugawa N, Yamada D, Watabe T, Onizawa M, Wang S, Nemoto Y, Oshima S, Tsubata T, Adachi T, Kawano Y, Watanabe M, Blumberg RS, Okamoto R, and Nagaishi T
- Published
- 2021
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34. Efferocytosis by Paneth cells within the intestine.
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Shankman LS, Fleury ST, Evans WB, Penberthy KK, Arandjelovic S, Blumberg RS, Agaisse H, and Ravichandran KS
- Subjects
- Animals, Apoptosis, Humans, Inflammation, Intestines, Mice, Phagocytes, Paneth Cells, Phagocytosis
- Abstract
Apoptotic cells are quickly and efficiently engulfed and removed via the process of efferocytosis by either professional phagocytes, such as macrophages, or non-professional phagocytes, including epithelial cells.
1 , 2 In addition to debris removal, a key benefit of efferocytosis is that phagocytes engulfing apoptotic cells release anti-inflammatory mediators3 , 4 that help reduce local tissue inflammation;5 conversely, accumulation of uncleared apoptotic cells predisposes to a pro-inflammatory tissue milieu.6-8 Due to their high proliferative capacity, intestinal epithelial cells (iECs) are sensitive to inflammation, irradiation, and chemotherapy-induced DNA damage, leading to apoptosis. Mechanisms of iEC death in the context of irradiation has been studied,9 , 10 but phagocytosis of dying iECs is poorly understood. Here, we identify an unexpected efferocytic role for Paneth cells, which reside in intestinal crypts and are linked to innate immunity and maintenance of the stem cell niche in the crypt.11 , 12 Through a series of studies spanning in vitro efferocytosis, ex vivo intestinal organoids ("enteroids"), and in vivo Cre-mediated deletion of Paneth cells, we show that Paneth cells mediate apoptotic cell uptake of dying neighbors. The relevance of Paneth-cell-mediated efferocytosis was revealed ex vivo and in mice after low-dose cesium-137 (137 Cs) irradiation, mimicking radiation therapies given to cancer patients often causing significant apoptosis of iECs. These data advance a new concept that Paneth cells can act as phagocytes and identify another way in which Paneth cells contribute to the overall health of the intestine. These observations also have implications for individuals undergoing chemotherapy or chronic inflammatory bowel disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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35. Embryonic macrophages function during early life to determine invariant natural killer T cell levels at barrier surfaces.
- Author
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Gensollen T, Lin X, Zhang T, Pyzik M, See P, Glickman JN, Ginhoux F, Waldor M, Salmi M, Rantakari P, and Blumberg RS
- Subjects
- Animals, Cell Proliferation genetics, Colitis microbiology, Colitis pathology, Colon cytology, Colon embryology, Colon immunology, Colon pathology, Cytokines metabolism, Diphtheria Toxin administration & dosage, Diphtheria Toxin immunology, Disease Models, Animal, Embryo, Mammalian, Female, Gastrointestinal Microbiome immunology, Gene Expression Regulation, Developmental immunology, Germ-Free Life, Humans, Intestinal Mucosa cytology, Intestinal Mucosa embryology, Intestinal Mucosa pathology, Listeriosis microbiology, Listeriosis pathology, Macrophages metabolism, Male, Membrane Proteins genetics, Mice, Mice, Knockout, RNA-Seq, Signal Transduction genetics, Signal Transduction immunology, Colitis immunology, Intestinal Mucosa immunology, Listeriosis immunology, Macrophages immunology, Mucosal-Associated Invariant T Cells immunology
- Abstract
It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.
- Published
- 2021
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36. Structural basis of the dynamic human CEACAM1 monomer-dimer equilibrium.
- Author
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Gandhi AK, Sun ZJ, Kim WM, Huang YH, Kondo Y, Bonsor DA, Sundberg EJ, Wagner G, Kuchroo VK, Petsko GA, and Blumberg RS
- Subjects
- Antigens, CD chemistry, Antigens, CD genetics, Cell Adhesion Molecules chemistry, Cell Adhesion Molecules genetics, Crystallography, X-Ray, Dynamic Light Scattering, Fluorometry, Humans, Magnetic Resonance Spectroscopy, Mutation, Protein Conformation, Protein Multimerization, Structure-Activity Relationship, Antigens, CD metabolism, Cell Adhesion Molecules metabolism
- Abstract
Human (h) carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) function depends upon IgV-mediated homodimerization or heterodimerization with host ligands, including hCEACAM5, hTIM-3, PD-1, and a variety of microbial pathogens. However, there is little structural information available on how hCEACAM1 transitions between monomeric and dimeric states which in the latter case is critical for initiating hCEACAM1 activities. We therefore mutated residues within the hCEACAM1 IgV GFCC' face including V39, I91, N97, and E99 and examined hCEACAM1 IgV monomer-homodimer exchange using differential scanning fluorimetry, multi-angle light scattering, X-ray crystallography and/or nuclear magnetic resonance. From these studies, we describe hCEACAM1 homodimeric, monomeric and transition states at atomic resolution and its conformational behavior in solution through NMR assignment of the wildtype (WT) hCEACAM1 IgV dimer and N97A mutant monomer. These studies reveal the flexibility of the GFCC' face and its important role in governing the formation of hCEACAM1 dimers and selective heterodimers.
- Published
- 2021
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37. IL-22 receptor signaling in Paneth cells is critical for their maturation, microbiota colonization, Th17-related immune responses, and anti-Salmonella immunity.
- Author
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Gaudino SJ, Beaupre M, Lin X, Joshi P, Rathi S, McLaughlin PA, Kempen C, Mehta N, Eskiocak O, Yueh B, Blumberg RS, van der Velden AWM, Shroyer KR, Bialkowska AB, Beyaz S, and Kumar P
- Subjects
- Animals, Cell Differentiation, Immunity, Mucosal, Interleukins genetics, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Paneth Cells pathology, Receptors, Interleukin genetics, Signal Transduction, Interleukin-22, Interleukins metabolism, Microbiota physiology, Paneth Cells metabolism, Receptors, Interleukin metabolism, Salmonella typhi physiology, Th17 Cells immunology, Typhoid Fever immunology
- Abstract
Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1
fl/fl ;Lgr5-EGFP-creERT2 -specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5+ intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl ;Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.- Published
- 2021
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38. Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells.
- Author
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Valestrand L, Berntsen NL, Zheng F, Schrumpf E, Hansen SH, Karlsen TH, Blumberg RS, Hov JR, Jiang X, and Melum E
- Subjects
- Animals, Antigens, CD1d immunology, Cell Line, Humans, Killer Cells, Natural immunology, Liver immunology, Mice, RNA, Ribosomal, 16S immunology, Antigens immunology, Bile immunology, Lipids immunology, Liver Diseases immunology, Lymphocyte Activation immunology, Natural Killer T-Cells immunology
- Abstract
Natural killer T (NKT) cells are an abundant subset of liver lymphocytes activated by lipid antigens presented on CD1d molecules that are expressed by cholangiocytes. We aimed to determine if bile from patients with chronic liver diseases contains antigenic lipids that can activate NKT cells. Using murine invariant (24.7, 24.8 and DN32.D3) and non-invariant (14S.6, 14S.7 and 14S.10) NKT hybridomas we investigated the presence of lipid antigens in bile collected from the gallbladder of patients undergoing liver transplantation due to end-stage liver disease. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing. We found that the patient bile samples contain antigens that activate both invariant and non-invariant NKT hybridomas (24.7, 24.8, DN32.D3, 14S.6, 14S.7 and 14S.10), as demonstrated by activation of at least one hybridoma by eight of 10 bile samples. Activation at high dilutions suggests that some antigens are highly potent. We used the non-invariant NKT hybridoma 14S.6 to screen 21 additional patient bile samples for NKT-reactivity and demonstrated that 12 of 21 bile samples resulted in activation, three of which gave a strong activation. Four of 12 activating bile samples contained microbial DNA. Our results reveal an immunological pathway that could be of critical importance in biliary immunology., (© 2020 British Society for Immunology.)
- Published
- 2021
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39. CEACAM1 specifically suppresses B cell receptor signaling-mediated activation.
- Author
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Tsugawa N, Yamada D, Watabe T, Onizawa M, Wang S, Nemoto Y, Oshima S, Tsubata T, Adachi T, Kawano Y, Watanabe M, Blumberg RS, Okamoto R, and Nagaishi T
- Subjects
- Animals, B-Lymphocytes metabolism, Cell Differentiation, Cell Lineage, Cells, Cultured, Cytokines biosynthesis, Female, Mice, Inbred C57BL, Mice, Antigens, CD metabolism, Cell Adhesion Molecules metabolism, Receptors, Antigen, B-Cell metabolism, Signal Transduction
- Abstract
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressed in T cells may regulate immune responses in the gut. In addition to T cells, B cells are also an important population in the gut-associated lymphoid tissues that orchestrate mucosal homeostasis. However, the role of CEACAM1 in B cells has not been elucidated. We herein analyzed mature B cells to determine the functions of CEACAM1. Flow cytometry revealed high expression of CEACAM1 on B cells in secondary lymphoid tissues. Cytokine production induced by activation of B cell receptor (BCR) signaling was suppressed by CEACAM1 signaling in contrast to that associated with either Toll-like receptor 4 or CD40 signaling. Confocal microscopy revealed co-localization of CEACAM1 and BCR when activated with anti-Igμ F(ab')
2 fragment. Overexpression of CEACAM1 in a murine B cell line, A20, resulted in reduced expressions of activation surface markers with decreased Ca2+ influx after BCR signal activation. Overexpression of CEACAM1 suppressed BCR signal cascade in A20 cells in association with decreased spontaneous proliferation. Our results suggest that CEACAM1 can regulate BCR-mediated mature B cell activation in lymphoid tissues. Therefore, further studies of this molecule may lead to greater insights into the mechanisms of immune responses within peripheral tissues and the potential treatment of inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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40. Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis.
- Author
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Jackson DN, Panopoulos M, Neumann WL, Turner K, Cantarel BL, Thompson-Snipes L, Dassopoulos T, Feagins LA, Souza RF, Mills JC, Blumberg RS, Venuprasad K, Thompson WE, and Theiss AL
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Male, Mice, Organophosphorus Compounds, Piperidines, Prohibitins, Ileitis etiology, Ileitis pathology, Mitochondria physiology, Paneth Cells pathology, Repressor Proteins physiology
- Abstract
Objective: Although perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn's disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD., Design: Male and female mice with inducible intestinal epithelial cell deletion of Phb1 ( Phb1
iΔIEC ) or Paneth cell-specific deletion of Phb1 ( Phb1ΔPC ) and Phb1fl/fl control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1iΔIEC or Phb1ΔPC mice., Results: Phb1iΔIEC mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1iΔIEC ileum. Deletion of Phb1 specifically in Paneth cells ( Phb1ΔPC ) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1iΔIEC or Phb1ΔPC mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo., Conclusion: Our results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn's disease patients exhibiting Paneth cell defects., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2020
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41. A nano-engager for iNKT cells in cancer.
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Exley MA, Gensollen T, and Blumberg RS
- Subjects
- Humans, Immunotherapy, Natural Killer T-Cells, Neoplasms therapy
- Published
- 2020
- Full Text
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42. FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity.
- Author
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Hubbard JJ, Pyzik M, Rath T, Kozicky LK, Sand KMK, Gandhi AK, Grevys A, Foss S, Menzies SC, Glickman JN, Fiebiger E, Roopenian DC, Sandlie I, Andersen JT, Sly LM, Baker K, and Blumberg RS
- Subjects
- Adaptive Immunity immunology, Animals, Arthritis, Rheumatoid immunology, Disease Susceptibility, Histocompatibility Antigens Class I immunology, Humans, Immunity, Innate immunology, Male, Mice, Mice, Inbred C57BL, Receptors, Fc immunology, Receptors, IgG immunology, Autoimmunity immunology, Histocompatibility Antigens Class I physiology, Immunoglobulin G immunology, Receptors, Fc physiology
- Abstract
IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) γ-receptors (FcγRs). Of these, the highly prevalent FcγRIIa (CD32a) histidine (H)-131 variant (CD32aH) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32aR) variant, CD32aH more avidly bound human (h) IgG1 IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32aH. Conversely, FcRn induced responses to IgG IC independently of classical FcγR, but optimal responses required FcRn and FcγR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn's direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32aH variant, providing a novel mechanism for its disease association., Competing Interests: Disclosures: J.J. Hubbard reported a patent to US2019/017880 pending. M. Pyzik reported a patent to PCT/US2019/017880 pending, "Brigham and Women's Hospital." T. Rath reported a patent to 61/984,652 licensed and a patent to 61/909,229 licensed. A.K. Gandhi reported a patent for therapeutic FcRn-based bispecific monoclonal antibodies pending (PCT/US2019/107880). D.C. Roopenian reported a patent to US20190135915A1 licensed, "Alexion Pharmaceuticals"; and served as consultant with equity interests in Syntimmune Inc., a company developing therapeutic agents to target FcRn. Syntimmune is now a wholly owned subsidiary of Alexion Pharmaceuticals, Inc., following its acquisition by Alexion in November 2018. I. Sandlie has served as a consultant with equity interests in Syntimmune Inc., a company developing therapeutic agents to target FcRn. Syntimmune is now a wholly owned subsidiary of Alexion Pharmaceuticals, Inc., following its acquisition by Alexion in November 2018. K. Baker reported a patent to 61/984,652 issued and a patent to 61/909,229 issued. R.S. Blumberg served as consultant with equity interests in Syntimmune Inc., a company developing therapeutic agents to target FcRn. Syntimmune is now a wholly owned subsidiary of Alexion Pharmaceuticals, Inc., following its acquisition by Alexion in November 2018. In addition, R.S. Blumberg has a pending patent PCT/US2019/017880 to “BWH" and two patents licensed to "Alexion" (US2017/002073 and US2017/0045528). No other disclosures were reported., (© 2020 Hubbard et al.)
- Published
- 2020
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43. Microbial RNAs Pressure Piezo1 to Respond.
- Author
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Matute JD, Duan J, and Blumberg RS
- Subjects
- Enterochromaffin Cells, Ion Channels genetics, RNA, Gastrointestinal Microbiome, Serotonin
- Abstract
Serotonin production by enterochromaffin cells (ECs) is microbiota-dependent, but the mechanism of this is unknown. In this issue of Cell, Sugisawa et al. demonstrate that Piezo1 in ECs senses single-strand RNA (ssRNA) from intestinal microbiota to promote serotonin production. Deletion of Piezo1 in intestinal epithelium promotes bone formation, decreases peristalsis, and protects from colitis because of decreased serotonin., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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44. FcRn augments induction of tissue factor activity by IgG-containing immune complexes.
- Author
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Cines DB, Zaitsev S, Rauova L, Rux AH, Stepanova V, Krishnaswamy S, Sarkar A, Kowalska MA, Zhao G, Mast AE, Blumberg LJ, McCrae KR, Poncz M, Hubbard JJ, Pyzik M, and Blumberg RS
- Subjects
- Animals, Anticoagulants toxicity, Antigen-Antibody Complex, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Humans, Immunoglobulin G genetics, Immunoglobulin G immunology, Male, Mice, Monocytes immunology, Monocytes metabolism, Monocytes pathology, Platelet Factor 4 genetics, Platelet Factor 4 metabolism, Receptors, Fc genetics, Receptors, Fc immunology, Thrombocytopenia chemically induced, Thrombocytopenia metabolism, Thrombocytopenia pathology, Antibodies, Monoclonal, Humanized immunology, Heparin toxicity, Histocompatibility Antigens Class I metabolism, Immunoglobulin G metabolism, Receptors, Fc metabolism, Thrombocytopenia immunology, Thromboplastin metabolism
- Abstract
Thromboembolism complicates disorders caused by immunoglobulin G (IgG)-containing immune complexes (ICs), but the underlying mechanisms are incompletely understood. Prior evidence indicates that induction of tissue factor (TF) on monocytes, a pivotal step in the initiation, localization, and propagation of coagulation by ICs, is mediated through Fcγ receptor IIa (FcγRIIa); however, the involvement of other receptors has not been investigated in detail. The neonatal Fc receptor (FcRn) that mediates IgG and albumin recycling also participates in cellular responses to IgG-containing ICs. Here we asked whether FcRn is also involved in the induction of TF-dependent factor Xa (FXa) activity by IgG-containing ICs by THP-1 monocytic cells and human monocytes. Induction of FXa activity by ICs containing IgG antibodies to platelet factor 4 (PF4) involved in heparin-induced thrombocytopenia (HIT), β-2-glycoprotein-1 implicated in antiphospholipid syndrome, or red blood cells coated with anti-(α)-Rh(D) antibodies that mediate hemolysis in vivo was inhibited by a humanized monoclonal antibody (mAb) that blocks IgG binding to human FcRn. IgG-containing ICs that bind to FcγR and FcRn induced FXa activity, whereas IgG-containing ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an α-FcRn mAb prevented fibrin deposition after microvascular injury in a murine model of HIT in which human FcγRIIa was expressed as a transgene. These data implicate FcRn in TF-dependent FXa activity induced by soluble and cell-associated IgG-containing ICs. Antibodies to FcRn, now in clinical trials in warm autoimmune hemolytic anemia to lower IgG antibodies and IgG containing ICs may also reduce the risk of venous thromboembolism., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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45. Neutrophil Extracellular Trap-Associated CEACAM1 as a Putative Therapeutic Target to Prevent Metastatic Progression of Colon Carcinoma.
- Author
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Rayes RF, Vourtzoumis P, Bou Rjeily M, Seth R, Bourdeau F, Giannias B, Berube J, Huang YH, Rousseau S, Camilleri-Broet S, Blumberg RS, Beauchemin N, Najmeh S, Cools-Lartigue J, Spicer JD, and Ferri LE
- Subjects
- A549 Cells, Animals, Cell Line, Tumor, Colonic Neoplasms immunology, HT29 Cells, Humans, Mice, Neutrophils pathology, Antigens, CD metabolism, Carcinoembryonic Antigen metabolism, Cell Adhesion Molecules metabolism, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Extracellular Traps immunology, Extracellular Traps metabolism, Neutrophils immunology
- Abstract
Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications. Multiple studies have since shown that NETs play a role in tumor progression and metastasis. NETs are composed of nuclear DNA-derived web-like structures decorated with neutrophil-derived proteins. However, it is unknown which, if any, of these NET-affiliated proteins is responsible for inducing the metastatic phenotype. In this study, we identify the NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction. Indeed, blocking CEACAM1 on NETs, or knocking it out in a murine model, leads to a significant decrease in colon carcinoma cell adhesion, migration and metastasis. Thus, this work identifies NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of colon carcinoma., (Copyright © 2020 by The American Association of Immunologists, Inc.)
- Published
- 2020
- Full Text
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46. Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.
- Author
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Blumberg LJ, Humphries JE, Jones SD, Pearce LB, Holgate R, Hearn A, Cheung J, Mahmood A, Del Tito B, Graydon JS, Stolz LE, Bitonti A, Purohit S, de Graaf D, Kacena K, Andersen JT, Christianson GJ, Roopenian DC, Hubbard JJ, Gandhi AK, Lasseter K, Pyzik M, and Blumberg RS
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Autoantibodies drug effects, Autoimmune Diseases drug therapy, Cohort Studies, Double-Blind Method, Female, Healthy Volunteers, Histocompatibility Antigens Class I, Humans, Macaca fascicularis, Male, Mice, Protein Binding, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Humanized pharmacokinetics, Antigen-Antibody Complex immunology, Immunity, Humoral immunology, Immunoglobulin G blood, Immunoglobulin G immunology, Receptors, Fc antagonists & inhibitors
- Abstract
The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Published
- 2019
- Full Text
- View/download PDF
47. Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin.
- Author
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Melum E, Jiang X, Baker KD, Macedo MF, Fritsch J, Dowds CM, Wang J, Pharo A, Kaser A, Tan C, Pereira CS, Kelly SL, Duan J, Karlsen TH, Exley MA, Schütze S, Zajonc DM, Merrill AH, Schuchman EH, Zeissig S, and Blumberg RS
- Subjects
- Animals, Antigen Presentation, Antigens, CD1d metabolism, Cell Differentiation, Clonal Selection, Antigen-Mediated, Enzyme Replacement Therapy, Humans, Lymphocyte Activation, Lymphocyte Count, Mice, Mice, Inbred C57BL, Mice, Knockout, Sphingomyelin Phosphodiesterase genetics, Sphingomyelins metabolism, Inflammation immunology, Natural Killer T-Cells immunology, Niemann-Pick Diseases genetics, Sphingomyelin Phosphodiesterase metabolism, Sphingomyelins immunology, Thymus Gland immunology
- Abstract
Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection in the thymus, resulting in decreased iNKT cell levels and resistance to iNKT cell-mediated inflammatory conditions. Defective antigen presentation and decreased iNKT cells are also observed in ASM-deficient humans with Niemann-Pick disease, and ASM activity in healthy humans correlates with iNKT cell phenotype. Pharmacological ASM administration facilitates antigen presentation and restores the levels of iNKT cells in ASM-deficient mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represents a tight link between cellular sphingolipid metabolism and immunity.
- Published
- 2019
- Full Text
- View/download PDF
48. Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells.
- Author
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Bedard M, Shrestha D, Priestman DA, Wang Y, Schneider F, Matute JD, Iyer SS, Gileadi U, Prota G, Kandasamy M, Veerapen N, Besra G, Fritzsche M, Zeissig S, Shevchenko A, Christianson JC, Platt FM, Eggeling C, Blumberg RS, Salio M, and Cerundolo V
- Subjects
- Animals, Antigen Presentation, Antigens, CD1d biosynthesis, Antigens, CD1d immunology, Autoantigens immunology, Carcinoma, Lewis Lung pathology, Cell Line, Tumor, Coculture Techniques, Cytoskeleton ultrastructure, Endosomes immunology, Glycosphingolipids immunology, Glycosphingolipids metabolism, Humans, Interleukin-2 Receptor alpha Subunit biosynthesis, Lipids immunology, Lysosomes immunology, Mice, Mice, Inbred C57BL, THP-1 Cells, Thapsigargin pharmacology, Unfolded Protein Response immunology, eIF-2 Kinase deficiency, eIF-2 Kinase physiology, Antigen-Presenting Cells immunology, Dendritic Cells immunology, Endoplasmic Reticulum Stress immunology, Lymphocyte Activation, Natural Killer T-Cells immunology
- Abstract
Invariant NKT (iNKT) cells have the unique ability to shape immunity during antitumor immune responses and other forms of sterile and nonsterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and nonsterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Here we report that endoplasmic reticulum (ER)-stressed myeloid cells, via signaling events modulated by the protein kinase RNA-like ER kinase (PERK) pathway, increase CD1d-mediated presentation of immunogenic endogenous lipid species, which results in enhanced iNKT cell activation both in vitro and in vivo. In addition, we demonstrate that actin cytoskeletal reorganization during ER stress results in an altered distribution of CD1d on the cell surface, which contributes to enhanced iNKT cell activation. These results define a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)
- Published
- 2019
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49. The Neonatal Fc Receptor (FcRn): A Misnomer?
- Author
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Pyzik M, Sand KMK, Hubbard JJ, Andersen JT, Sandlie I, and Blumberg RS
- Subjects
- Animals, Antigen-Antibody Complex immunology, Female, Histocompatibility Antigens Class I immunology, Humans, Immune Tolerance, Immunity, Immunoglobulin G immunology, Pregnancy, Protein Conformation, Protein Transport, Receptors, Fc immunology, Antigen-Antibody Complex metabolism, Histocompatibility Antigens Class I metabolism, Immunoglobulin G metabolism, Placenta immunology, Receptors, Fc metabolism
- Abstract
Antibodies are essential components of an adaptive immune response. Immunoglobulin G (IgG) is the most common type of antibody found in circulation and extracellular fluids. Although IgG alone can directly protect the body from infection through the activities of its antigen binding region, the majority of IgG immune functions are mediated via proteins and receptors expressed by specialized cell subsets that bind to the fragment crystallizable (Fc) region of IgG. Fc gamma (γ) receptors (FcγR) belong to a broad family of proteins that presently include classical membrane-bound surface receptors as well as atypical intracellular receptors and cytoplasmic glycoproteins. Among the atypical FcγRs, the neonatal Fc receptor (FcRn) has increasingly gained notoriety given its intimate influence on IgG biology and its ability to also bind to albumin. FcRn functions as a recycling or transcytosis receptor that is responsible for maintaining IgG and albumin in the circulation, and bidirectionally transporting these two ligands across polarized cellular barriers. More recently, it has been appreciated that FcRn acts as an immune receptor by interacting with and facilitating antigen presentation of peptides derived from IgG immune complexes (IC). Here we review FcRn biology and focus on newer advances including how emerging FcRn-targeted therapies may affect the immune responses to IgG and IgG IC.
- Published
- 2019
- Full Text
- View/download PDF
50. SLAM-ing the brakes on iNKT cell selection.
- Author
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Iyer SS, Huang YH, and Blumberg RS
- Subjects
- Receptors, Antigen, T-Cell, Signal Transduction, Signaling Lymphocytic Activation Molecule Family, Signaling Lymphocytic Activation Molecule Family Member 1, Natural Killer T-Cells
- Published
- 2019
- Full Text
- View/download PDF
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