Journal articles: 'Experimental autoimmune encephalomyelitis, mast cells, histamine'

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Dietsch, G. N., and D. J. Hinrichs. "The role of mast cells in the elicitation of experimental allergic encephalomyelitis." Journal of Immunology 142, no. 5 (March 1, 1989): 1476–81. http://dx.doi.org/10.4049/jimmunol.142.5.1476.

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Abstract Experimental allergic encephalomyelitis (EAE), a T cell-mediated autoimmune disease can be transferred with lymphoid cells from actively immunized rats into naive recipients. In the mouse, previous studies have suggested a role for histamine/serotonin in the development of active EAE. We have found that myelin basic protein-reactive cells transfer a biphasic skin test response to naive rats analogous to what has been described in the mouse contact dermatitis system, where mast cell sensitization by Ag-specific T cell factors is required for the induction of skin test responses. Treatment of cell recipients with the serotonin receptor antagonists, cyproheptadine or methysergide, blocked or significantly reduced the development of EAE. Furthermore, it was found that treatment with cyproheptadine was effective in blocking clinical disease when administered day 3 to day 6 after cell transfer. In contrast, cyproheptadine treatments before induction of paralysis day 0 to 3, failed to alter the course of clinical disease. The inhibitor of mast cell degranulation, proxicromil, was also found to effectively block the elicitation of adoptively transferred EAE and was also found to be effective when administered just before the onset of clinical disease. Reserpine, a compound known to deplete mast cells of vasoactive amines by forcing granule contents into the cytoplasm where they are degraded by cell enzymes, was also effective in blocking both active and adoptively transferred EAE. Disease inhibition was found to be partially reversed with pargyline, an inhibitor of monoamine oxidase. In addition lymphocytes from treated animals were capable of transferring disease to naive recipients and appeared to have normal activity as assessed by Ag-or mitogen-driven proliferation in addition to IL-2 production.

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Musio, Silvia, Massimo Costanza, Pietro Luigi Poliani, Elena Fontana, Manuela Cominelli, Gabriella Abolafio, Lawrence Steinman, and Rosetta Pedotti. "Treatment with anti-FcεRIα antibody exacerbates EAE and T-cell immunity against myelin." Neurology - Neuroimmunology Neuroinflammation 4, no. 3 (April 14, 2017): e342. http://dx.doi.org/10.1212/nxi.0000000000000342.

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Objective:To investigate the effects of targeting the high-affinity receptor for immunoglobulin E (FcεRI), that plays a central role in allergic responses and is constitutively expressed on mast cells and basophils, in clinical disease and autoimmune T-cell response in experimental MS.Methods:Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein 35–55. Anti-FcεRI α-chain antibody was administered intraperitoneally. CNS immunohistochemistry, flow cytometry analysis of immune cell populations, IgE and histamine serum concentration, immune cell proliferation, and cytokine measurement were performed. In BALB/c mice, EAE was induced by immunization with myelin proteolipid protein 185–206.Results:Treatment with anti-FcεRIα antibody resulted in exacerbation of EAE and increased CNS inflammation in C57BL/6 mice. Treated mice displayed long-lasting complete depletion of basophils in the blood stream and peripheral lymphoid organs and increased antigen-induced immune cell proliferation and production of interferon-γ, interleukin (IL)-17, IL-6, and granulocyte-macrophage colony-stimulating factor. In BALB/c mice, which are T-helper (Th) 2 prone and resistant to EAE, treatment with anti-FcεRIα antibody restored susceptibility to EAE.Conclusion:Our observations that anti-FcεRIα antibody increases Th1 and Th17 responses against myelin antigen and exacerbates EAE suggest that FcεRI, basophils, and possibly other FcεRI-bearing cells that might be affected by this antibody play important roles in influencing the severity of CNS autoimmunity.

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Costanza, Massimo, Mario Colombo, and Rosetta Pedotti. "Mast Cells in the Pathogenesis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis." International Journal of Molecular Sciences 13, no. 12 (November 16, 2012): 15107–25. http://dx.doi.org/10.3390/ijms131115107.

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Yin, Jun-Jie, Xue-Qiang Hu, Zhi-Feng Mao, Jian Bao, Wei Qiu, Zheng-Qi Lu, Hao-Tian Wu, and Xiao-Nan Zhong. "Neutralization of Interleukin-9 Decreasing Mast Cells Infiltration in Experimental Autoimmune Encephalomyelitis." Chinese Medical Journal 130, no. 8 (April 2017): 964–71. http://dx.doi.org/10.4103/0366-6999.204110.

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Elieh-Ali-Komi, Daniel, and Yonghao Cao. "Role of Mast Cells in the Pathogenesis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis." Clinical Reviews in Allergy & Immunology 52, no. 3 (December 26, 2016): 436–45. http://dx.doi.org/10.1007/s12016-016-8595-y.

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ORR, EDWARD L. "Presence and Distribution of Nervous System-Associated Mast Cells That May Modulate Experimental Autoimmune Encephalomyelitis." Annals of the New York Academy of Sciences 540, no. 1 Advances in N (November 1988): 723–26. http://dx.doi.org/10.1111/j.1749-6632.1988.tb27226.x.

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Orr, Edward L. "Presence and distribution of nervous system — associated mast cells which may modulate experimental autoimmune encephalomyelitis." Journal of Neuroimmunology 16, no. 1 (September 1987): 136. http://dx.doi.org/10.1016/0165-5728(87)90341-9.

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Hatfield, Julianne, and Melissa Brown. "The meninges: A staging site for immune cell interactions in early experimental autoimmune encephalomyelitis (P4166)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 172.10. http://dx.doi.org/10.4049/jimmunol.190.supp.172.10.

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Abstract Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system in which immune mediate damage to white matter myelin is well characterized. However, improved imaging has revealed that inflammation in the meninges, tissues that are proximal to the CNS, also occurs and corresponds to cortical grey matter lesion formation in early disease. Together with evidence of activated T cells and tertiary lymphoid follicle formation within these tissues, these data suggest that the meninges are critical sites of immune cell activity. Yet little is known about the basal and disease-associated immune status of these tissues. Using a murine model of MS, we evaluated the immune cell makeup of the meninges in naïve mice and asked how this changes during the course of disease. CD4+ and CD8+ T cells, macrophages, dendritic cells, mast cells and neutrophils are detected in naïve mice and increased numbers of neutrophils and macrophages are observed in preclinical disease. A population of innate lymphoid cells (ILCs: CD3-, CD4+/-, RORγt+, IL-7Rα+) also normally resides in the meninges and this population is reduced in mast cell deficient mice. These data confirm that the meninges are an active site of immune response in early disease. We speculate that meningeal ILCs may provide a mechanism for the development of tertiary lymphoid follicle formation as well as contribute to Th17 cell activation and thereby amplify meningeal inflammation.

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Teuscher, Cory, Meena Subramanian, Rajkumar Noubade, Jian Feng Gao, Halina Offner, James F. Zachary, and Elizabeth P. Blankenhorn. "Central Histamine H3 Receptor Signaling Negatively Regulates Autoimmune Inflammation (129.31)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S223. http://dx.doi.org/10.4049/jimmunol.178.supp.129.31.

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Abstract Histamine is a ubiquitous regulator of diverse physiologic processes including inflammation, immune modulation and neurotransmission. Four subtypes of histamine receptors are currently recognized and genetic and pharmacological studies have shown that the H1 and H2 receptors play a role in susceptibility to experimental allergic encephalomyelitis (EAE), the primary autoimmune model of multiple sclerosis. Histamine H3 receptor (H3R), which is not expressed in hematopoietic cells, is a presynaptic auto- and hetero-receptor. Here we show that H3RKO mice develop significantly more severe acute phase clinical disease and neuropathology compared to wild-type controls. In H3RKO mice this is preceded by disruption of the blood brain barrier and increased chemokine/chemokine receptor expression in peripheral T-cells. These data are consistent with inhibition of H3R-mediated neurogenic control of cerebrovascular tone and T-cell function. Additionally, genetic studies indicate that an H3R polymorphism leading to differential expression of H3R isoforms underlies eae8, a locus controlling disease associated weight loss, a phenotype known to be regulated by central H3R activity.

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Russi, Abigail E., Mark E. Ebel, Yuchen Yang, and Melissa A. Brown. "Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility." Proceedings of the National Academy of Sciences 115, no. 7 (January 29, 2018): E1520—E1529. http://dx.doi.org/10.1073/pnas.1710401115.

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The cellular and molecular basis of sex-dimorphic autoimmune diseases, such as the CNS demyelinating disease multiple sclerosis (MS), remains unclear. Our studies in the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), reveal that sex-determined differences in Il33 expression by innate immune cells in response to myelin peptide immunization regulate EAE susceptibility. IL-33 is selectively induced in PLP139–151-immunized males and activates type 2 innate lymphoid cells (ILC2s), cells that promote and sustain a nonpathogenic Th2 myelin-specific response. Without this attenuating IL-33 response, females generate an encephalitogenic Th17-dominant response, which can be reversed by IL-33 treatment. Mast cells are one source of IL-33 and we provide evidence that testosterone directly induces Il33 gene expression and also exerts effects on the potential for Il33 gene expression during mast cell development. Thus, in contrast to their pathogenic role in allergy, we propose a sex-specific role for both mast cells and ILC2s as attenuators of the pathogenic Th response in CNS inflammatory disease.

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Bicer, Fuat, Cengiz Z. Altuntas, Kenan Izgi, Ahmet Ozer, Michael Kavran, Vincent K. Tuohy, and Firouz Daneshgari. "Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model." American Journal of Physiology-Renal Physiology 308, no. 2 (January 15, 2015): F103—F113. http://dx.doi.org/10.1152/ajprenal.00202.2014.

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The cause of chronic pelvic pain in interstitial cystitis/painful bladder syndrome (IC/PBS) remains unclear; autoimmunity is a possible etiology. We have recently shown that injection of a single immunogenic peptide of uroplakin 3A (UPK3A 65-84) induces experimental autoimmune cystitis (EAC) in female BALB/cJ mice that is unique among experimental models in accurately reflecting both the urinary symptoms and pelvic pain of IC/PBS. The aim of this project was to identify the roles of mast cells and mast cell chemoattractant/activator monocyte chemoattractant protein-1 [chemokine (C-C motif) ligand 2 (CCL2)] in the allodynia in this model. We immunized 6- to 8-wk-old female BALB/cJ mice with UPK3A 65-84 peptide and, 5–40 days later, observed increased responses to stimulation of the suprapubic abdominal and hindpaw surfaces with von Frey monofilaments compared with mice injected with adjuvant alone. Suprapubic and hindpaw tactile allodynia responses by EAC mice were blocked by instillation of lidocaine into the bladder but not by lidocaine in the uterus, confirming the bladder as the source of the hypersensitivity. Markedly increased numbers of activated mast cells and expression of CCL2 were found in the bladder after immunization with UPK3A 65-84. Hypersensitive responses were inhibited by mast cell stabilizer cromolyn sodium and antagonists of histamine receptors 1 and 2. Furthermore, BALB/cJ mice with deletion of the Ccl2 or chemokine (C-C motif) receptor 2 gene exhibited markedly reduced allodynia and accumulation of mast cells after UPK3A 65-84 immunization. These results show that UPK3A 65-84 immunization causes chronic visceral allodynia and suggest that it is mediated by CCL2-driven mast cell accumulation in the bladder.

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Desbiens, Louisane, Catherine Lapointe, Marjan Gharagozloo, Shaimaa Mahmoud, Gunnar Pejler, Denis Gris, and Pedro D’Orléans-Juste. "Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis." Mediators of Inflammation 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/9797021.

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Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized withMOG35–55plus complete Freund’s adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS.

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Secor, Virginia H., W. Evan Secor, Claire-Anne Gutekunst, and Melissa A. Brown. "Mast Cells Are Essential for Early Onset and Severe Disease in a Murine Model of Multiple Sclerosis." Journal of Experimental Medicine 191, no. 5 (March 6, 2000): 813–22. http://dx.doi.org/10.1084/jem.191.5.813.

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In addition to their well characterized role in allergic inflammation, recent data confirm that mast cells play a more extensive role in a variety of immune responses. However, their contribution to autoimmune and neurologic disease processes has not been investigated. Experimental allergic encephalomyelitis (EAE) and its human disease counterpart, multiple sclerosis, are considered to be CD4+ T cell–mediated autoimmune diseases affecting the central nervous system. Several lines of indirect evidence suggest that mast cells could also play a role in the pathogenesis of both the human and murine disease. Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell–deficient W/Wv mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates. No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/Wv animals. Reconstitution of the mast cell population in W/Wv mice restores induction of early and severe disease to wild-type levels, suggesting that mast cells are critical for the full manifestation of disease. These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.

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Finlay, Conor M., Kyle T. Cunningham, Benjamin Doyle, and Kingston H. G. Mills. "IL-33–Stimulated Murine Mast Cells Polarize Alternatively Activated Macrophages, Which Suppress T Cells That Mediate Experimental Autoimmune Encephalomyelitis." Journal of Immunology 205, no. 7 (August 28, 2020): 1909–19. http://dx.doi.org/10.4049/jimmunol.1901321.

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Shi, Yaru, Zhenlong Li, Ran Chen, Jiang Zhang, Xuefei Hu, Cong He, Qiong Su, et al. "Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells." Oncotarget 8, no. 43 (August 24, 2017): 75038–49. http://dx.doi.org/10.18632/oncotarget.20500.

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Weiskirchen, Ralf, Steffen K. Meurer, Christian Liedtke, and Michael Huber. "Mast Cells in Liver Fibrogenesis." Cells 8, no. 11 (November 13, 2019): 1429. http://dx.doi.org/10.3390/cells8111429.

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Mast cells (MCs) are immune cells of the myeloid lineage that are present in the connective tissue throughout the body and in mucosa tissue. They originate from hematopoietic stem cells in the bone marrow and circulate as MC progenitors in the blood. After migration to various tissues, they differentiate into their mature form, which is characterized by a phenotype containing large granules enriched in a variety of bioactive compounds, including histamine and heparin. These cells can be activated in a receptor-dependent and -independent manner. Particularly, the activation of the high-affinity immunoglobulin E (IgE) receptor, also known as FcεRI, that is expressed on the surface of MCs provoke specific signaling cascades that leads to intracellular calcium influx, activation of different transcription factors, degranulation, and cytokine production. Therefore, MCs modulate many aspects in physiological and pathological conditions, including wound healing, defense against pathogens, immune tolerance, allergy, anaphylaxis, autoimmune defects, inflammation, and infectious and other disorders. In the liver, MCs are mainly associated with connective tissue located in the surrounding of the hepatic arteries, veins, and bile ducts. Recent work has demonstrated a significant increase in MC number during hepatic injury, suggesting an important role of these cells in liver disease and progression. In the present review, we summarize aspects of MC function and mediators in experimental liver injury, their interaction with other hepatic cell types, and their contribution to the pathogenesis of fibrosis.

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Saligrama, Naresha, Rajkumar Noubade, Laure Case, Matthew Poynter, and Cory Teuscher. "H1R signaling in antigen presenting cells is dispensable for eliciting pathogenic T cells in experimental allergic encephalomyelitis (123.14)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 123.14. http://dx.doi.org/10.4049/jimmunol.188.supp.123.14.

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Abstract The histamine H1 receptor (Hrh1/H1R) was identified as a shared autoimmune disease (SAID) gene in experimental allergic encephalomyelitis (EAE) and autoimmune orchitis, the principal AI models of multiple sclerosis (MS) and idiopathic male infertility, respectively. As a SAID gene, Hrh1/H1R can exert effects in multiple cell types including endothelial cells, T cells, and antigen presenting cells at critical check points during both the induction and effector phases of disease. In this regard, we showed that selective re-expression of H1R by endothelial cells in Hrh1-KO (H1RKO) mice significantly reduced disease severity whereas H1R expression by H1RKO T cells complemented EAE severity and cytokine responses. Given that the H1R has been reported to influence innate immune cell maturation, differentiation, chemotaxis, and cytokine production, which in turn influences CD4+ T cell effector responses, we selectively re-expressed H1R in CD11b+ myeloid cells of H1RKO mice to test the hypothesis that H1R signaling in these cells contributes to EAE susceptibility and/or T cell effector responses. We demonstrate that transgenic re-expression of H1R by H1RKO-CD11b+ cells neither complements EAE susceptibility nor T cell cytokine responses. These results further highlight the cell-specific effects that an AID gene can play in the pathogenesis of complex diseases such as EAE and MS, and the need for cell-specific targeting in optimizing therapeutic interventions based on such genes.

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Hong, Gwan Ui, Young Min Ahn, and Jai Youl Ro. "Transglutaminase 2 over-Expressed By Interaction of Mast Cells and Oligodendrocytes Induces Demyelination in the Experimental Autoimmune Encephalomyelitis." Journal of Allergy and Clinical Immunology 137, no. 2 (February 2016): AB76. http://dx.doi.org/10.1016/j.jaci.2015.12.257.

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Brown, Melissa Ann, and Yuchen Yang. "Distinct chromatin modifications at the Il33 locus in mast cells contribute to sex dimorphic susceptibility to EAE, an autoimmune CNS demyelinating disease." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 219.8. http://dx.doi.org/10.4049/jimmunol.204.supp.219.8.

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Abstract Many autoimmune diseases, including multiple sclerosis (MS) exhibit a striking female bias, but the underlying mechanisms remain poorly understood. Using the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which recapitulates this sex dimorphism, we previously demonstrated that preferential IL-33 expression contributes to male protection. IL-33 expression by mast cells in PLP139–151-immunized males activates type 2 innate lymphoid cells, which in turn drives a non-pathogenic Th2 response to myelin peptide. Testosterone directly activates Il33 in male but not female mast cells, but this male-specific response is also maintained with other modes of activation, including FcɛR1-crosslinking, suggesting there are constraints on the chromatin landscape that limit Il33 expression in females. Here we use ChIP and ATAC-seq to show that the dynamics of chromatin modifications at the Il33 locus is sex-dimorphic. At steady state, ChIP assays reveal activating H3K4me3 and H3K9ac histone modifications at the promoter and conserved non-coding sequences within the Il33 gene are most prevalent in male-derived cells, while H3K27me3 repressive marks dominate in females. This pattern is similar in IgE-DNP-activated mast cells. Increased basal Il33 chromatin accessibility assessed by ATAC-seq is evident in males. Together, these results indicate that while testosterone can directly stimulate IL-33 production, it also exerts effects on Il33 during development conferring a higher potential for expression in males.

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Brown, Melissa Ann, and Yuchen Yang. "Distinct chromatin modifications at the Il33 locus in mast cells contribute to sex dimorphic susceptibility to EAE, an autoimmune CNS demyelinating disease." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 64.15. http://dx.doi.org/10.4049/jimmunol.206.supp.64.15.

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Abstract Many autoimmune diseases, including multiple sclerosis (MS), exhibit a striking female bias, but the underlying mechanisms remain poorly understood. Using the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which recapitulates this sex dimorphism, we previously demonstrated that preferential IL-33 expression contributes to male protection. IL-33 expression by mast cells in PLP139–151-immunized males activates type 2 innate lymphoid cells, which in turn drives a non-pathogenic Th2 response to myelin peptide. Testosterone directly activates Il33 in male but not female mast cells, but this male-specific response is also observed with other modes of activation, suggesting there are constraints on the chromatin landscape that limit Il33 expression in females. Here we use chromatin immunoprecipitation (ChIP) and ATAC-seq to examine chromatin modifications at the Il33 locus. At steady state, ChIP assays reveal activating H3K4me3 and H3K9ac histone modifications at the promoter and conserved non-coding sequences within the Il33 gene are most prevalent in male-derived cells, while H3K27me3 repressive marks dominate in females. Increased basal Il33 chromatin accessibility assessed by ATAC-seq is also evident in males. Together, these results indicate that while testosterone can directly stimulate IL-33 production, it also exerts effects on Il33 during development conferring a higher potential for expression in males by altering the chromatin landscape. RNAseq analyses of IgE-activated mast cells revealed a broad range of sex-biased gene expression, indicating that sex hormone influences during development drive epigenetic changes and may be a common mechanism to explain sex dimorphism in immunity.

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Nowak, Elizabeth C., Casey T. Weaver, Henrietta Turner, Sakhina Begum-Haque, Burkhard Becher, Bettina Schreiner, Anthony J. Coyle, Lloyd H. Kasper, and Randolph J. Noelle. "IL-9 as a mediator of Th17-driven inflammatory disease." Journal of Experimental Medicine 206, no. 8 (July 13, 2009): 1653–60. http://dx.doi.org/10.1084/jem.20090246.

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We report that like other T cells cultured in the presence of transforming growth factor (TGF) β, Th17 cells also produce interleukin (IL) 9. Th17 cells generated in vitro with IL-6 and TGF-β as well as purified ex vivo Th17 cells both produced IL-9. To determine if IL-9 has functional consequences in Th17-mediated inflammatory disease, we evaluated the role of IL-9 in the development and progression of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. The data show that IL-9 neutralization and IL-9 receptor deficiency attenuates disease, and this correlates with decreases in Th17 cells and IL-6–producing macrophages in the central nervous system, as well as mast cell numbers in the regional lymph nodes. Collectively, these data implicate IL-9 as a Th17-derived cytokine that can contribute to inflammatory disease.

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Piconese, Silvia, Giorgia Gri, Claudio Tripodo, Silvia Musio, Andrea Gorzanelli, Barbara Frossi, Rosetta Pedotti, Carlo E. Pucillo, and Mario P. Colombo. "Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation." Blood 114, no. 13 (September 24, 2009): 2639–48. http://dx.doi.org/10.1182/blood-2009-05-220004.

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Abstract The development of inflammatory diseases implies inactivation of regulatory T (Treg) cells through mechanisms that still are largely unknown. Here we showed that mast cells (MCs), an early source of inflammatory mediators, are able to counteract Treg inhibition over effector T cells. To gain insight into the molecules involved in their interplay, we set up an in vitro system in which all 3 cellular components were put in contact. Reversal of Treg suppression required T cell–derived interleukin-6 (IL-6) and the OX40/OX40L axis. In the presence of activated MCs, concomitant abundance of IL-6 and paucity of Th1/Th2 cytokines skewed Tregs and effector T cells into IL-17–producing T cells (Th17). In vivo analysis of lymph nodes hosting T-cell priming in experimental autoimmune encephalomyelitis revealed activated MCs, Tregs, and Th17 cells displaying tight spatial interactions, further supporting the occurrence of an MC-mediated inhibition of Treg suppression in the establishment of Th17-mediated inflammatory responses.

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Noubade, Rajkumar, Mercedes Rincon, and Cory Teuscher. "IFN-gamma production by CD4 T cells requires Histamine H1 receptor during their initial phase of activation (87.25)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S132. http://dx.doi.org/10.4049/jimmunol.178.supp.87.25.

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Abstract Histamine H1 receptor (H1R) signaling in T cells plays an important role Th1 effector functions. H1R is an autoimmune susceptibility gene controlling experimental autoimmune encephalomyelitis (EAE). H1R knockout (H1RKO) mice also develop significantly less severe EAE compared to C57BL/6J wild-type mice in association with immune deviation of the CD4+ T-cell response from a Th1- to a Th2-like response. Little is known about the role of direct H1R signaling in the regulation of T-cell effector responses. In this study, T-cells from C57BL/6J and H1RKO mice were used to study H1R signaling in directly regulating such responses. Attempts to restore IFN-gammaproduction in H1RKO T-cells following retroviral transduction of the H1R were unsuccessful. In contrast, H1RKO transgenic mice selectively expressing the H1R in peripheral CD4+ T-cells under the control of the distal-lck promoter restored the IFN-gamma response and susceptibility to EAE in an H1R gene dose-dependent fashion. Moreover, activated H1RKO CD4+ T-cells show reduced phosphorylation of p38 MAP kinase compared to T-cells from wild-type mice which was again restored in activated T-cells from transgenic mice. These results show that H1R signaling regulates IFN-gamma production in CD4+ effector T-cells by direct signaling during initial activation of naïve T-cells through phosphorylation of p38 MAP kinase.

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Bennett, Jami L., Marie-Renée Blanchet, Linlin Zhao, Lori Zbytnuik, Frann Antignano, Matthew Gold, Paul Kubes, and Kelly M. McNagny. "Bone Marrow-Derived Mast Cells Accumulate in the Central Nervous System During Inflammation but Are Dispensable for Experimental Autoimmune Encephalomyelitis Pathogenesis." Journal of Immunology 182, no. 9 (April 20, 2009): 5507–14. http://dx.doi.org/10.4049/jimmunol.0801485.

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Piacente, Francesco, Marta Bottero, Andrea Benzi, Tiziana Vigo, Antonio Uccelli, Santina Bruzzone, and Giovanni Ferrara. "Neuroprotective Potential of Dendritic Cells and Sirtuins in Multiple Sclerosis." International Journal of Molecular Sciences 23, no. 8 (April 14, 2022): 4352. http://dx.doi.org/10.3390/ijms23084352.

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Myeloid cells, including parenchymal microglia, perivascular and meningeal macrophages, and dendritic cells (DCs), are present in the central nervous system (CNS) and establish an intricate relationship with other cells, playing a crucial role both in health and in neurological diseases. In this context, DCs are critical to orchestrating the immune response linking the innate and adaptive immune systems. Under steady-state conditions, DCs patrol the CNS, sampling their local environment and acting as sentinels. During neuroinflammation, the resulting activation of DCs is a critical step that drives the inflammatory response or the resolution of inflammation with the participation of different cell types of the immune system (macrophages, mast cells, T and B lymphocytes), resident cells of the CNS and soluble factors. Although the importance of DCs is clearly recognized, their exact function in CNS disease is still debated. In this review, we will discuss modern concepts of DC biology in steady-state and during autoimmune neuroinflammation. Here, we will also address some key aspects involving DCs in CNS patrolling, highlighting the neuroprotective nature of DCs and emphasizing their therapeutic potential for the treatment of neurological conditions. Recently, inhibition of the NAD+-dependent deac(et)ylase sirtuin 6 was demonstrated to delay the onset of experimental autoimmune encephalomyelitis, by dampening DC trafficking towards inflamed LNs. Thus, a special focus will be dedicated to sirtuins’ role in DCs functions.

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Hong, Gwan Ui, Nam Goo Kim, Dooil Jeoung, and Jai Youl Ro. "Anti-CD40 Ab- or 8-oxo-dG-enhanced Treg cells reduce development of experimental autoimmune encephalomyelitis via down-regulating migration and activation of mast cells." Journal of Neuroimmunology 260, no. 1-2 (July 2013): 60–73. http://dx.doi.org/10.1016/j.jneuroim.2013.04.002.

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Lee, Sung Won, Hyun Jung Park, Jungmin Jeon, Yun Hoo Park, Tae-Cheol Kim, Sung Ho Jeon, Rho Hyun Seong, Luc Van Kaer, and Seokmann Hong. "Ubiquitous Overexpression of Chromatin Remodeling Factor SRG3 Exacerbates Atopic Dermatitis in NC/Nga Mice by Enhancing Th2 Immune Responses." International Journal of Molecular Sciences 22, no. 4 (February 4, 2021): 1553. http://dx.doi.org/10.3390/ijms22041553.

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The SWItch (SWI)3-related gene (SRG3) product, a SWI/Sucrose Non-Fermenting (SNF) chromatin remodeling subunit, plays a critical role in regulating immune responses. We have previously shown that ubiquitous SRG3 overexpression attenuates the progression of Th1/Th17-mediated experimental autoimmune encephalomyelitis. However, it is unclear whether SRG3 overexpression can affect the pathogenesis of inflammatory skin diseases such as atopic dermatitis (AD), a Th2-type immune disorder. Thus, to elucidate the effects of SRG3 overexpression in AD development, we bred NC/Nga (NC) mice with transgenic mice where SRG3 expression is driven by the β-actin promoter (SRG3β-actin mice). We found that SRG3β-actin NC mice exhibit increased AD development (e.g., a higher clinical score, immunoglobulin E (IgE) hyperproduction, and an increased number of infiltrated mast cells and basophils in skin lesions) compared with wild-type NC mice. Moreover, the severity of AD pathogenesis in SRG3β-actin NC mice correlated with expansion of interleukin 4 (IL4)-producing basophils and mast cells, and M2 macrophages. Furthermore, this accelerated AD development is strongly associated with Treg cell suppression. Collectively, our results have identified that modulation of SRG3 function can be applied as one of the options to control AD pathogenesis.

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Nowak, Elizabeth C., Victor C. de Vries, Anna Wasiuk, Cory Ahonen, Kathryn A. Bennett, Isabelle Le Mercier, Dae-Gon Ha, and Randolph J. Noelle. "Tryptophan hydroxylase-1 regulates immune tolerance and inflammation." Journal of Experimental Medicine 209, no. 11 (September 24, 2012): 2127–35. http://dx.doi.org/10.1084/jem.20120408.

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Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control inflammatory responses and immune tolerance. Here we report the novel finding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 deficiency breaks allograft tolerance, induces tumor remission, and intensifies neuroinflammation, respectively. All of these effects of Tph-1 deficiency are independent of its downstream product serotonin. Because mast cells (MCs) appear to be the major source of Tph-1 and restoration of Tph-1 in the MC compartment in vivo compensates for the defect, these experiments introduce a fundamentally new mechanism of MC-mediated immune suppression that broadly impacts multiple arms of immunity.

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Short, Abigail, Margaret Walker-Caulfield, and Melissa Brown. "c-kit signaling pathways regulate EAE susceptibility in male SJL mice (P3119)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 43.21. http://dx.doi.org/10.4049/jimmunol.190.supp.43.21.

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Abstract Females are more susceptible to autoimmune diseases, including multiple sclerosis (MS), a demyelinating disease of the central nervous system. While genetic, hormonal, and immune differences have been implicated, the mechanism for this female bias remains unclear. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), recapitulates many of the features of the human disease; including the significant sex dimorphism. We previously reported that wild type (WT) female SJL mice exhibit more severe disease than their c-kit mutant counterparts and that this phenotype is mast cell dependent. In contrast, male SJL-Kit-W/W-v mice develop significantly more severe EAE than their WT littermates. This c-kit dependent difference in male disease corresponds to a more robust peripheral CD4+ T cell response at day 10 post disease induction. Male SJL-Kit-W/W-v mice demonstrate a higher percentage and number of encephalitogenic GM-CSF producing PLP(139-151)-specific CD4+ T cells when compared to their WT controls. These data indicate that c-kit signaling exerts its protective effects in the periphery by regulating the magnitude and quality of the autoreactive T cell response. This effect is male specific given that the peripheral T cell GM-CSF responses in WT and Kit-W/W-v females are equivalent. Further studies are ongoing to define the cell type that is the target of c-kit signals and the mechanism by which c-kit exerts its disparate effects in male and female SJL mice.

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Alrashdi, Barakat, Bassel Dawod, Sabine Tacke, Stefanie Kuerten, Patrice D. Côté, and Jean S. Marshall. "Mice Heterozygous for the Sodium Channel Scn8a (Nav1.6) Have Reduced Inflammatory Responses During EAE and Following LPS Challenge." Frontiers in Immunology 12 (March 19, 2021). http://dx.doi.org/10.3389/fimmu.2021.533423.

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Voltage gated sodium (Nav) channels contribute to axonal damage following demyelination in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). The Nav1.6 isoform has been implicated as a primary contributor in this process. However, the role of Nav1.6 in immune processes, critical to the pathology of both MS and EAE, has not been extensively studied. EAE was induced with myelin oligodendrocyte (MOG35-55) peptide in Scn8admu/+ mice, which have reduced Nav1.6 levels. Scn8admu/+ mice demonstrated improved motor capacity during the recovery and early chronic phases of EAE relative to wild-type animals. In the optic nerve, myeloid cell infiltration and the effects of EAE on the axonal ultrastructure were also significantly reduced in Scn8admu/+ mice. Analysis of innate immune parameters revealed reduced plasma IL-6 levels and decreased percentages of Gr-1high/CD11b+ and Gr-1int/CD11b+ myeloid cells in the blood during the chronic phase of EAE in Scn8admu/+ mice. Elevated levels of the anti-inflammatory cytokines IL-10, IL-13, and TGF-β1 were also observed in the brains of untreated Scn8admu/+ mice. A lipopolysaccharide (LPS) model was used to further evaluate inflammatory responses. Scn8admu/+ mice displayed reduced inflammation in response to LPS challenge. To further evaluate if this was an immune cell-intrinsic difference or the result of changes in the immune or hormonal environment, mast cells were derived from the bone marrow of Scn8admu/+ mice. These mast cells also produced lower levels of IL-6, in response to LPS, compared with those from wild type mice. Our results demonstrate that in addition to its recognized impact on axonal damage, Nav1.6 impacts multiple aspects of the innate inflammatory response.

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Journal articles on the topic 'Experimental autoimmune encephalomyelitis, mast cells, histamine'

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