Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The costimulatory CD40-CD40L pathway plays a critical role in the generation and maintenance of adaptive immune responses. Genetic interference of CD40-CD40L interactions strongly influences the onset and course in many autoimmune disease models including experimental autoimmune encephalomyelitis. We analysed the association of a single nucleotide polymorphism of the CD40 gene (C/T(-1)) in 287 patients with multiple sclerosis (MS) and 184 matched controls. No significant differences were found in the frequency of the C/T(-1) polymorphism between the patients with MS and the controls (53% vs 49%) or among different MS subtypes. Cell surface expression of CD40 did not differ within the different genotypes, but carriers of the T allele showed a trend for a lower stimulatory index compared with individuals with the CC genotype. Although these subtle differences indicate functional consequences in the immune stimulatory capabilities related to the CD40 C/T(-1) polymorphism, our population-based study found no association with disease susceptibility or disease course in MS.
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PMID:Analysis of the C/T(-1) single nucleotide polymorphism in the CD40 gene in multiple sclerosis. 1702 70

Dendritic cells (DC) are key regulators of T cell immunity and tolerance. NKT cells are well-known enhancers of Th differentiation and regulatory T cell function. However, the nature of the DC directing T and NKT cell activation and polarization as well as the role of the respective CD1d Ags presented is still unclear. In this study, we show that peptide-specific CD4(+)IL-10(+) T cell-mediated full experimental autoimmune encephalomyelitis (EAE) protection by TNF-treated semimatured DCs was dependent on NKT cells recognizing an endogenous CD1d ligand. NKT cell activation by TNF-matured DCs induced high serum levels of IL-4 and IL-13 which are absent in NKT cell-deficient mice, whereas LPS plus anti-CD40-treated fully mature DCs induce serum IFN-gamma. In the absence of IL-4Ralpha chain signaling or NKT cells, no complete EAE protection was achieved by TNF-DCs, whereas transfer of NKT cells into Jalpha281(-/-) mice restored it. However, activation of NKT cells alone was not sufficient for EAE protection and early serum Th2 deviation. Simultaneous activation of NKT cells and CD4(+) T cells by the same DC was required for EAE protection. Blocking experiments demonstrated that NKT cells recognize an endogenous glycolipid presented on CD1d on the injected DC. Together, this indicates that concomitant and interdependent presentation of MHC II/self-peptide and CD1d/self-isoglobotrihexosylceramide to T and NKT cells by the same partially or fully matured DC determines protective and nonprotective immune responses in EAE.
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PMID:Interdependency of MHC class II/self-peptide and CD1d/self-glycolipid presentation by TNF-matured dendritic cells for protection from autoimmunity. 1740 72

Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10(+) Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4(+) T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3(+) Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3(+) T cell-inducing tolerogenic DCs. SOCS3(-/-) DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3(-) effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3(+) Treg cells were selectively expanded by SOCS3(-/-) DCs. Adoptive transfer of SOCS3(-/-) DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3(+) T cell expansion was blocked by anti-TGF-beta Ab, and SOCS3(-/-) DCs produced higher levels of TGF-beta than WT-DCs, suggesting that TGF-beta plays an essential role in the expansion of Foxp3(+) Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs.
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PMID:Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells. 1767 76

Treatment with immune complexes, which ligate Fcgamma receptors (FcgammaRs), suppresses the development of experimental autoimmune encephalomyelitis (EAE). To determine the mechanism of action, we investigated how these immune complexes affected type II activation of macrophages (that is, exposure to immune complexes in a proinflammatory environment). Our results show that lower doses of interferon-gamma (IFN-gamma) were more effective at priming bone marrow-derived macrophages (BMMphi) to produce more interleukin 10 (IL-10) and less IL-12p40 in response to lipopolysaccharide (LPS) and immune complexes compared with LPS alone. Moreover, at the lowest level of IFN-gamma (20 U ml(-1)), a significant downregulation in the surface expression of CD40, CD80 and PD-L1 was observed in LPS and immune complex-stimulated macrophages (that is, type II activated) than macrophages stimulated with LPS alone (that is, classically activated). Finally, treatment of mice with type II-activated macrophages protected them from developing EAE, suggesting that administration of immune complexes is protective against EAE by inducing type II-activated macrophages.
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PMID:Type II-activated macrophages suppress the development of experimental autoimmune encephalomyelitis. 1910 4

The costimulatory requirements for Th17 development remain to be defined. In this study, we show that CD40-deficient animals immunized with the gram-positive bacterium Propionibacterium acnes were specifically impaired in their ability to mount an IL-17 response, but not that of IFN-gamma. The same cytokine imbalance resulted from in vivo priming with pathogen-pulsed, CD40-deficient dendritic cells (DC). Engagement of CD40 on P. acnes-conditioned DC stimulated the release of IL-12, IL-23, and IL-6, of which IL-6 alone proved essential for Th17 differentiation. Compared with wild-type DC, priming with those lacking expression of CD40 resulted in reduced disease severity during experimental autoimmune encephalomyelitis, coincident with reduced IL-17 production. Our data delineate sequential requirements for DC expression of CD40 and production of IL-6 during Th17 polarization in vitro and in vivo, and reveal distinct costimulatory requirements for Th1 vs Th17 generation.
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PMID:A pivotal role for CD40-mediated IL-6 production by dendritic cells during IL-17 induction in vivo. 1923 75

The objective of our study was to determine granulocyte-macrophage colony-stimulating factor (GM-CSF) activity in the brain following GM-CSF induction. We injected recombinant mouse GM-CSF into the brains of 8-month-old C57BL6 mice via intracerebroventricular injections and studied the activities of microglia, astrocytes, and neurons. We also sought to determine whether an anti-GM-CSF antibody could suppress endogenous microglial activity in the C57BL6 mice and could also suppress microglial activity induced by the recombinant mouse GM-CSF in another group of C57BL6 mice. Using quantitative real-time RT-PCR, we assessed microglial, astrocytic, and neuronal activity by measuring mRNA expression of pro-inflammatory cytokines, GFAP, and the neuronal marker NeuN in the cerebral cortex tissues from C57BL6 mice. We performed immunoblotting and immunohistochemistry of activated microglia in different regions of the brains from control (phosphate-buffered saline-injected C57BL6 mice) and experimental mice (recombinant GM-CSF-injected C57BL6 mice, GM-CSF antibody-injected C57BL6 mice, and recombinant mouse GM-CSF plus anti-GM-CSF antibody-injected C57BL6 mice). We found increased mRNA expression of CD40 (9.75-fold), tumor necrosis factor-alpha (2.1-fold), CD45 (1.73-fold), and CD11c (1.70-fold) in the cerebral cortex of C57BL6 mice that were induced with recombinant GM-CSF, compared with control mice. Further, the anti-GM-CSF antibody suppressed microglia in mice that were induced with recombinant GM-CSF. Our immunoblotting and immunohistochemistry findings of GM-CSF-associated cytokines in C57BL6 mice induced with recombinant GM-CSF, in C57BL6 mice injected with the anti-GM-CSF antibody, and in C57BL6 mice injected with recombinant mouse GM-CSF plus anti-GM-CSF antibody concurred with our real-time RT-PCR findings. These findings suggest that GM-CSF is critical for microglial activation and that anti-GM-CSF antibody suppresses microglial activity in the CNS. The findings from this study may have implications for anti-inflammatory effects of Alzheimer's disease and experimental autoimmune encephalomyelitis mice (a multiple sclerosis mouse model).
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PMID:Granulocyte-macrophage colony-stimulating factor antibody suppresses microglial activity: implications for anti-inflammatory effects in Alzheimer's disease and multiple sclerosis. 1984 Feb 15

Interleukin (IL)-23 is a heterodimeric cytokine composed of the IL-23-specific subunit p19 and the p40 subunit which also constitutes part of IL-12. IL-23 propagates development of Th17 cells, a novel T cell subset which produces IL-17 but no interferon-gamma or IL-4. For both, IL-23 and IL-23-driven IL-17, a crucial role in autoimmune diseases such as experimental autoimmune encephalomyelitis, collagen-induced arthritis, and colitis is well accepted. Recent studies indicate that there is also a role for IL-23 and IL-17 in tumorigenesis, promoting tumor growth and vascularization, and affecting tumor incidence. We show that human CD14(+) peripheral blood monocyte-derived dendritic cells (DC), as used for clinical applications in anti-tumor immunization strategies, produce high amounts of IL-23. CD40-triggering of immature and mature DC but not of primary monocytes induced a rapid expression of high levels of IL-23, free p40, and minor levels of IL-12. Upon stimulation of DC subsets with a variety of different danger signals such as single stranded and double stranded RNA, bacterial components or viral infections, IL-23 expression pattern was analyzed. Interestingly, co-stimulation with CD40L enabled IL-23 expression by DC subsets towards danger signals to which they have been unresponsive upon single stimulation. Furthermore, we detected two novel splice variants of the IL-23-specific subunit p19 that could be associated with the regulation of IL-23 expression. Data presented here might have an impact on DC-based cancer vaccination strategies and contribute to a better understanding of the complex regulation of the heterodimeric cytokine IL-23.
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PMID:CD40 ligand-triggered human dendritic cells mount interleukin-23 responses that are further enhanced by danger signals. 2007 Oct 30

The immunosuppressive function of regulatory B cells has been shown in several murine models of chronic inflammation, including collagen-induced arthritis, inflammatory bowel disease, and experimental autoimmune encephalomyelitis. Despite interest in these cells, their relevance to the maintenance of peripheral tolerance in humans remains elusive. Here, we demonstrate that human CD19(+)CD24(hi)CD38(hi) B cells possessed regulatory capacity. After CD40 stimulation, CD19(+)CD24(hi)CD38(hi) B cells suppressed the differentiation of T helper 1 cells, partially via the provision of interleukin-10 (IL-10), but not transforming growth factor-beta (TGF-beta), and their suppressive capacity was reversed by the addition of CD80 and CD86 mAbs. In addition, CD19(+)CD24(hi)CD38(hi) SLE B cells isolated from the peripheral blood of systemic lupus erythematosus (SLE) patients were refractory to further CD40 stimulation, produced less IL-10, and lacked the suppressive capacity of their healthy counterparts. Altered cellular function within this compartment may impact effector immune responses in SLE and other autoimmune disorders.
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PMID:CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. 2007 67

Mast cells in the CNS participate in the pathophysiology of chronic neurodegenerative inflammatory diseases. This study aimed to investigate the signaling pathway of mast cells activated in an environment cocultured with astrocytes and to explore the role of their colocalization in brain of experimental allergic encephalomyelitis. Human mast cell line-1 cells and human U87 glioblastoma cell lines (U87) or mouse bone marrow-derived mast cells and mouse cerebral cortices-derived astrocytes were cocultured. Intracellular Ca(2+) was measured by confocal microscopy; histamine by fluorometric analyzer; leukotrienes by ELISA; small GTPases, protein kinase Cs, MAPK, c-kit, CD40, and CD40L by Western blot; NF-kappaB and AP-1 by EMSA; cytokines by RT-PCR; and colocalization of mast cells and astrocytes in brain by immunohistochemistry. Mast cells cocultured with astrocytes showed time-dependent increases in intracellular Ca(2+) levels, release of histamine and leukotrienes, and cytokine production. Mast cells or astrocytes showed enhanced surface expression of CD40L and CD40, respectively, during coculture. Mast cells cocultured with astrocytes induced small GTPases (Rac1/2, cdc42), protein kinase Cs, MAPK, NF-kappaB, and AP-1 activities. These changes were blocked by anti-CD40 Ab pretreatment or CD40 small interfering RNA. Mast cells increased in the thalamus of experimental allergic encephalomyelitis model, particularly colocalized with astrocytes in the thalamic border region of the habenula. In conclusion, the data suggest that activation of mast cells cocultured with astrocytes induces release of mediators by small GTPases/Ca(2+) influx through CD40-CD40L interactions to participate in the pathophysiology of chronic neurodegenerative inflammatory diseases, such as multiple sclerosis.
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PMID:Signaling pathways in the activation of mast cells cocultured with astrocytes and colocalization of both cells in experimental allergic encephalomyelitis. 2051 59

B cells regulate autoimmune pathologies and chronic inflammatory conditions such as autoimmune encephalomyelitis and inflammatory bowel disease. The potential counterregulatory role of B cells in balancing pathogen-specific immune responses and the associated immunopathology is less well understood owing to the lack of appropriate persistent infection models. In this paper, we show that B cells have the ability to negatively regulate adaptive immune responses to bacterial pathogens. Using mouse models of infection with Helicobacter felis, a close relative of the human gastrointestinal pathogen H. pylori, we found that B cells activated by Helicobacter TLR-2 ligands induce IL-10-producing CD4(+)CD25(+) T regulatory-1 (Tr-1)-like cells in vitro and in vivo. Tr-1 conversion depends on TCR signaling and a direct T-/B-interaction through CD40/CD40L and CD80/CD28. B cell-induced Tr-1 cells acquire suppressive activity in vitro and suppress excessive gastric Helicobacter-associated immunopathology in vivo. Adoptive cotransfer of MyD88-proficient B cells and Tr-1 cells restores a normal gastric mucosal architecture in MyD88(-/-) and IL-10(-/-) mice in a manner that depends on T cellular, but not B cellular, IL-10 production. Our findings describe a novel mechanism of B cell-dependent Tr-1 cell generation and function in a clinically relevant disease model. In conclusion, we demonstrate that the B cell/Tr-1 cell axis is essential for balancing the control of Helicobacter infection with the prevention of excessive Th1-driven gastric immunopathology, promoting gastric mucosal homeostasis on the one hand and facilitating Helicobacter persistence on the other.
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PMID:TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. 2114 7


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