Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To better understand how innate and adaptive immune responses interact with each other, we combined 4-1BB T cell costimulation with specific adjuvants to determine whether these treatments would influence specific T cell expansion and function in vivo. In the presence of 4-1BB ligation and Toll-like receptor 3 (TLR)3 and/or TLR4 triggering, CD8 T cell clonal expansion and survival was augmented profoundly. Specific T cells primed in vivo with TLR ligands responded normally to in vitro recall stimulus, but, surprisingly, copriming with 4-1BB costimulation significantly impaired the recall response even though many more specific effector T cells were rescued in vivo. Here, we demonstrate that the rescued CD8 T cells suppressed CD4 T cell proliferation via a type beta transforming growth factor-dependent mechanism. Thus, 4-1BB and TLR ligands induce survival of specific effector CD8 T cells with suppressive recall potential, which may explain the dual role that 4-1BB activation plays in mediating tumor clearance and prevention of autoimmune disease.
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PMID:Effector CD8 T cells possess suppressor function after 4-1BB and Toll-like receptor triggering. 1269 69

Adjuvants historically are considered to stimulate immune responses 'non-specifically'. Recently, a renewed understanding of the critical role of innate immunity in influencing the development of an adaptive immune response has led researchers to a better understanding of 'the adjuvant effect'. Although innate immune cells do not respond to specific antigenic epitopes on pathogens, they do produce restricted responses to particular classes of pathogens via pattern recognition receptors such as Toll-like receptors (TLR). Coxsackievirus infection was found to upregulate TLR4 on mast cells and macrophages immediately following infection. Although both susceptible and resistant mice produce a mixture of Th1 and Th2 cytokines, susceptible mice have increased levels of key proinflammatory cytokines, increased numbers of mast cells, and go on to develop chronic autoimmune heart disease. TLR4 signalling also increases acute myocarditis and proinflammatory cytokines in the heart. Many similarities are described in the pathogenesis of Coxsackievirus and the adjuvant-induced model of myocarditis including upregulation of particular TLRs and cytokines soon after inoculation. Recent findings suggest that mast cell activation by viruses or adjuvants may be important in initiating autoimmune disease.
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PMID:Viruses as adjuvants for autoimmunity: evidence from Coxsackievirus-induced myocarditis. 1538 90

Environmental factors strongly influence the development of autoimmune diseases, including multiple sclerosis. Despite this clear association, the mechanisms through which environment mediates its effects on disease are poorly understood. Pertussis toxin (PTX) functions as a surrogate for environmental factors to induce animal models of autoimmunity, such as experimental autoimmune encephalomyelitis. Although very little is known about the molecular mechanisms behind its function in disease development, PTX has been hypothesized to facilitate immune cell entry to the CNS by increasing permeability across the blood-brain barrier. Using intravital microscopy of the murine cerebromicrovasculature, we demonstrate that PTX alone induces the recruitment of leukocytes and of active T cells to the CNS. P-selectin expression was induced by PTX, and leukocyte/endothelial interactions could be blocked with a P-selectin-blocking Ab. P-selectin blockade also prevented PTX-induced increase in permeability across the blood-brain barrier. Therefore, permeability is a secondary result of recruitment, rather than the primary mechanism by which PTX induces disease. Most importantly, we show that PTX induces intracellular signals through TLR4, a receptor intimately associated with innate immune mechanisms. We demonstrate that PTX-induced leukocyte recruitment is dependent on TLR4 and give evidence that the disease-inducing mechanisms initiated by PTX are also at least partly dependent on TLR4. We propose that this innate immune pathway is a novel mechanism through which environment can initiate autoimmune disease of the CNS.
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PMID:TLR4 contributes to disease-inducing mechanisms resulting in central nervous system autoimmune disease. 1555 5

Loss of tolerance is considered to be an early event that is essential for the development of autoimmune disease. In contrast to this expectation, autoimmune (type 1) diabetes develops in NOD mice that harbor an anti-insulin Ig transgene (125Tg), even though anti-insulin B cells are tolerant. Tolerance is maintained in a similar manner in both normal C57BL/6 and autoimmune NOD mice, as evidenced by B cell anergy to stimulation through their Ag receptor (anti-IgM), TLR4 (LPS), and CD40 (anti-CD40). Unlike B cells in other models of tolerance, anergic 125Tg B cells are not arrested in development, and they enter mature subsets of follicular and marginal zone B cells. In addition, 125Tg B cells remain competent to increase CD86 expression in response to both T cell-dependent (anti-CD40) and T cell-independent (anti-IgM or LPS) signals. Thus, for anti-insulin B cells, tolerance is characterized by defective B cell proliferation uncoupled from signals that promote maturation and costimulator function. In diabetes-prone NOD mice, anti-insulin B cells in this novel state of tolerance provide the essential B cell contribution required for autoimmune beta cell destruction. These findings suggest that the degree of functional impairment, rather than an overt breach of tolerance, is a critical feature that governs B cell contribution to T cell-mediated autoimmune disease.
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PMID:Uncoupling of anergy from developmental arrest in anti-insulin B cells supports the development of autoimmune diabetes. 1563 4

Toll-like receptors (TLR) represent an ancient front-line defence system that enables the host organism to sense the presence of microbial components within minutes. As inducers of inflammation, TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation. We report here that vitamin D3 [1alpha,25-dihydroxycholecalciferol, 1,25(OH)(2)D3] suppresses the expression of TLR2 and TLR4 protein and mRNA in human monocytes in a time- and dose-dependent fashion. Despite 1,25(OH)(2)D3-induced up-regulation of CD14, challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired TNF-alpha and procoagulatory tissue factor (CD142) production, emphasizing the critical role of TLR in the induction of inflammation. Moreover, reduced TLR levels in 1,25(OH)(2)D3-treated phagocytes were accompanied by impaired NF-kappaB/RelA translocation to the nucleus and by reduced p38 and p42/44 (extracellular signal-regulated kinase 1/2) phosphorylation upon TLR-ligand engagement. Both TLR down-regulation and CD14 up-regulation were substantially inhibited by the vitamin D receptor (VDR) antagonist ZK 159222, indicating that the immunomodulatory effect of 1,25(OH)(2)D3 on innate immunity receptors requires VDR transcription factor activation. Our data provide strong evidence that 1,25(OH)(2)D3 primes monocytes to respond less effectively to bacterial cell wall components in a VDR-dependent mechanism, most likely due to decreased levels of TLR2 and TLR4.
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PMID:Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. 1640 4

Inflammatory bowl disease (IBD) is a type 1 T helper cell (Th1)-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide (NO) released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Th1 cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-gamma (IFN-gamma)-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-gamma produced by Th1 cells.
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PMID:Inflammatory bowel disease requires the interplay between innate and adaptive immune signals. 1646 77

Inflammation under sterile conditions is not well understood despite its importance in trauma and autoimmune disease. To investigate this process we established mouse models of sterile injury and explored the role of hyaluronan in mediating inflammation following injury. The response of cultured monocytes to hyaluronan was different than the response to lipopolysaccharide (LPS) despite both being dependent on Toll-like receptor 4 (TLR4). Cultured cells exposed to hyaluronan showed a pattern of gene induction that mimics the response seen in mouse skin after sterile injury with an increase in molecules such as transforming growth factor-beta2 and matrix metalloproteinase-13. These factors were not induced by LPS despite the mutual dependence of both hyaluronan and LPS on TLR4. Explanation for the unique response to hyaluronan was provided by observations that a lack of TLR4 or CD44 in mice diminished the response to sterile injury, and together with MD-2, was required for responsiveness to hyaluronan in vitro. Thus, a unique complex of TLR4, MD-2, and CD44 recognizes hyaluronan. Immunoprecipitation experiments confirmed the physical association of TLR4 and CD44. Taken together, our results define a previously unknown mechanism for initiation of sterile inflammation that involves recognition of released hyaluronan fragments as an endogenous signal of tissue injury.
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PMID:Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. 1740 May 52

Autoimmune diseases such as glomerulonephritis are exacerbated by infection. This study examined the effect of the Toll-like receptor 4 (TLR4) ligand lipid A on the development of heterologous nephrotoxic nephritis. Administration of nephrotoxic antibody resulted in significant glomerular neutrophil infiltration and albuminuria only when a TLR4 ligand was administered simultaneously. The contribution of TLR4 on renal cells and circulating leukocytes was assessed. Bone marrow chimeras were constructed with TLR4 only on renal cells or bone marrow-derived cells. The administration of nephrotoxic serum and lipid A caused a neutrophil influx in both chimeric groups greater than in sham chimeras that were totally TLR4 deficient but significantly less than in sham chimeras that were totally TLR4 sufficient. Both chimeric groups had greater albuminuria than totally TLR4-deficient sham chimeras; however, the chimeras with TLR4 only on intrinsic renal cells had significantly less than the sham positive group. In situ hybridization showed expression of TLR4 mRNA in mesangial cells and glomerular epithelial cells. For investigation of the potential mechanism by which renal cells could contribute to disease exacerbation, mesangial cells were cultured and found to express mRNA for TLR4, and stimulation of wild-type and TLR4-deficient mesangial cells with LPS caused production of CXC chemokines by wild-type cells only. Treatment of chimeras with TLR4 present only on intrinsic renal cells with anti-CXCL1 and anti-CXCL2 antibody before disease induction significantly reduced renal neutrophil infiltration. These results show that TLR4 on both circulating leukocytes and intrinsic renal cells contributes to the inflammatory effects of antibody deposition within the glomerulus, which depends at least in part on the production of CXC chemokines by intrinsic renal cells.
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PMID:Toll-like receptor 4 ligation on intrinsic renal cells contributes to the induction of antibody-mediated glomerulonephritis via CXCL1 and CXCL2. 1746 Jan 47

Previous studies have shown that cannabinoids have anti-inflammatory and immune-modulating effects, but the precise mechanisms of action remain to be elucidated. In this study, we investigated the effect of JWH 133, a selective agonist for cannabinoid receptor 2, the main receptor expressed on immune cells, in a model of autoimmune disease, experimental autoimmune uveoretinitis (EAU). JWH 133 suppressed EAU in a dose-dependent manner (0.015-15 mg/kg), and the suppressive effect could be achieved in the disease-induction stage and the effector stage. Leukocytes from mice, which had been treated with JWH 133, had diminished responses to retinal peptide and mitogen Con A stimulation in vitro. In vivo JWH 133 treatment also abrogated leukocyte cytokine/chemokine production. Further in vitro studies indicated that JWH 133 down-regulated the TLR4 via Myd88 signal transduction, which may be responsible for its moderate, suppressive effect on antigen presentation. In vivo JWH 133 treatment (1 mg/kg) also suppressed leukocyte trafficking (rolling and infiltration) in inflamed retina as a result of an effect on reducing adhesion molecules CD162 (P-selectin glycoprotein ligand 1) and CD11a (LFA-1) expression on T cells. In conclusion, the cannabinoid agonist JWH 133 has a high in vivo, anti-inflammatory property and may exert its effect via inhibiting the activation and function of autoreactive T cells and preventing leukocyte trafficking into the inflamed tissue.
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PMID:Anti-inflammatory property of the cannabinoid receptor-2-selective agonist JWH-133 in a rodent model of autoimmune uveoretinitis. 1753 89

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic joint inflammation and variable degrees of bone and cartilage erosion. Studies in animal models of arthritis provide insight into elements which can amplify destructive features. The presence of immune complexes in the joint makes arthritis more erosive. Although considerable bone erosion still occurs in the absence of FcgammaR triggering by immune complexes, through cytokine-induced RANKL and direct osteoclast activation, cartilage erosion is heavily dependent on the FcgammaR pathway. T cell factors such as IFNgamma and IL17 further amplify erosion through upregulation of the damaging FcgammaRI and stimulation of the influx of granulocytes, respectively. Apart from immune elements, environmental pressure and components of tissue damage contribute through innate pathways. Spontaneous T cell-dependent arthritis in IL1Ra-/- mice is absent under germ-free conditions, and markedly suppressed in TLR4-deficient mice. Moreover, TLR4 blocking with a receptor antagonist suppresses erosive arthritis.
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PMID:Amplifying elements of arthritis and joint destruction. 1793 95


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