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)

IL-12 and IL-12 antagonist administration to nonobese diabetic (NOD) mice accelerates and prevents insulin-dependent diabetes mellitus (IDDM), respectively. To further define the role of endogenous IL-12 in the development of diabetogenic Th1 cells, IL-12-deficient NOD mice were generated and analyzed. Th1 responses to exogenous Ags were reduced by approximately 80% in draining lymph nodes of these mice, and addition of IL-12, but not IL-18, restored Th1 development in vitro, indicating a nonredundant role of IL-12. Moreover, spontaneous Th1 responses to a self Ag, the tyrosine phosphatase-like IA-2, were undetectable in lymphoid organs from IL-12-deficient, in contrast to wild-type, NOD mice. Nevertheless, wild-type and IL-12-deficient NOD mice developed similar insulitis and IDDM. Both in wild-type and IL-12-deficient NOD mice, approximately 20% of pancreas-infiltrating CD4+ T cells produced IFN-gamma, whereas very few produced IL-10 or IL-4, indicating that IDDM was associated with a type 1 T cell infiltrate in the target organ. T cell recruitment in the pancreas seemed favored in IL-12-deficient NOD mice, as revealed by increased P-selectin ligand expression on pancreas-infiltrating T cells, and this could, at least in part, compensate for the defective Th1 cell pool recruitable from peripheral lymphoid organs. Residual Th1 cells could also accumulate in the pancreas of IL-12-deficient NOD mice because Th2 cells were not induced, in contrast to wild-type NOD mice treated with an IL-12 antagonist. Thus, a regulatory pathway seems necessary to counteract the pathogenic Th1 cells that develop in the absence of IL-12 in a spontaneous chronic progressive autoimmune disease under polygenic control, such as IDDM.
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PMID:Pancreas-infiltrating Th1 cells and diabetes develop in IL-12-deficient nonobese diabetic mice. 1045 45

Experimental Allergic Encephalomyelitis (EAE) is a demyelinating disease of the central nervous system which is an animal model for the human autoimmune disease, multiple sclerosis. EAE is mediated by CD4+ T cells and the T cells responsible for disease induction produce Th1 cytokines. IL-12 produced by monocytes and dendritic cells is the most critical factor which influences the development and differentiation of pathogenic autoreactive Th1 cells. Here, we review our recent studies on the critical contributions of IL-12 and the IL-12R beta 2 subunit to the generation of autoreactive effector cells which mediate EAE. In addition, we discuss the potential contribution of IL-18 to the upregulation of the IL-12/IL-12R beta 2 pathway and the contribution of the suppressor cytokines, IL-4 and IL-10, in downregulating this pathway. Collectively, our studies demonstrate that the IL-12/IL-12R beta 2 pathway is a critical intermediary in the process of Th1 differentiation which can be both positively or negatively regulated. This pathway remains an attractive immunotherapeutic target for blockade of function with inhibitory reagents or downregulation by Th2 cytokines.
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PMID:The critical role of IL-12 and the IL-12R beta 2 subunit in the generation of pathogenic autoreactive Th1 cells. 1066 72

Natural killer (NK) cells can affect the outcome of adaptive immune responses. NK cells, but not NK1.1+T cells, were found to participate in the development of myasthenia gravis (a T cell-dependent, B cell- and antibody-mediated autoimmune disease) in C57BL/6 mice. The requirement for NK cells was reflected by the lack of a type I helper T cell response and antibodies to the acetylcholine receptor in both NK1.1+ cell-depleted and NK cell-deficient IL-18-/- mice. These findings establish a previously unrecognized link between NK cells and autoreactive T and B cells.
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PMID:Natural killer cells determine the outcome of B cell-mediated autoimmunity. 1097 83

B10.Q mice are normally susceptible to the induction of collagen-induced arthritis. We noted that one subline of B10.Q mice, B10.Q/J, was completely resistant to disease induction when immunized with collagen in CFA. B10.Q/J mice have a global defect in the generation of Th1 responses, and Ag-specific T cells derived from this strain failed to produce IFN-gamma. Because T cells from these mice could produce normal amounts of IFN-gamma when activated by IL-12/IL-18-independent stimuli, the defect appeared to be a failure to respond to IL-12. This defect extended to NK cells, which also failed to produce IFN-gamma when stimulated by IL-12. The capacity of NK cells, but not activated T cells, to produce IFN-gamma in response to IL-12 could be partially restored by IL-18. The expression of the IL-12R beta1- and beta2-chains on T cells and NK cells from B10.Q/J mice was normal. However, activated T cells from B10.Q/J mice did not signal normally through the IL-12R and manifested a defect in their capacity to phosphorylate Stat4. This defect was partial in that it could be overcome by increasing both the concentration of IL-12 and the incubation times in the Stat4 phosphorylation assays. Because Stat4 function is apparently intact in B10.Q/J mice, the defect in IL-12 signaling can be localized between the IL-12R complex and Stat4. This subtle abnormality in IL-12 responsiveness results in a profound defect in the generation of Th1 cells and the development of autoimmune disease.
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PMID:A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis. 1131 13

The apoptosis-defective lpr (fas) mutation in MRL mice causes the early onset of a lupus-like autoimmune disease with concomitant inflammation. In order to analyse the consequences of the impaired Fas-dependent apoptosis on inflammation, the susceptibility to apoptosis of polymorphonuclear leukocytes (PMN), obtained from MRL lpr/lpr mice, has been studied. Peritoneal PMN from lpr/lpr and control (+/+) mice were recruited with a mild inflammatory stimulus. The number of cells collected from the peritoneal cavity of young lpr/lpr mice was comparable to that obtained from age-matched control mice, indicating that PMN homeostasis is maintained regardless of the loss-of-function Fas mutation. Recruited neutrophils were exposed in culture to apoptosis-inducing stimuli. Treatment with agonist anti-Fas antibody increased apoptosis of +/+ PMN, but did not affect lpr/lpr PMN which do not express Fas on their surface. However, lpr/lpr PMN could undergo both spontaneous and stimulus-induced apoptosis in a fashion comparable to or higher than that of control +/+ mice. Analysis of mRNA expression revealed that lpr/lpr PMN have reduced expression of IL-18, whereas IL-1beta, IFNgamma, caspase 1 and caspase 3 are expressed at levels comparable to those of +/+ cells. However, caspase-3-like activity was higher in PMN from lpr/lpr mice than in +/+ cells, and correlated with enhanced apoptosis. It could be concluded that in young, uncompromised lpr/lpr mice, PMN homeostasis is still fully regulated through the involvement of Fas-independent, compensatory, apoptotic mechanisms. This could include an increased participation of caspase 3 in the apoptotic pathway, consequent to enhanced activation of the enzyme and to the decreased production of IL-18, which acts as a competitive caspase 3 substrate.
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PMID:Neutrophil apoptosis in autoimmune Fas-defective MRL lpr/lpr mice. 1156 32

Serum from patients with systemic lupus erythematosus (SLE) contained significantly higher concentrations of IL-18 than normal individuals. MRL/lpr mice, which develop spontaneous lupus-like autoimmune disease, also had higher serum levels of IL-18 than wild-type MRL/++ mice. Daily injections of IL-18 or IL-18 plus IL-12 resulted in accelerated proteinuria, glomerulonephritis, vasculitis, and raised levels of proinflammatory cytokines in MRL/lpr mice. IL-18-treated MRL/lpr mice also developed a "butterfly" facial rash resembling clinical SLE. In contrast, MRL/lpr mice treated with IL-18 plus IL-12 did not develop a facial rash. The facial lesion in the IL-18-treated mice showed epidermal thickening with intense chronic inflammation accompanied by increased apoptosis, Ig deposition, and early systemic Th2 response compared with control or IL-12 plus IL-18-treated mice. These data therefore show that IL-18 is an important mediator of lupus-like disease and may thus be a novel target for therapeutic intervention of spontaneous autoimmune diseases.
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PMID:A proinflammatory role of IL-18 in the development of spontaneous autoimmune disease. 1167 50

In this study, the authors show that MG as an autoantibody-mediated disorder of neuromuscular transmission is associated with elevated serum levels of the interferon-gamma-inducing cytokine interleukin (IL)-18. IL-18 levels were higher in generalized than in ocular myasthenia and tended to decrease on clinical improvement. These findings suggest an unexpected role of IL-18 in B-cell-mediated autoimmune disease.
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PMID:Increased serum levels of the interferon-gamma-inducing cytokine interleukin-18 in myasthenia gravis. 1213 75

IL-12 is thought to be involved in the susceptibility to experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. IL-12 signals through a heterodimeric receptor (IL-12Rbeta1/IL-12Rbeta2), whose beta2-chain is up-regulated on activated, autoreactive Th1 cells. Contrary to the expectation that the absence of IL-12Rbeta2 would protect from EAE, we found that IL-12Rbeta2-deficient mice developed earlier and more severe disease, with extensive demyelination and CNS inflammation. The inflammatory cells were mainly comprised of CD4(+) T cells, monocyte/macrophages, and dendritic cells. Compared to wild-type mice, IL-12Rbeta2-deficient mice exhibited significantly increased autoantigen-induced proliferative response and increased production of TNF-alpha, GM-CSF, IL-17, IL-18/IL-18Ralpha, and NO. In addition, we found significantly increased levels of IL-23p19 mRNA expression in spleen cells from immunized IL-12Rbeta2(-/-) mice compared with wild-type mice. These findings indicate that IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS, and that, in the absence of IL-12Rbeta2, increased IL-23 and other inflammatory molecules may be responsible for increased severity of EAE.
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PMID:Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. 1257 88

Oral administration of Hachimi-jio-gan (HMG, Ba-Wei-Di-Huang-Wan), a traditional Japanese herbal medicine, for several weeks, ameliorates some autoimmune symptoms of MRL/lpr mice. In the short time treatment for 9 days, hyperresponsiveness of mesenteric lymph node (MLN) cells to interleukin (IL)-18 manifested by the proliferation or the production of interferon (IFN)-gamma was significantly suppressed. Additionally, the treatment with HMG suppressed the expressions of IL-18Ralpha and IL-18Rbeta mRNA in CD45R(-) T cells, and also the expression of IL-18Ralpha mRNA in unpurified whole cells. Although the short treatment with HMG had no effect on the mRNA expressions of IL-10, IL-12 and IL-18, or the phosphorelated signal transducer and activator transcription (STAT)4 protein level in CD45R(-) MLN cells, the IL-4 mRNA expression or the phosphorelated STAT6 protein level were up-regulated by HMG, and the IL-4 mRNA up-regulation was clearer in whole cells than CD45R(-) cells. Furthermore, the treatment with HMG promoted the mRNA expression of invariant Valpha14 TCR that is uniquely expressed on NKT cells. Valpha14 NKT cells can produce large amount of IL-4 and play a crucial role in controlling the development of MRL/lpr mouse autoimmune disease. Therefore, these results suggested that HMG reduced the hyperresponsiveness of MRL/lpr mouse MLN cells to IL-18 through the reduction of IL-18Rs caused by Valpha14 NKT cell-produced IL-4, and consequently HMG suppressed the development of MRL/lpr autoimmune diseases.
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PMID:Suppressive effect of a traditional Japanese medicine, Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan), on the hyperresponsiveness to IL-18 in autoimmune MRL/MPJ-lpr/lpr mice. 1263 14

Autoimmune disease in MRL-Fas(lpr) mice is characterized by fatal nephritis, systemic pathology, and autoantibodies, mimicking human lupus. We previously reported that 1) intrarenal IL-12 elicits nephritis by fostering the accumulation of intrarenal IFN-gamma-secreting T cells, and 2) MRL-Fas(lpr) mice deficient in the IFN-gamma receptor were spared from nephritis. Therefore, we hypothesized that eliminating IL-12 in MRL-Fas(lpr) mice reduces IFN-gamma-secreting cells and thereby prevents systemic pathology. For this purpose, we constructed an IL-12p40-deficient MRL-Fas(lpr)(IL-12(-/-)) strain. We determined that glomerular and interstitial, but not perivascular, renal pathology were decreased in IL-12(-/-) mice vs the wild-type (WT) strain (5 mo of age). Similarly, systemic pathology (lung, lacrimal and salivary glands, skin, and lymphadenopathy) was diminished. The intrarenal accumulation of T cells (CD4(+), CD8(+), CD4(-)CD8(-)B220(+)) and macrophages was dramatically reduced in IL-12(-/-) MRL-Fas(lpr) kidneys. We determined that there were fewer IFN-gamma transcripts (>70%) in the IL-12(-/-) protected kidneys compared with the WT kidneys. Similarly, cells propagated from IL-12(-/-) MRL-Fas(lpr) kidneys generated substantially less IFN-gamma when stimulated with IL-12 and IL-18 compared with those from WT kidneys, and we detected fewer CD8 and B220 T cells producing IFN-gamma in these IL-12(-/-) MRL-Fas(lpr) kidneys. Of note, survival was modestly extended in the IL-12(-/-) MRL-Fas(lpr) mice. While lung and lacrimal and salivary gland pathology remained reduced in moribund IL-12(-/-) MRL-Fas(lpr) mice, renal pathology and IFN-gamma expression were equivalent to those in the WT strain. Thus, we suggest that IL-12 is a therapeutic target for multiple tissues in lupus; however blocking IL-12 alone is not sufficient to confer enduring protection from lupus nephritis.
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PMID:IL-12 deficiency in MRL-Fas(lpr) mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology. 1264 61


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