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

Mucosal administration of autoantigens results in the development of a state of peripheral immunological tolerance. Depending upon the dose of antigen administered, anergy/deletion of antigen-specific T cells (higher doses) and/or selective expansion of cells producing immunosuppressive cytokines (TGF-beta, IL-4, and IL-10) (lower doses) are two major mechanisms in mucosal tolerance induction. Mucosal tolerance is more effective after nasal compared to oral administration of antigens at the same dose. A large series of studies have demonstrated that mucosal tolerance by oral or nasal antigen administration effectively prevents several experimental disease models (EAE, EAMG, EAN, EAU, IDDM, and CIA). Mucosal antigen administration is superior in prevention to treatment of autoimmune diseases. To broaden the effectiveness of mucosal tolerance, a conjunction of tolerogens with cytokines/CTB might enhance suppression of clinical disease. Based on experimental experience with mucosal tolerance, trials in humans are ongoing in MS, RA, and uveitis. However, mucosal tolerance induction is related to the route of antigen administration (oral, nasal, parentetal), type of antigen (whole protein, peptide, altered peptide), and timing with regard to disease onset and may represent a two-edged sword. In particular, the risks of worsening an ongoing autoimmune disease by mucosal antigen administration have been incompletely addressed. Here we give an overview on some recent developments in this field where, however, much more studies are needed to define an ultimate and safe procedure.
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PMID:Mucosal tolerance: a two-edged sword to prevent and treat autoimmune diseases. 934 93

Autoimmune diseases induced by mercuric chloride are genetically determined, at least one gene being major histocompatibility complex (MHC)-linked. Previously, we showed that in vitro mercury stimulation induced a high proliferative response in lymphocytes from susceptible mice (high-responders) and that the proliferative response could be restored in lymphocytes from low-responders by pretreating the cells with mercury. We also found that the continuous presence of mercury induced IL-2 and IFN-gamma production, while pretreatment with mercury induced IL-4 production. In this study, we showed that anti-MHC class II monoclonal antibodies blocked both the mercury-induced proliferative responses in lymphocytes from high-responders and the restored proliferative responses in low-responders. In addition, anti-MHC class II antibodies also inhibited the mercury-induced IL-2, IFN-gamma and IL-4 cytokine production in vitro. The results demonstrate that MHC class II antigens directly participate in mercury-induced cytokine production and cell activation, and are required at the onset of the initiation.
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PMID:Major histocompatibility complex class II antigens are required for both cytokine production and proliferation induced by mercuric chloride in vitro. 937 71

Mercuric chloride (HgCl2) induces T helper 2 (Th2) autoreactive anti-class II T cells in Brown Norway rats. These cells produce interleukin (IL)-4 and induce a B cell polyclonal activation that is responsible for autoimmune disease. In Brown Norway rats, HgCl2 triggers early IL-4 mRNA expression both in vivo and in vitro by T cells, which may explain why autoreactive anti-class II T cells acquire a Th2 phenotype. The aim of this study was to explore the transduction pathways by which this chemical operates. By using two murine T cell hybridomas that express IL-4 mRNA upon stimulation with HgCl2, we demonstrate that: 1) HgCl2 acts at the transcriptional level without requiring de novo protein synthesis; 2) HgCl2 induces a protein kinase C-dependent Ca2+ influx through L-type calcium channels; 3) calcium/calcineurin-dependent pathway and protein kinase C activation are both implicated in HgCl2-induced IL-4 gene expression; and 4) HgCl2 can activate directly protein kinase C, which might be one of the main intracellular target for HgCl2. These data are in agreement with an effect of HgCl2 which is independent of antigen-specific recognition. It may explain the T cell polyclonal activation in the mercury model and the expansion of pathogenic autoreactive anti-class II Th2 cells in this context.
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PMID:HgCl2-induced interleukin-4 gene expression in T cells involves a protein kinase C-dependent calcium influx through L-type calcium channels. 940 50

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by the destruction of insulin-producing beta-cells in the pancreatic islets. A single administration of CFA prevents clinical hyperglycaemia in non-obese diabetic (NOD) mice. We have previously shown that CFA administration does not eliminate insulitis in the pancreas of the treated animals, but diverts the disease process from a destructive to a non-destructive pathway. We provide evidence that this phenomenon may be under cytokine control. Neutralizing monoclonal antibodies against IL-4 and IL-10 were injected, singularly or in combination, into CFA-treated NOD mice. Antibody treatment did not lead to the development of overt diabetes; however, a marked impairment of glucose tolerance was shown in about one half of the mice treated with a combination of the two antibodies at the end of the study. This functional abnormality correlated with the histological loss of pancreatic islet tissue. These studies suggest a role for IL-4 and IL-10 in CFA-induced protection from diabetes in the NOD mouse. They also suggest that, in this animal model, the nature of the autoimmune response to islet tissue (either destructive or non-destructive) may reflect the relative proportion of Th1- and Th2-type cytokines produced in the lesions.
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PMID:Protection from autoimmune diabetes by adjuvant therapy in the non-obese diabetic mouse: the role of interleukin-4 and interleukin-10. 942 94

Graves' ophthalmopathy is an organ-specific autoimmune disorder in which the target organs are infiltrated by T lymphocytes and polymorphonuclear neutrophils that release immunoregulatory cytokines in the thyroid and retrobulbar tissues. Th2-type cytokines (IL-4, IL-5, IL-6) support the inflammatory symptoms and immunoglobulin production, e.g. IgE isotype. IgE is thought to play a part not only in allergy but also in the normal immune responses, antigen processing and presentation. Since studies report IgE accumulation around the extraocular muscles in ophthalmopathy and a correlation between the total IgE levels and the severity of ophthalmopathy in Graves' disease, we measured the total IgE levels in 56 patients with Graves' disease (associated with ophthalmopathy in 47 patients) and in 42 healthy subjects as controls to determine if IgE plays a part in the autoimmune or the local inflammatory processes. For detection we used the Enzymun-Test IgE, which was a two-step ELISA sandwich assay. Elevated circulating IgE levels could be demonstrated in non-treated hyperthyroid Graves' patients in comparison with the controls (51.02 +/- 113.16 IU/ml vs 34.95 +/- 54.91 IU/ml, P < 0.01). The IgE levels were higher in patients with active inflammatory eye signs (63.65 +/- 130.41 IU/ml) than in controls (P < 0.007). The anti-thyroid drug and glucocorticoid management decreased the total IgE levels, and the difference was significant after the treatment compared with the values at the beginning of the therapy in the Graves' patients without ophthalmopathy (17.34 +/- 6.34 IU/ml vs 13.01 +/- 9.86 IU/ml, P < 0.03). In conclusion, since the results suggested that IgE plays a role in the inflammatory eye signs in Graves' ophthalmopathy, we propose administering antihistamines for medical management.
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PMID:Detectable serum IgE levels in Graves' ophthalmopathy. 943 58

Infant-onset myasthenia gravis, an autoimmune disease specific to Asians predominantly affects neuromuscular junctions in ocular muscles. An AChR alpha peptide (p71-91) specific autoreactive CD4+ alpha beta T cell clone was established by stimulating PBMC from a patient heterozygous for two disease-susceptible HLA-DR9-DQ9 and DR13-DQ6 haplotypes with a mixture of overlapping peptides covering AChR alpha. The T cell clone recognized the AChR alpha peptide in the context of the HLA-DQ6 molecule and produced a large amount of IFN-gamma and a trace amount of IL-4. A part (p75-83) of the core epitope of the autoantigenic peptide (p75-87) is encoded for by an exon P3A of the AChR alpha gene which can be alternatively spliced. The T cell clone responded to the recombinant AChR alpha protein with a P3A exon product, but not without a P3A exon product. We investigated responses of the T cell clone to 114 analogue peptides carrying single residue substitutions of the core AChR alpha peptide. The majority of analogues substituted at residues Phe-77, Leu-80 and Asn-82 stimulated proliferation of the T cell clone. Conversely, the majority of analogue peptides substituted at either Gln-81 or Glu-83 did not stimulate proliferative responses, and all exhibited strong or intermediate inhibitory effects on proliferative responses of the T cell clone to the wild type peptide, possibly by TCR antagonism. Thus, an HLA class II allele specific to Asians may directly control susceptibility to the Asian-specific type of myasthenia gravis. Analogues of the auto-antigenic AChR alpha peptide may prove effective for new immunosuppressive therapy.
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PMID:Immuno-suppressive peptides for a human T cell clone autoreactive to a unique acetylcholine receptor alpha subunit peptide presented by the disease-susceptible HLA-DQ6 in infant-onset myasthenia gravis. 945 91

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune demyelinating disease of the central nervous system that serves as an animal model for multiple sclerosis. Antigen-specific tolerance regimens, including oral tolerance, have been used prophylactically to prevent development of acute EAE as well as a number of other autoimmune diseases. Two mechanisms have been proposed to explain the immunologic basis for disease inhibition: bystander immune suppression and clonal anergy/deletion. This report demonstrates a novel mechanism for monocyte chemotactic protein (MCP)-1 as a regulatory factor of oral tolerance. Oral administration of proteolipid protein peptide (PLP139-151) increased MCP-1 expression in the intestinal mucosa, Peyer's patch, and mesenteric lymph nodes. Increase in MCP-1 expression resulted in downregulation of mucosal interleukin (IL)-12 expression with concomitant increase in mucosal IL-4 expression. Functionally, MCP-1 upregulation was shown to regulate oral tolerance induction by the ability of antibodies to MCP-1 to inhibit tolerance induction. The anti-MCP-1 abrogation of oral tolerance induction also resulted in restoration of mucosal IL-12 expression as well as peripheral antigen-specific T helper cell 1 responses. These results demonstrate a novel and important role for MCP-1 in the regulation or oral tolerance for the prevention and treatment of autoimmune disease.
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PMID:Monocyte chemotactic protein 1 regulates oral tolerance induction by inhibition of T helper cell 1-related cytokines. 948 Sep 83

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the accumulation of inflammatory cells into the synovium and the destruction of joints. Cytokines are important regulators of the synovial inflammation. Some cytokines, such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1, function by promoting inflammatory responses and by inducing cartilage degradation. Other cytokines, such as IL-4, IL-10 and IL-13, function mainly as anti-inflammatory molecules. Although anti-inflammatory cytokines are present in rheumatoid joints, in progressive RA their levels obviously are too low to neutralize the deleterious effects of proinflammatory cytokines. Inhibiting the action of proinflammatory cytokines by using specific cytokine inhibitors or anti-inflammatory cytokines is the basis for new therapies currently tested in patients with RA. Promising results on the use of neutralizing anti-TNF-alpha monoclonal antibodies in the treatment of RA have been reported. The results from a trial using recombinant IL-10 in the treatment of patients with RA are available in the near future and will be important in determining the therapeutic potential of this cytokine.
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PMID:Pro- and anti-inflammatory cytokines in rheumatoid arthritis. 956 16

Experimental autoimmune encephalomyelitis (EAE) is a Th1-type cell-mediated autoimmune disease directed against central nervous system (CNS) myelin antigens such as myelin basic protein (MBP). EaE is usually characterized by spontaneous remission of clinical disease and immune pathology despite the persistence of self myelin antigens in the central nervous system. Following induction of an acute episode of EAE, spontaneous remission also occurs in MBP T cell receptor (TCR) transgenic mice even through most T cells express a TCT specific for MBP. To investigate the mechanisms of recovery associated with EAE, we examined the behavior of MBP-specific T cells in the MBP TCR transgenic mouse model during disease progression and recovery. We found that recovery from EAE was associated with three major immunologic changes: (1) deletion of encephalitogenic T cells in the brain; (2) deviation of MBP-specific transgenic (Tg+) T cells both in the periphery and in the central nervous system from INF- gamma secretin Th1 type cells to cells that secrete IL-4, IL-10, and TGF- beta ; and (3) deletion of Tg+ T cells in the thymus through apoptosis. Thus spontaneous recovery from a classic Th1 type organ specific autoimmune disease is associated with two mechanisms of immune tolerance, deletion of autoreactive cells and immune deviation of autoreactive cells to a non-pathogenic phenotype.
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PMID:Mechanisms of recovery from experimental autoimmune encephalomyelitis: T cell deletion and immune deviation in myelin basic protein T cell receptor transgenic mice. 958 11

Oral administration of Ag results in systemic hyporesponsiveness termed oral tolerance. The regulatory cells induced by oral Ag are effective in the suppression of Th1-type autoimmune diseases. We examined the cytokine microenvironment in gut-associated lymphoid tissue in response to orally administered OVA in OVA TCR-transgenic mice. Mice were fed a low (0.5 mg) or high (500 mg) dose of OVA one time or five times. Immunohistochemical analysis demonstrated increased IL-4, IL-10, and TGF-beta in the gut within 6 h of a low-dose feeding and after five low-dose or high-dose feedings. IFN-gamma and IL-2 either decreased or showed no change, with the exception of a small transient increase in IL-2 at 6 h after a low dose. Increases in IL-4 and IL-10 were found in the dome of the Peyer's patch, and increases in TGF-beta were observed in the interfollicular region and the villi. IL-10 was also substantially increased in the villi. IL-4 and IL-10 were produced predominately by CD4+ T cells. TGF-beta was found predominately in macrophages and CD4+ T cells. Peyer's patches had a marked up-regulation of TGF-beta mRNA as measured by RT-PCR. These results demonstrate the differential activation of cytokine production in discrete regions of gut-associated lymphoid tissue. The induction of cytokines known to inhibit autoimmune disease at the site of Ag absorption indicates an important role for the mucosal immune system in the establishment of oral tolerance.
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PMID:In situ immune response in gut-associated lymphoid tissue (GALT) following oral antigen in TCR-transgenic mice. 959 Feb 16


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