UMLS:C0003864 - FACTA Search

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Query: UMLS:C0003864 (arthritis)
69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study the roles of different T-cell subsets, and produced cytokines, were investigated in an animal model for acute exacerbations. Flare-up reactions are inducible in the chronic phase of a smouldering antigen-induced inflammation by injection of a small amount of an antigen into a hyper-reactive knee joint. In vivo treatment with anti-CD4 monoclonal antibodies (mAb) almost totally blocked the flare reaction, whereas anti-CD8 treatment did not exert any effect. The role of T-helper 1 (Th1) cells in delayed-type hypersensitivity-resembling diseases is generally entitled proinflammatory, whereas Th2 cells act in an anti-inflammatory manner. To investigate the role of these T-cell subsets in flare-up reactions, anti-interleukin-2 (IL-2) and anti-IL-4 mAb treatments were performed. Anti-IL-2 treatment partly blocked the flare reaction, and anti-IL-4 treatment, although the result was unexpected, blocked the flare more efficiently. Furthermore, when human recombinant IL-2 (hrIL-2) and murine recombinant IL-4 (mrIL-4) were co-injected with the antigen to test their ability respectively to potentiate or down-regulate the flare reaction, both cytokines demonstrated additional pro-inflammatory effects, although hrIL-2 was more potent than mrIL-4. The mere effect of hrIL-2 and mrIL-4 was studied by direct injection into a hyperreactive joint. No flare-up reaction or cell-influx could be induced, suggesting that other mediators are needed to exert pro-inflammatory effects of IL-2 or IL-4. We conclude that not only Th1 cells, but also Th2 lymphocytes (at least regarding IL-4 production) may play a pro-inflammatory role in flare-up reactions of chronic arthritis. Considering therapeutic application of Th2 cell-derived cytokines, one should be aware of the possible pro-inflammatory potential of IL-4.
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PMID:Role of IL-2 and IL-4 in exacerbations of murine antigen-induced arthritis. 783 64

Infection of inbred mice with Borrelia burgdorferi results in strain-specific variation in the severity of pathogen-induced arthritis: BALB/c mice develop only mild disease whereas C3H/HeJ mice develop severe arthritis. The immunologic basis for varying host susceptibility has yet to be defined. We modified experimental Lyme disease to facilitate measurement of antigen-specific cytokine production in resistant and susceptible mice. The analysis revealed highly polarized lymphokine patterns directly linked to differing disease outcomes. Among the inbred strains of mice challenged with B. burgdorferi, production of interleukin 4 (IL-4) correlated to resistance whereas production of interferon gamma (IFN-gamma) correlated to susceptibility. We also demonstrate that production of IL-4 or IFN-gamma regulates the severity of arthritis after infection. Neutralization of IL-4 in resistant BALB/c mice resulted in more severe arthritis whereas neutralization of IFN-gamma in susceptible C3H/HeJ mice attenuated the severity of disease. These results suggest a primary relationship between T helper cell phenotype and the genetic basis for susceptibility to experimental Lyme borreliosis.
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PMID:T helper phenotype and genetic susceptibility in experimental Lyme disease. 786 43

The mechanism by which PG of the E series (PGE) promote murine B lymphocyte IgE production was investigated. We previously reported that PGE, and other agents that increase intracellular cAMP, synergize with IL-4 and LPS to induce IgE and IgG1 production while inhibiting IgM and IgG3 synthesis. These data suggested that PGE may promote IL-4-induced class switching, but the mechanism by which PGE increases IgE synthesis remained obscure. We report here that 1) PGE increases (up to 14-fold) the number of splenic B cells secreting IgE, even though PGE mildly inhibits proliferation. 2) PGE acts on sorted surface IgM positive B cells, consistent with PGE acting on uncommitted B cells to promote class switching to IgE. 3) PGE synergizes with IL-4 to induce germline epsilon transcripts, demonstrating that PGE acts at the level of transcription in cells that have not yet switched to IgE. 4) In the presence of PGE, rearranged mature V(D)J epsilon mRNA transcripts can be detected earlier and at higher levels than with IL-4 and LPS alone. Taken together, these data provide strong evidence that PGE synergizes with IL-4 and LPS to direct isotype switching to the epsilon heavy chain gene in purified B lymphocytes. PGE is a potentially important in vivo immunoregulator, particularly with regard to IgE production and the genesis of allergy. In support of this hypothesis, there are numerous clinical conditions (hyper-IgE, trauma, sepsis, Hodgkin's lymphoma, arthritis) in which overproduction of PGE is coincident with elevated IgE titers.
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PMID:Prostaglandin E2 promotes B lymphocyte Ig isotype switching to IgE. 799 35

The oral administration of CII by gavage to WA/KIR rats before a conventional arthritogenic challenge with bovine CII in FIA reduced the incidence (by 23%) and delayed the onset of collagen-induced arthritis in about 50% of the animals. Selective changes in B cell and T cell responses to CII in animals treated this way are interpreted to indicate a state of tolerance or hyporesponsiveness to CII. Tolerant animals made less serum antibody, to bovine and rat CII, of the IgG2b isotype and more of the IgG1 isotype. Phenotypic and functional analysis of peripheral lymph node cells showed that those from tolerized animals expressed less MHC Class II, proliferated less and secreted less IgG2b anti-CII antibody in response to stimulation in vitro with CII when compared with cells from non-tolerant animals. However, this depression of the immune responses to CII seen in vitro was overcome when the cells were incubated with increasing amounts of CII. Tolerance could be transferred to normal animals. Spleen cells, and nylon wool-filtered splenic T cells (but not mesenteric lymph node cells) adoptively transferred hyporesponsiveness to normal recipients which were then less susceptible to collagen-induced arthritis. Transfer of serum from gavaged animals did not modify the susceptibility of normal recipients to arthritis. Spleen cells from gavaged animals suppressed proliferative and antibody responses in co-cultures in vitro with lymph node cells from animals immunized with CII in FIA. The suppressive spleen cell population contained more cells expressing MHC Class II, in both the CD8+ and CD4+ populations. These studies show that the oral administration of CII alters the subsequent immune response to the arthritogenic challenge and indicate that this oral tolerance of CII is due, not to clonal deletion or anergy, but rather to an antigen-driven active suppression mechanism that affects both T cells and B cells, most likely through the action of regulatory cytokines IL-4, IL-10 and TGF beta.
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PMID:Suppression of collagen induced arthritis by oral administration of type II collagen: changes in immune and arthritic responses mediated by active peripheral suppression. 800 14

OT is a relevant biological pathway for generating peripheral tolerance against both self and external antigens with minimal side effects (fig. 3). This route might, therefore, contain promising potential for the treatment of autoimmune and allergic diseases in the human (fig. 3). Thus, oral administration of autoantigens suppresses experimental autoimmune diseases (EAE, EAU, AA, collagen-induced arthritis, NOD diabetes) in a disease- and antigen-specific manner, and oral administration of alloantigens has led to increase of allograft survival. OT might be important in treatment of immune complex diseases and food allergies. OT is mediated by T lymphocytes using at least two nonmutually exclusive mechanisms: suppression and anergy. Suppression can be adoptively transferred by CD8+ T lymphocytes which act by releasing TGF-beta and IL-4 following antigen-specific triggering. Antigen-driven tissue-directed suppression occurs following oral administration of an antigen from the target organ, even if it is not the disease-inducing antigen (bystander suppression). Thus, synthetic peptides can induce OT, and tolerogenic epitopes of antigen may be different from the autoreactive epitope. Due to the promising results in animal models, OT is being tested in clinical trials in multiple sclerosis, rheumatoid arthritis and uveitis [193, 194].
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PMID:Oral tolerance: a biologically relevant pathway to generate peripheral tolerance against external and self antigens. 801 Nov 55

Oral tolerance is a long recognized method to induce peripheral immune tolerance. The primary mechanisms by which orally administered antigen induces tolerance are via the generation of active suppression or clonal anergy. Low doses of orally administered antigen favor active suppression whereas higher doses favor clonal anergy. The regulatory cells that mediate active suppression act via the secretion of suppressive cytokines such as TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore, antigen that stimulates the gut-associated lymphoid tissue preferentially generates a Th2 type response. Because the regulatory cells generated following oral tolerization are triggered in an antigen-specific fashion but suppress in an antigen nonspecific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. Thus it may not be necessary to identify the target autoantigen to suppress an organ-specific autoimmune disease via oral tolerance; it is necessary only to administer orally a protein capable of inducing regulatory cells that secrete suppressive cytokines. Orally administered autoantigens suppress several experimental autoimmune models in a disease- and antigen-specific fashion; the diseases include experimental autoimmune encephalomyelitis (EAE), uveitis, and myasthenia, collagen- and adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition, orally administered alloantigen suppresses alloreactivity and prolongs graft survival. Initial clinical trials of oral tolerance in multiple sclerosis, rheumatoid arthritis, and uveitis have demonstrated positive clinical effects with no apparent toxicity and decreases in T cell autoreactivity.
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PMID:Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. 801 Dec 98

A major immunoregulatory mechanism in inflammatory infections and allergic diseases is the control of the balance of cytokines secreted by Th1/Th2 subsets of T helper (Th) cells. This might also be true in autoimmune diseases; a Th2 pattern that prevents an effective immune response in infections with intracellular bacteria may favor immunosuppression in autoimmune disease. The pattern of cytokine expression was compared in the synovial tissue from patients with a typical autoimmune disease, rheumatoid arthritis, and with a disorder with similar synovial pathology but driven by persisting exogenous antigen, reactive arthritis. We screened 12 rheumatoid and 9 reactive arthritis synovial tissues by PCR and in situ hybridization for their expression of T-cell cytokines. The cytokine pattern differs significantly between the two diseases; rheumatoid arthritis samples express a Th1-like pattern whereas in reactive arthritis interferon gamma expression is accompanied by that of interleukin 4. Studying the expression of cytokines by in situ hybridization confirmed the results found by PCR; they also show an extremely low frequency of cytokine-transcribing cells. In a double-staining experiment, it was demonstrated that interleukin 4 is made by CD4 cells. These experiments favor the possibility of therapeutic intervention in inflammatory rheumatic disease by means of inhibitory cytokines.
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PMID:Divergent T-cell cytokine patterns in inflammatory arthritis. 807 23

Autoimmune diseases can be characterized by increases in Th cell activities, suggesting that inhibition of Th cell function might ameliorate autoimmunity. We have recently reported that administration of nonmitogenic anti-CD3 mAb (nmCD3) to nonautoimmune mice can induce long-term Th cell hyporesponsiveness, reflected by reduced IL-2 secretion upon re-exposure to Ag. This study was designed to determine the effects of nmCD3 on autoimmunity by using the murine collagen-induced arthritis model. Treatment of DBA/1 mice with nmCD3 delayed the onset and reduced the severity of arthritis in mice immunized with type II collagen (CII). This effect was not caused by depletion of T cells or modulation of TCR. The observed inhibition of arthritis was not caused by decreased Ab production, as anti-CII titers were not affected. Rather, lymph node cells from CII-immunized mice treated with nmCD3 were hyporesponsive to in vitro stimulation with CII. This hyporesponsiveness was reflected by a marked decrease in secretion of IL-2 and IFN-gamma, but not of IL-4, which suggests that nmCD3 had its principal effect on Th1 cells. The hyporesponsiveness was not Ag-specific, because IL-2 and IFN-gamma production in response to a pan-T cell mitogen was also reduced. These results demonstrate that induction of Th1 cell hyporesponsiveness with nmCD3 can significantly alter the course of CIA and suggest that IL-2 and/or IFN-gamma play a crucial role in disease pathogenesis.
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PMID:Induction of T helper cell hyporesponsiveness in an experimental model of autoimmunity by using nonmitogenic anti-CD3 monoclonal antibody. 808 1

Subpopulations of human T cells (Th0, Th1 and Th2) can be distinguished by their cytokine-secretion pattern. Evidence is increasing from other studies that the outcome of a human disease may depend on the subpopulation of T cells that predominates at the site of inflammation. Reactive arthritis serves as a useful model of chronic inflammatory diseases, because the triggering antigen can be identified. Using this triggering antigen we raised 33 T cell clones reactive with Chlamydia trachomatis and 25 T cell clones that were not reactive, all from the synovial fluid of two patients suffering from Chlamydia-induced arthritis. Their cytokine secretion patterns for interferon-gamma (IFN-gamma), IL-2 and IL-4 were analysed, as also were mRNAs for IFN-gamma and IL-10 by in situ hybridization. Out of the 33 antigen-reactive clones 23 showed a Th1 pattern with IFN-gamma but not IL-4 secretion, while the remaining 10 exhibited a Th0 pattern. The clones that did not react with Chlamydia expressed all patterns of cytokine secretion, including a Th2 pattern, thus providing a control population that excludes bias in the sampling procedure. CD4 and CD8 clones displayed a similar cytokine-secretion pattern. In addition this study demonstrates for the first time the expression of IL-10 mRNA in T cell clones derived from synovial fluid, and this was not confined to the Th2 subset. The Th1 response that Chlamydia provoke can be regarded as appropriate for such an obligate intracellular pathogen.
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PMID:Analysis of cytokine profiles in synovial T cell clones from chlamydial reactive arthritis patients: predominance of the Th1 subset. 840 93

IL-4 has diverse effects on hematopoietic cells, including the ability to suppress certain mononuclear cell functions. To evaluate the effect of IL-4 on the evolution of acute and chronic arthritis, murine recombinant IL-4 was administered systemically to animals receiving an arthropathic dose of group A streptococcal cell wall fragments. Daily treatment with IL-4 had a minimal effect on the acute phase, but significantly suppressed the chronic, destructive phase. By 4 wk after initiation of disease, the articular index of IL-4-treated animals was reduced > 60% (articular index = 4 +/- 0.9) compared with the untreated rats (11.5 +/- 0.48, p < 0.001). A substantial decrease in the influx of inflammatory cells and virtual elimination of pannus and erosions occurred after IL-4 therapy. Associated with the reduced accumulation of mononuclear leukocytes was a decrease in their proinflammatory functions including cytokine production and reactive oxygen intermediate metabolism. These observations are consistent with the selective effects of IL-4 on phagocytic cell function demonstrated in vitro. Furthermore, IL-4 induced gene expression for IL-1ra, a protein that antagonizes the action of IL-1 by binding to the IL-1 receptor without agonist activity. Through an expanding spectrum of effects on monocyte-macrophage phenotypic and functional parameters, IL-4 is emerging as an important inhibitor of cell-mediated immune responses and pathogenic processes.
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PMID:Suppression of monocyte function and differential regulation of IL-1 and IL-1ra by IL-4 contribute to resolution of experimental arthritis. 840 6

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