From T to B and back again: positive feedback in systemic autoimmune disease

Shlomchik, Mark J.; Craft, Joseph; Mamula, Mark J.

doi:10.1038/35100573

Cited by 507 publications

(352 citation statements)

References 109 publications

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“…It is not known, and this study did not address, whether the signaling process in autoimmune cells is sustained for a longer period of time either because suppressive molecules function inadequately or because the altered composition of the signaling apparatus leads to sustained responses. Molecular mimicry by altered biochemical modifications in proteins have been shown to contribute to a breakdown of immune tolerance and induce autoimmune responses (35,36). Understanding the cellular biochemistry that leads to autoimmune responses will enable us to develop means to modulate the signaling process and treat autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Forced Expression of the Fc Receptor γ-Chain Renders Human T Cells Hyperresponsive to TCR/CD3 Stimulation

Nambiar

Fisher

Kumar

et al. 2003

The Journal of Immunology

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High level expression of FcεRIγ chain replaces the deficient TCR ζ-chain and contributes to altered TCR/CD3-mediated signaling abnormalities in T cells of patients with systemic lupus erythematosus. Increased responsiveness to Ag has been considered to lead to autoimmunity. To test this concept, we studied early signaling events and IL-2 production in fresh cells transfected with a eukaryotic expression vector encoding the FcεRIγ gene. We found that the overexpressed FcεRIγ chain colocalizes with the CD3ε chain on the surface membrane of T cells and that cross-linking of the new TCR/CD3 complex leads to a dramatic increase of intracytoplasmic calcium concentration, protein tyrosine phosphorylation, and IL-2 production. We observed that overexpression of FcεRIγ is associated with increased phosphorylation of Syk kinase, while the endogenous TCR ζ-chain is down-regulated. We propose that altered composition of the CD3 complex leads to increased T cell responsiveness to TCR/CD3 stimulation and sets the biochemical grounds for the development of autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Forced Expression of the Fc Receptor γ-Chain Renders Human T Cells Hyperresponsive to TCR/CD3 Stimulation

Nambiar

Fisher

Kumar

et al. 2003

The Journal of Immunology

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“…Autoimmune hemolytic anemia and myasthenia gravis belong to the category of B-cell dominant autoimmune diseases while experimental autoimmune encephalomyelitis, insulin-dependent diabetes mellitus and the collagen-induced arthritis are T-cell dominant autoimmune diseases. SLE arises from the emergence of both autoreactive T and B cells with an aetiology [6,[20][21][22].…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

Autoimmunity and oxidatively modified autoantigens

Kurien

Scofield

2008

Autoimmunity Reviews

246

194

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Oxidative damage mediated by reactive oxygen species results in the generation of deleterious byproducts. The oxidation process itself and the proteins modified by these molecules are important mediators of cell toxicity and disease pathogenesis. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immunogenic. Proteins modified in this manner have been shown to induce pathogenic antibodies in a variety of diseases including systemic lupus erythematosus (SLE), alcoholic liver disease, diabetes mellitus (DM) and rheumatoid arthritis (RA). 8-oxodeoxyguanine (oxidatively modified DNA) and low density lipoproteins (LDL) occur in SLE, a disease in which premature atherosclerosis is a serious problem. In addition, immunization with 4-hydroxy-2-nonenal (HNE) modified 60 kD Ro autoantigen induces an accelerated epitope spreading in an animal model of SLE. Advanced glycation end product (AGE) pentosidine and AGE modified IgG have been shown to correlate with RA disease activity. Oxidatively modified glutamic acid decarboxylase is important in type 1 DM, while autoantibodies against oxidized LDL are prevalent in Behcet's disease. The fragmentation of scleroderma specific autoantigens occurs as a result of oxidative modification and is thought to be responsible for the production of autoantibodies through the release of cryptic epitopes. The administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease, particularly on account of the overwhelming evidence for the involvement of oxidative damage in autoimmunity. However, this should be viewed in the light of disappointing results obtained with the use of antioxidants in cardiovascular disease. Keywordslupus; autoimmunity; epitopes; autoantibodies; antigens Free radicalsReactive oxygen species (ROS) are oxygen-based molecules possessing high chemical reactivity. These include free radicals (superoxide and hydroxyl radicals) and non-radical species (hydrogen peroxide) which can be produced even at basal conditions by a number of ways. Free radicals are active species containing atoms or molecules with one or more unpaired electrons occupying an outer orbital. They can arise either by the univalent pathway of oxygen

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“…CD4 ϩ ␣␤ T cells are required for full penetrance of disease in MRL and other murine models of lupus, largely via their help to autoreactive B cells (2)(3)(4).…”

Section: Il-10 Regulates Murine Lupusmentioning

confidence: 99%

IL-10 Regulates Murine Lupus

Yin

Bahtiyar

Zhang

et al. 2002

The Journal of Immunology

210

175

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MRL/MpJ-Tnfrsf6lpr (MRL/MpJ-Faslpr; MRL-Faslpr) mice develop a spontaneous lupus syndrome closely resembling human systemic lupus erythematosus. To define the role of IL-10 in the regulation of murine lupus, IL-10 gene-deficient (IL-10−/−) MRL-Faslpr (MRL-Faslpr IL-10−/−) mice were generated and their disease phenotype was compared with littermates with one or two copies of an intact IL-10 locus (MRL-Faslpr IL-10+/− and MRL-Faslpr IL-10+/+ mice, respectively). MRL-Faslpr IL-10−/− mice developed severe lupus, with earlier appearance of skin lesions, increased lymphadenopathy, more severe glomerulonephritis, and higher mortality than their IL-10-intact littermate controls. The increased severity of lupus in MRL-Faslpr IL-10−/− mice was closely associated with enhanced IFN-γ production by both CD4+ and CD8+ cells and increased serum concentration of IgG2a anti-dsDNA autoantibodies. The protective effect of IL-10 in this lupus model was further supported by the observation that administration of rIL-10 reduced IgG2a anti-dsDNA autoantibody production in wild-type MRL-Faslpr animals. In summary, our results provide evidence that IL-10 can down-modulate murine lupus through inhibition of pathogenic Th1 cytokine responses. Modulation of the level of IL-10 may be of potential therapeutic benefit for human lupus.

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From T to B and back again: positive feedback in systemic autoimmune disease

Cited by 507 publications

References 109 publications

Forced Expression of the Fc Receptor γ-Chain Renders Human T Cells Hyperresponsive to TCR/CD3 Stimulation

Forced Expression of the Fc Receptor γ-Chain Renders Human T Cells Hyperresponsive to TCR/CD3 Stimulation

Autoimmunity and oxidatively modified autoantigens

IL-10 Regulates Murine Lupus

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