The T cell enigma in lupus

Dayal, Agam; Kammer, Gary M.

doi:10.1002/art.1780390104

Cited by 107 publications

(78 citation statements)

References 81 publications

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“…Nucleosome-reactive T cells promote autoantibody synthesis in SLE (25), and modification of T cells by genetic manipulation or DNA hypomethylation can cause a lupus-like disease (6)(7)(8). T cells from lupus patients demonstrate multiple biochemical and functional abnormalities, including relative anergy, altered signaling, and impaired protein synthesis (27,28), suggesting profound biochemical abnormalities in these cells. Included in these biochemical abnormalities are decreased expression of DNA methyltransferase enzyme activity (11), decreased expression of DNA methyltransferase 1 (Dnmt1) mRNA (17), and globally hypomethylated DNA (11).…”

Section: Discussionmentioning

confidence: 99%

Clinical images: Epidural lipomatosis in a 14‐year‐old boy with systemic lupus erythematosus

Miller¹,

Blaser²,

Laxer³

2002

Arthritis & Rheumatism

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Objective. Inhibition of T cell DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo, suggesting that T cell DNA hypomethylation may contribute to autoimmunity. The hypomethylation effects are due, in part, to overexpression of lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18). Importantly, T cells from patients with active lupus have hypomethylated DNA and overexpress LFA-1 on an autoreactive subset, suggesting that the same mechanism could contribute to human lupus. The present study investigated the nature of the methylation change that affects LFA-1 expression in vitro and in human lupus.Methods. Bisulfite sequencing was used to determine the methylation status of the ITGAL promoter and flanking regions in T cells from lupus patients and healthy subjects, and in T cells treated with DNA methylation inhibitors. "Patch" methylation of promoter sequences in reporter constructs was used to determine the functional significance of the methylation changes.Results. Hypomethylation of specific sequences flanking the ITGAL promoter was seen in T cells from patients with active lupus and in T cells treated with 5-azacytidine and procainamide. Patch methylation of this region suppressed ITGAL promoter function.Conclusion. DNA methylation changes occur in specific sequences that regulate LFA-1 expression in lupus T cells and in the hypomethylation model, indicating that altered methylation of specific genes may play a role in the pathogenesis of lupus.The mechanisms initiating human systemic lupus erythematosus (SLE) remain unknown. The finding that exposure to certain drugs can induce a lupus-like disease has provided leads into the nature of biochemical alterations associated with lupus. The 2 drugs most frequently associated with lupus, procainamide and hydralazine, can cause a lupus-like disease through effects on T cell DNA methylation. Treating T cells with procainamide, hydralazine, or 5-azacytidine (5-azaC; the prototypic DNA methylation inhibitor) demethylates DNA, alters gene expression, and induces major histocompatibility complex-specific T cell autoreactivity (1-5). Adoptive transfer of the autoreactive cells causes a lupus-like disease in animal models (5-7). The autoimmune effects of the methylation inhibitors are due, in part, to overexpression of lymphocyte functionassociated antigen 1 (LFA-1) (CD11a/CD18), because increasing T cell LFA-1 by transfection causes an identical autoreactivity in vitro, and a similar autoimmune disease in vivo (4,8).Altered DNA methylation has also been implicated in human lupus. T cells from patients with active lupus have an ϳ17% decrease in genomic deoxymethylcytosine content and overexpress LFA-1 on an autoreactive subset (9-11). However, whether the DNA hypomethylation occurring in lupus affects transcriptionally relevant regions is not known. It is similarly unknown if the DNA hypomethylation induced by 5-azaC or procainamide affects the same sequences as those affected in SLE.DNA methylation inhibitors increase LFA-1 through thei...

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Section: Discussionmentioning

confidence: 99%

Clinical images: Epidural lipomatosis in a 14‐year‐old boy with systemic lupus erythematosus

Miller¹,

Blaser²,

Laxer³

2002

Arthritis & Rheumatism

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“…Briefly, 1 ϫ 10 6 cells͞ml were cultured in RPMI-1640 media supplemented with 25 mM Hepes͞10% heat-inactivated FCS͞ 100 IU penicillin͞100 g͞ml streptomycin͞2 mM L-glutamine for varying intervals to 72 h. In experiments using TSA, cells were preincubated with the inhibitor for 18 h and were then subsequently activated. Because SLE T cells respond suboptimally to activation by antigens, mitogens, or anti-CD3͞anti-CD28 mAbs because of defects of signal transduction (32,33), cellular activation was induced by 20 ng͞ml phorbol 12-myristate 13-acetate (PMA) and 0.5 M ionomycin (IO) for varying intervals. Activation of cells by PMA ϩ IO bypasses the defective proximal signaling cascade, stimulating protein kinase C and releasing intracellular Ca 2ϩ .…”

Section: Methodsmentioning

confidence: 99%

Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-γ gene and protein expression in lupus T cells

Mishra

Brown

Olorenshaw

2001

Proc. Natl. Acad. Sci. U.S.A.

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171

114

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In systemic lupus erythematosus (SLE), T helper cells exhibit increased and prolonged expression of cell-surface CD40 ligand (CD154), spontaneously overproduce interleukin-10 (IL-10), but underproduce interferon-gamma (IFN-␥). We tested the hypothesis that the imbalance of these gene products reflects skewed expression of CD154, IL-10, and IFN-␥ genes. Here, we demonstrate that the histone deacetylase inhibitor, trichostatin A, significantly down-regulated CD154 and IL-10 and up-regulated IFN-␥ gene expression in SLE T cells. This reversal corrected the aberrant expression of these gene products, thereby enhancing IFN-␥ production and inhibiting IL-10 and CD154 expression. That trichostatin A can simultaneously reverse the skewed expression of multiple genes implicated in the immunopathogenesis of SLE suggests that this pharmacologic agent may be a candidate for the treatment of this autoimmune disease.

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“…Although there are many examples of T cell dysfunction in SLE (4-11), those that contribute to B cell hyperactivity are poorly understood. Possible explanations include an intrinsic abnormality of CD4+ T cells in SLE (12,13), abnormal CD8+ regulatory T cells (14), or inhibitory serum factors (15J6). In addition, inhibition or lack of costimulation by antigen-presenting cells can lead to T cell dysfunction (17)(18)(19).…”

Section: Decreased T Cell Response To Anti-cd2 In Systemic Lupus Erytmentioning

confidence: 99%

Decreased T cell response to anti‐CD2 in systemic lupus erythematosus and reversal by anti‐CD28. Evidence for Impaired T Cell‐Accessory Cell Interaction

Horwitz

Tang

Stimmler

et al. 1997

Arthritis & Rheumatism

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Objective. To assess the ability of T cells from patients with systemic lupus erythematosus (SLE) to respond to a mitogenic combination of anti-CD2 monoclonal antibodies (MAb), and to learn the molecular basis of the documented defect.Methods. Peripheral blood mononuclear cell (PBMC) populations from individuals with SLE and paired controls were stimulated in vitro with anti-CD2, and the proliferative response was compared with that evoked by stimulation with phytohemagglutinin (PHA) and anti-CD3. Surface markers on lymphocyte populations were assessed by flow cytometry after staining with specific MAb.Results. The proliferative response to anti-CD2 was decreased to a greater extent than was the response to anti-CD3 or PHA in SLE patients. This defect was found in approximately one-half of the patients examined, was not associated with disease activity, and was maintained upon repeated testing. Since either monocytes or resting B cells can serve as accessory cells for T cells following activation by anti-CD2, we examined the T cell response after depletion of adherent cells. In approximately two-thirds of the individuals with a decreased response, depletion of monocytes or substitution of monocytes with allogeneic, resting B cells from normal donors corrected the defect. The addition to PBMC of anti-CD28, but not of a neutralizing antibody Submitted for publication June 10, 1996; accepted in revised form November 22, 1996. to interleukin-10, largely reversed the anti-CD2 proliferative defect. Significantly fewer CDS+ T cells expressed CD28 in SLE, and this defect was also documented, to a lesser extent, in CD4+ cells.Conclusion. This study provides evidence that some functional T cell defects in SLE may be due, at least in part, to decreased CD28-mediated costimulatory activity following the interaction of T cells with conventional accessory cells.

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The T cell enigma in lupus

Cited by 107 publications

References 81 publications

Clinical images: Epidural lipomatosis in a 14‐year‐old boy with systemic lupus erythematosus

Clinical images: Epidural lipomatosis in a 14‐year‐old boy with systemic lupus erythematosus

Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-γ gene and protein expression in lupus T cells

Decreased T cell response to anti‐CD2 in systemic lupus erythematosus and reversal by anti‐CD28. Evidence for Impaired T Cell‐Accessory Cell Interaction

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