Valencia, X., Yarboro, C., Illei, G. & Lipsky, P. E. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J. Immunol. 178, 2579-2588

Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2007; 178(4):2579-88. DOI: 10.4049/jimmunol.178.4.2579
Source: PubMed

ABSTRACT CD4(+)CD25(+) T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance to nuclear components. We hypothesized that altered function of CD4(+)CD25(high) Tregs might play a role in the breakdown of immunologic self-tolerance in patients with SLE. In this study, we report a significant decrease in the suppressive function of CD4(+)CD25(high) Tregs from peripheral blood of patients with active SLE as compared with normal donors and patients with inactive SLE. Notably, CD4(+)CD25(high) Tregs isolated from patients with active SLE expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4(+) effector T cells in vitro. In contrast, the expression of FoxP3 mRNA and protein and in vitro suppression of the proliferation of CD4(+) effector T cells by Tregs isolated from inactive SLE patients, was comparable to that of normal individuals. In vitro activation of CD4(+)CD25(high) Tregs from patients with active SLE increased FoxP3 mRNA and protein expression and restored their suppressive function. These data are the first to demonstrate a reversible defect in CD4(+)CD25(high) Treg function in patients with active SLE, and suggest that strategies to enhance the function of these cells might benefit patients with this autoimmune disease.

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    • "Moreover, a Treg cell dysfunction was recently found in rheumatoid arthritis patients [17]. Similar results were observed in patients with systemic lupus erythematosus (SLE)[6] [18] [19] [20]. "
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    ABSTRACT: Autoimmune diseases decrease life expectancy and quality of life for millions of women and men. Although treatments can slow disease progression and improve quality of life, all currently available drugs have adverse effects and none of them are curative; therefore, requiring patients to take immunosuppressive drugs for the remainder of their lives.A curative therapy that is safe and effective is urgently needed. We believe that therapies promoting the in vivo expansion of regulatory T cells (Tregs) or injection of in vitro expanded autologous/heterologous Tregs (cellular therapy) can alter the natural history of autoimmune diseases.In this review, we present data from murine and human studies suggesting that 1) glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) plays a crucial role in thymic Treg (tTreg) differentiation and expansion; 2) GITR plays a crucial role in peripheral Treg (pTreg) expansion; 3) in patients with Sjögren syndrome and systemic lupus erythematosus, CD4+GITR+ pTregs are expanded in patients with milder forms of the disease; and 4) GITR is superior to other cell surface markers to differentiate Tregs from other CD4+ T cells.In this context, we consider two potential new approaches for treating autoimmune diseases consisting of the in vivo expansion of GITR+ Tregs by GITR-triggering drugs and in vitro expansion of autologous or heterologous GITR+ Tregs to be infused in patients. Advantages of such an approach, technical problems, and safety issues are discussed.
    Autoimmunity Reviews 10/2014; 14(2). DOI:10.1016/j.autrev.2014.10.011 · 7.93 Impact Factor
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    • "Studies in SLE patients have reported conflicting data regarding the frequency, phenotype, and function of these cells. The heterogeneity in findings of decreased (7-13), normal, or even increased frequency of TREG cells in SLE (14-18) may be partially due to the criteria adopted in each study to define the TREG cell phenotype. We recently demonstrated that the CD25high gate, considered by some studies as characteristic for TREG cells, contains high levels of activated effector T cells in the active stages of SLE (4). "
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    ABSTRACT: Regulatory T (TREG) cells play an important role in maintaining immune tolerance and avoiding autoimmunity. We analyzed the expression of membrane molecules in TREG and effector T cells in systemic lupus erythematosus (SLE). TREG and effector T cells were analyzed for the expression of CTLA-4, PD1, CD28, CD95, GITR, HLA-DR, OX40, CD40L, and CD45RO in 26 patients with active disease, 31 with inactive disease, and 26 healthy controls. TREG cells were defined as CD25+/highCD127Ø/lowFoxP3+, and effector T cells were defined as CD25+CD127+FoxP3Ø. The ratio of TREG to effector T cells expressing GITR, PD1, HLA-DR, OX40, CD40L, and CD45RO was determined in the three groups. The frequency of TREG cells was similar in patients with SLE and controls. However, SLE patients had a decreased frequency of CTLA-4+TREG and CD28+TREG cells and an increased frequency of CD40L+TREG cells. There was a decrease in the TREG/effector-T ratio for GITR+, HLA-DR+, OX40+, and CD45RO+ cells, and an increased ratio of TREG/effector-T CD40L+ cells in patients with SLE. In addition, CD40L+TREG cell frequency correlated with the SLE disease activity index (P=0.0163). In conclusion, our findings showed several abnormalities in the expression of functionally critical surface molecules in TREG and effector T cells in SLE that may be relevant to the pathogenesis of this disease.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 08/2014; 47(8):662-9. DOI:10.1590/1414-431X20143483 · 1.01 Impact Factor
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    • "In humans, the number of CD4+ Tregs was generally found to be lower in patients with active SLE as compared with those with inactive disease and healthy individuals [54]. Reduced levels of forkhead box P3 (FoxP3) in CD4+ Tregs in patients with active lupus are generally believed to be the reason why these patients have less Tregs-suppressive activity than their counterparts with inactive disease [55–57]. Interestingly, effective immunosuppressive therapies with glucocorticoids and rituximab have been shown to restore the number of functional Tregs in patients with SLE [58–60]. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies. Thus, the condition was traditionally classified as a "B-cell disease". Compelling evidence has however shown that without the assistance of the helper T lymphocytes, it is indeed difficult for the "helpless" B cells to become functional enough to trigger SLE-related inflammation. T cells have been recognized to be crucial in the pathogenicity of SLE through their capabilities to communicate with and offer enormous help to B cells for driving autoantibody production. Recently, a number of phenotypic and functional alterations which increase the propensity to trigger lupus-related inflammation have been identified in lupus T cells. Here, potential mechanisms involving alterations in T-cell receptor expressions, postreceptor downstream signalling, epigenetics, and oxidative stress which favour activation of lupus T cells will be discussed. Additionally, how regulatory CD4+, CD8+, and γδ T cells tune down lupus-related inflammation will be highlighted. Lastly, while currently available outcomes of clinical trials evaluating therapeutic agents which manipulate the T cells such as calcineurin inhibitors indicate that they are at least as efficacious and safe as conventional immunosuppressants in treating lupus glomerulonephritis, larger clinical trials are undoubtedly required to validate these as-yet favourable findings.
    Research Journal of Immunology 04/2014; 2014(22):419029. DOI:10.1155/2014/419029
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