Abstract
BackgroundAdaptive immune cells, including CD4+CD69+ and CD4+CD25+FoxP3+ regulatory T (Treg) cells, are important for maintaining immunological tolerance. In human systemic lupus erythematosus (SLE), CD4+CD25+FoxP3+ Treg cells are reduced, whereas CD69 expression is increased, resulting in a homeostatic immune imbalance that may intensify autoreactive T cell activity. To analyze the mechanisms implicated in autotolerance failure, we evaluated CD4+CD69+ and CD4+CD25+FoxP3+ T cells and interleukin profiles in a pristane-induced SLE experimental model.MethodsFor lupus induction, 26 female Balb/c mice received a single intraperitoneal 0.5 ml dose of pristane, and 16 mice received the same dose of saline. Blood and spleen samples were collected from euthanized mice 90 and 120 days after pristane or saline inoculation. Mononuclear cells from peripheral blood (PBMC), peritoneal lavage (PL) and splenocytes were obtained by erythrocyte lysis and cryopreserved for further evaluation by flow cytometry using the GuavaEasyCyte TM HT. After thawing, cells were washed and stained with monoclonal antibodies against CD3, CD4, CD8, CD25, CD28, CD69, FoxP3, CD14 and Ly6C (BD Pharmingen TM). Interleukins were quantified using Multiplex® MAP. The Mann-Whitney test and the Pearson coefficient were used for statistical analysis, and p < 0.05 considered significant.ResultsCompared with the controls, SLE-induced animals presented increased numbers of CD4+CD69+ T cells in the blood on T90 and T120 (p = 0.022 and p = 0.008) and in the spleen on T120 (p = 0.049), but there were decreased numbers in the PL (p = 0.049) on T120. The percentage of Treg was lower in blood (p < 0.005 and p < 0.012) on T90 and T120, in spleen (p = 0.043) on T120 and in PL (p = 0.001) on T90. Increased numbers of CD4 + CD69+ T cells in the PL were positively associated with high IL-2 (p = 0.486) and IFN-γ (p = 0.017) levels, whereas reduced Treg cells in the blood were negatively correlated with TNFα levels (p = 0.043) and positively correlated with TGFβ1 (p = 0.038).ConclusionIncreased numbers of CD4+CD69+ T cells and reduced numbers of CD4+CD25+FoxP3+ Treg cells with an altered interleukin profile suggests loss of autotolerance in pristane-induced lupus mice, which is similar to human lupus. Therefore, this model is useful in evaluating mechanisms of cellular activation, peripheral tolerance and homeostatic immune imbalance involved in human SLE.
Highlights
Systemic lupus erythematosus (SLE) is a complex multifactorial disease characterized by loss of autotolerance, autoreactive T cell activation and production of inflammatory mediators and auto-antibodies
The balance between adaptive immune cells such as CD4+CD69+ effector T cells and CD4+CD25+FoxP3+ suppressor/regulatory T (Treg) cells is important for the maintenance of immunological tolerance [4] [5] [6]
Lipogranulomas (B and C) and splenomegaly (E) developed in the peritoneal cavity, and greater spleen weights were demonstrated in the SLEinduced mice compared to controls (0.25 g ± 0.07 vs. 0.12 g ± 0.03, p < 0.001 on T90 and 0.11 g ± 0.01 vs. 0.30 g ± 0.04, p < 0.001 on T120)
Summary
Systemic lupus erythematosus (SLE) is a complex multifactorial disease characterized by loss of autotolerance, autoreactive T cell activation and production of inflammatory mediators and auto-antibodies. Because Treg cells can suppress the activation and proliferation of those effector T cells, Treg cells play a key role in the pathogenesis of inflammatory conditions [7]. If this process fails, the loss of tolerance may result in autoimmune disorders, including SLE [3]. The loss of tolerance may result in autoimmune disorders, including SLE [3] Dysregulation of both adaptive and innate immune systems mechanisms are marked in SLE, culminating with tissue and organ damage induced by chronic inflammation and a variety of clinical manifestations [8] [9] [10]. To analyze the mechanisms implicated in autotolerance failure, we evaluated CD4+CD69+ and CD4+CD25+FoxP3+ T cells and interleukin profiles in a pristane-induced SLE experimental model
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