Role of cellular immunity in systemic sclerosis pathogenesis: update on CD4+T cells population studies.

Immunologic abnormalities observed in Systemic Sclerosis (SSc) patients consist of chronic mononuclear cell infiltration of affected tissues, dysregulation of lymphokine and growth factor production, and autoantibodies production. Expansion of CD4+T cells within the tissue seems to involve their activation that precedes this process. Therefore, CD4+T cells activation, as an early immune event, appears to be an important process in the development and maintaining of SSc. In SSc the disturbance of peripheral tolerance mechanisms could be also responsible for CD4+T cells activation. Consequently, we reevaluated CD4+T cells positive for CD25, GITR, CTLA-4, CD45RO, or Foxp3 in SSc patients, by comparison with healthy donors (HDs), and in correlation with clinical features of the disease. Our results reargued for activation of peripheral blood CD4+T cells in SSc patients. Thus, increased percentages of CD25+ and GITR+ CD4+T cells were found in SSc patients by comparison with HDs. Direct correlation between the percentage of GITR+CD4+T cells and disease activity recommended these cells as a good candidate for disease progression. In SSc patients, the negative regulators of T cells activation are also affected. Thus, CTLA-4+ and Foxp3+ CD4+T cell percentages were significantly reduced in SSc patients when compared to HDs. Indirect correlation between the percentage of CD152+CD4+T cells and autoantibodies (aScl70) presence or disease type highlighted the role of these cells in the disturbance of peripheral tolerance. The absence of the direct correlation between CD152+CD4+T cells and CD45RO+CD4+T cells, correlation observed only in HDs, raised the hypothesis that in SSc patients, memory T cells can be easily activated, and by consequence, they can enter within affected tissues. These data reconfirm the activation state of SSc CD4+T cells and point out some abnormalities in peripheral tolerance mechanisms that can contribute to SSc pathogeny.

PI3K/Akt signaling in peripheral T lymphocytes from systemic lupus erythematosus patients.

PI3K/Akt/mTOR signaling pathway plays an important role in cellular proliferation and growth signaling. It was demonstrated that murine models presenting activated PI3K/Akt/mTOR signaling pathway in lymphocytes develop features of systemic autoimmunity, linking this pathway to autoimmune diseases. Therefore, the goal of our study was to analyze this signaling axis in Systemic Lupus Erythematosus (SLE), the prototype of systemic autoimmune diseases, focusing on Akt and p70S6k, two components of this pathway. Our results demonstrated that both expression and phosphorylation levels of Akt are more increased in SLE than in healthy donors (HDs) CD4+ T cells suggesting an up-regulation of PI3K and mTOR activities. This result was also suggested when p70S6k, one of mTOR substrate, was evaluated. Indeed, in SLE CD4+ T cells an enhancement of p70S6k activity, in direct correlation with its expression level, was found. Since p27kip1, an inhibitor of cell cycle progression, is one of the Akt substrates, we analyzed its expression level in relationship with cell cycle progression and apoptosis. The results demonstrated that p27kip1 expression level was significantly decreased in SLE than in HDs CD4+ T cells. In SLE p27kip1 level was inversely correlated with the percentage of peripheral lymphocytes in apoptosis and in S phase of the cell cycle. Therefore, the increased activity of PI3K/Akt/mTOR signaling pathway and, as a result, the drop of p27kip1 levels observed in CD4+ T cells isolated from SLE patients might explain the accumulation of SLE lymphocytes in S and G2/M cell cycle phases where they undergo apoptosis.