Immunity and Inflammation: from complement system activation in Rheumatoid Arthritis to dysregulated immunometabolism in Systemic Lupus Erythematosus

Autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are characterized by a dysregulation of the immune system, leading to a persistent inflammatory condition and the production of several autoreactive antibodies. The first project here described is focused on the complement system activation in RA patients before and after the administration of Abatacept, a biological drug functionally interfering with the second signal of activation of T cells, leading to a reduction the inflammatory status of patients. Particularly, to access the possible dysregulation of this mechanism linked to the inflammatory milieu, plasma and peripheral blood samples from 30 patients with active RA have been analysed by ELISA assay for SC5b-9, C5a and IL-6 and by FACS analysis for the expression of C5a receptor (C5aR or CD88) and CD86 on inflammatory cells (T lymphocytes and monocytes). Patients with active RA showed higher plasma levels of SC5b-9 and IL-6 and increased expression of C5aR and CD86 in circulating monocytes and T cells, compared to healthy controls. After Abatacept treatment all these parameters are decreased. No changing in C5a plasma concentrations have been observed. Data collected confirm the efficacy of Abatacept by interfering in T cells activation, with a consequent decrease of IL-6 plasma levels and CD86 expression on inflammatory cells. Moreover, a possible role of Abatacept in the down regulation of the terminal pathway of CS activation by inhibiting C5b-9 formation could be speculated. The second part of the thesis reports preliminary results about the dysregulated immunometabolism in CD8+ T cells in SLE patients. In order to better understand the possible implication of this subpopulation poorly investigated in the onset of SLE, a comparison between the mitochondrial phenotype CD4+ and CD8+ T cells has been conducted using FACS analysis. The same technique has been used to measure the mitochondrial mass and the transmembrane potential, as well as the ROS production of CD8+ T cells. Then, real-time qPCR allowed the measurement of expression levels of both mitochondrial and IFN-signature related genes. No significant differences have been found between healthy controls and SLE patients concerning the activation phenotype of both CD4+ and CD8+ T cells. Interestingly, effector memory CD8+ T cells show an increment of both mitochondria mass and transmembrane potential in IFNhi SLE patients compared to healthy donors. The 3 results collected need to be implemented and confirmed with other experiment and the cohort should be amplified. Indeed, the project is still on going.