Caracterização da imunossenescência na esclerose múltipla remitente-recorrente

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. The pathophysiology of MS results from complex interactions between autoreactive T cells and B cells that lead to inflammation and demyelination in the central nervous system (CNS). Aging rates (or trajectories) can influence individuals' morbidity and mortality rates. Individuals aging more quickly, as seen in MS, have an aging immune system (immunosenescence) that may compromise the clinical progression of the disease. A state of chronic low-grade inflammation, which has been referred to as inflammaging, may also influence clinical pictures in MS. In this work, we further characterized immunosenescence in relapsing-remitting MS (RRMS) and investigated its association with clinical progression. Twenty-two patients with RRMS were recruited for evaluation at the Neurology Service of Hospital São Lucas at PUCRS. A comprehensive flow cytometric multicolor immunophenotyping analysis was performed to investigate subsets of lymphocytes and monocytes, including their activation state, differentiation states, regulatory, senescence, and exhaustion profiles. Cytokines involved in inflammation (IL-1beta, IL-8, IL-6 and TNFalpha) or regulation (IL-10) were quantified in serum. Telomere length was measured by real-time PCR as a marker of biological aging. A total of 21 healthy controls and 25 patients were recruited and matched for age and sex. Patients with RRMS had shortened telomeres in mononuclear cells than controls. Concerning the cytokines, there were no differences between groups. Patients had lower proportions of nonclassical (CD16brightCD14+) and classical (CD16-CD14bright) monocytes, although increased proportions of intermediate monocytes (CD16+CD14bright) compared to controls (all p<0.05). The NK subsets (CD16+CD56dim and CD16lowCD56bright) did not differ between individuals. Lower proportions of transitional B cells (CD19+ CD38HIGH) and regulatory B cells (CD19+CD27+CD38+) were observed in RMSS (all p<0.05). Patients had lower proportions of early-differentiated (CD27+CD28+) T cells, but no change in intermediate (CD27-CD28+) or late-differentiated or senescent (CD27-CD28-) cells. Although patients had significantly lower proportions of activated T cells (CD25+) in both CD4+ and CD8+ cells (all p<0.0001), no changes were observed in regulatory T cells (CD4+FoxP3+). Regarding checkpoint molecules, patients had increased proportions of CD4+PD-1+ cells compared to controls (p<0.01), but lower percentages of CD8+CTLA-4+ cells (p<0.01). In addition, significantly lower proportions of CD4+ and CD8+ T cells expressing NKG2A or NKG2D were observed in patients (all p<0.05). Although early senescence in RMSS was confirmed by shortened telomeres and increased CD4+PD-1+ T cells, no changes were reported in more differentiated T cells.