The potential contribution of the adaptive immune system in frontotemporal dementia

Abstract

AbstractBackgroundInflammation is a significant component of neurodegenerative disorders including frontotemporal dementia (FTD). Co‐localization of neuroinflammation and brain protein aggregation with tau and TDP‐43 has been previously documented in the clinical setting of FTD. However, the role of the adaptive immune system particularly regulatory T cells (Tregs) is not clearly defined. We hypothesize that Tregs immunomodulatory mechanisms are compromised and shift the immune system towards a proinflammatory status which might contribute to disease progression.Method24 FTD patients and 11 age‐matched healthy controls were recruited by the Houston Methodist Nantz National Alzheimer’s Center (NNAC). Venous blood was processed for multicolor flow cytometry to assess the phenotype of Tregs. Tregs were also co‐cultured with corresponding responder T cells (Tresps) in various ratios and proliferation of Tresps was determined by 3H‐thymidine incorporation. Plasma assays of 48 cytokines were obtained through Olink® Target 48 Cytokine panel for FTD patients and age‐matched healthy controls and comparisons were made.ResultThe suppressive function of Tregs on corresponding Tresps proliferation was significantly compromised in both 1:1 (P = 0.034) and 1/2:1 (P = 0.024) Tregs:Tresps ratios. In immunophenotypic analyses, no differences were detected between FTD patients and controls regarding percentages of Tregs, Tresps, CD8+ T cells, or natural killer cells (NKC). The Olink® analysis revealed increased plasma levels of pro‐inflammatory cytokines and chemokines in FTD patients including CXCL9, CXCL10, CXCL11, and TNFα.ConclusionRegulatory T cells immunomodulatory function is compromised in patients with FTD, indicating a shift of peripheral immune cells towards an increased pro‐inflammatory state. In addition, there is upregulation of plasma chemokines CXCL9, CXCL10, CXCL11, which promote immune cell recruitment to CNS sites of inflammation. Combining these two key findings, we propose that pro‐inflammatory peripheral immune cells contribute to neuroinflammation and possibly disease progression in FTD.