T cell responses in amyotrophic lateral sclerosis : friends or foes?

Abstract: Amyotrophic lateral sclerosis (ALS) is an idiopathic fatal neurodegenerative disease that is characterized by the loss of upper and lower motor neurons. Inflammation is widely recognized as a hallmark of this disease; however, the intricate relationship between immune biomarkers and the pathogenesis of ALS is not fully understood yet. In this multidisciplinary thesis, by integrating multiple cohorts and employing diverse research methodologies, we delved deeper into the complex interplay of immune system dynamics and its impact on the risk, progression, and outcomes of this debilitating neurodegenerative disease. Study I conducted within a longitudinal population-based cohort explored the associations between blood and urine biomarkers and the future risk of ALS and Parkinson’s disease (PD). Although increasing concentrations of leukocytes, haptoglobin, and uric acid were associated with a lower risk of PD, no statistically significant associations were noted between the studied biomarkers and the risk of future ALS diagnosis. By analyzing repeated biomarker measurements, the study described the temporal changes of these biomarkers during the two decades preceding the diagnosis of these diseases, shedding light on the dynamic nature of the immune biomarkers during disease development. While levels of leukocytes and uric acid were consistently lower in PD cases compared to controls, we did not observe any consistent differences in the studied biomarkers between ALS cases and their matched controls. Study II investigated the contribution of T cell responses to disease pathology by using flow cytometric analysis of blood and cerebrospinal fluid (CSF) samples from a cohort of newly diagnosed ALS patients. Our findings suggested that T cell phenotypes, at the time of diagnosis, have the potential to serve as predictors of disease outcomes. A high frequency of CD4+FOXP3- effector T cells in both blood and CSF was associated with poor survival, while a high frequency of activated regulatory T cells and a high ratio of activated to resting regulatory T cells in blood were associated with better survival. Additionally, phenotypic profiling of T cells proved effective in predicting disease progression rate. Furthermore, single cell transcriptomic analysis of CSF samples revealed presence of clonally expanded CD4+ and CD8+ T cells with distinct gene expression patterns, further supporting the involvement of T cell responses in ALS progression and suggesting the modulation of adaptive immunity as a potential therapeutic avenue. Study III expanded the exploration of T cell responses in ALS by studying the temporal changes of these cells following ALS diagnosis. By phenotyping T cell subtypes longitudinally in the blood and CSF of ALS patients, we highlighted the predictive value of these cells in assessing disease progression. Moreover, higher levels of certain cell types, including CD3+ and CD8+ T cells, were associated with increased mortality in the months following measurement. These findings underscore the significance of T cells in monitoring the disease course and mortality in ALS. Additionally, this thesis book emphasizes the importance of methodological approaches such as data collection and analysis. Study IV highlighted the significance of analytical choices such as cohort size, follow-up time, sampling time, and choice of confounders in the context of survival analysis in ALS and their contributions to the interpretation of results. Building upon findings in Studies II and III, where the T cell subsets did not render similar associations with the disease outcome between blood and CSF, we aimed to contrast the T cell profiles between the two biospecimens. In Study V, leveraging data from a longitudinal cohort of ALS patients, we observed a weak association between the frequency of T cell subsets in blood and CSF, suggesting that the phenotypic characteristics of T cells in blood and their subsequent associations with ALS pathological features would not necessarily reflect those of the central nervous system. In conclusion, the findings of this thesis work offer valuable insights into potential prognostic assessments and potential therapeutic interventions in ALS, as well as help advance our understanding of this devastating disease and pave the way not only for future research but also for improved patient care and management.