The Potential Role of Cytotoxic Immune Effectors in Induction, Progression and Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)

Abstract

Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neuron system. The causes of ALS are heterogeneous, and are only partially understood. We studied different aspects of immune pathogenesis in ALS and found several basic mechanisms which are potentially involved in the disease. Our findings demonstrated that ALS patients’ peripheral blood contains higher proportions of NK and B cells in comparison to healthy individuals. Significantly increased IFN-γ secretion by anti-CD3/28 mAbs-treated peripheral blood mononuclear cells (PBMCs) were observed in ALS patients, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism for ALS progression. In addition, elevated granzyme B and perforin secretion at a single cell level, and increased cytotoxicity and secretion of IFN-γ by patients’ NK cells under specific treatment conditions were also observed. Increased IFN-γ secretion by ALS patients’ CD8+ T cells in the absence of IFN-γ receptor expression, and increased CD8+ T cell effector/memory phenotype as well as increased granzyme B at the single cell level points to the CD8+ T cells as potential cells in targeting motor neurons. Along with the hyper-responsiveness of cytotoxic immune cells, significantly higher levels of inflammatory cytokines including IFN-γ was observed in peripheral blood-derived serum of ALS patients. Supernatants obtained from ALS patients’ CD8+ T cells induced augmented cell death and differentiation of the epithelial cells. Weekly N-acetyl cysteine (NAC) infusion in patients decreased the levels of many inflammatory cytokines in peripheral blood of ALS patient except IFN-γ, TNF-α, IL-17a and GMCSF which remained elevated. Findings of this study indicated that CD8+ T cells and NK cells are likely culprits in targeting motor neurons and therefore, strategies should be designed to decrease their function, and eliminate the aggressive nature of these cells. Analysis of genetic mutations in ALS patient in comparison to identical twin revealed a number of differences and similarities which may be important in the pathogenesis of the disease.

Causal relationship between immune cells and neurodegenerative diseases: a two-sample Mendelian randomisation study

“…Regarding the role of CD8+ T cells in ALS, the research is relatively limited. The elimination of CD8+ T cells has been shown to increase the survival of motor neurons in an ALS model mouse ( 67 ). In vitro studies also show that CD8+ lymphocytes expressing mutant superoxide dismutase-1 (SOD-1) can recognize and selectively kill motor neurons, suggesting a potential autoimmune origin of ALS ( 68 ).…”

Immunology of amyotrophic lateral sclerosis – role of the innate and adaptive immunity

“…In a study published by Kaur et al (2022), CD8+ T cells of ALS patients had increased CD28 and CCR7 expression in contrast to decreased IFN-γ receptor, which may be due to the constitutive IFN-γ expression. Promoting not only activation of the immune cells but also regulating the survival and function of NK and CD8+ T cells, absence or decrease in IFN-γ receptors on CD8+ T cells is an important finding which may lead to aforementioned increase in their lifespan and cytotoxic capacity to kill motoneurons.…”

CD8+ T cells in brain injury and neurodegeneration

“…In the peripheral blood of ALS patients, an increased number of CD8 + T cell effector/memory cells was observed and these CD8 + T cells secreted increased granzyme B, IL-17 or IL-13 (Shi et al, 2007;Fiala et al, 2010;Kaur et al, 2022). Moreover, depletion of CD8 + T cells in MHC-I-deficient mice promotes the survival of motor neurons (Nardo et al, 2018;Coque et al, 2019; Table 1).…”