Advances on Cellular Clonotypic Immunity in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease, characterized by the progressive degeneration of the upper and lower motor neurons in the cortex and spinal cord. Although the pathogenesis of ALS remains unclear, evidence concerning the role of the clonotypic immune system is growing. Adaptive immunity cells often appear changed in number, or in terms of their activation profiles, both peripherally and centrally; however, their role in ALS appears conflictive. Data from human and animal model studies, which are currently reported in the literature, show that each subset of lymphocytes and their mediators may mediate a protective or toxic mechanism in ALS, affecting both its progression and risk of death. In the present review, an attempt is made to shed light on the actual role of cellular clonotypic immunity in ALS by integrating recent clinical studies and experimental observations.

Keywords: Amyotrophic lateral sclerosis (ALS); autoimmunity; neurodegeneration; neuroinflammation; neuromuscular disease; the clonotypic immune system.

Figure 1

Pathophysiological effects induced by C9OR72, TARDBP, SOD1, and FUS gene mutations that are associated with the onset of ALS. A: The C9ORF72 mutation induces a gain-of-function (GOF) mechanism. More precisely, GGGGCC (G4C2), when translocated to its cytosol form, aggregates poly-(GP) dipeptide-repeat proteins (DPR), or misfolded proteins, to produce aggregates of ubiquitinated (U) RNA foci that are associated with TDP43 or FUS proteins, which are both mediating neuronal toxins. B: The transactive response of the DNA-binding protein (TARDBP) mutation triggers both the loss of function (LOF) and GOF mechanisms. C: The superoxide dismutase 1 (SOD1) mutation provokes a GOF mechanism. Mutant SOD1 dimers in the cytosol collect as SOD1 inclusions within mitochondria, and Lewy-body-like hyaline (LBLH) inclusions in the cytosol, where they can trigger mitochondrial reactive oxygen species (ROS) a generation later, thus causing mitochondrial destruction. D: The fused-in sarcoma (FUS) mutation mediates both LOF and GOF mechanisms. Mutant FUS proteins cause LOF by preventing normal FUS from binding to pre-mRNA. E: Cytosol vacuolization is caused by all the above-mentioned mutations. By Biorender software.

Figure 2

C9ORF and SOD1 mouse models which are mainly used for providing evidence concerning the involvement of the clonotypic immune system in the pathogenesis of ALS. By Biorender software.

Figure 3

Correlation between the number and levels of clonotypic cells and related cytokines in terms of disease progression and outcomes. By Biorender software.