Interplay between immunity and amyotrophic lateral sclerosis: Clinical impact

Abstract

Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease. Despite decades of research and many new insights into disease biology over the 150 years since the disease was first described, causative pathogenic mechanisms in ALS remain poorly understood, especially in sporadic cases. Our understanding of the role of the immune system in ALS pathophysiology, however, is rapidly expanding. The aim of this manuscript is to summarize the recent advances regarding the immune system involvement in ALS, with particular attention to clinical translation. We focus on the potential pathophysiologic mechanism of the immune system in ALS, discussing local and systemic factors (blood, cerebrospinal fluid, and microbiota) that influence ALS onset and progression in animal models and people. We also explore the potential of Positron Emission Tomography to detect neuroinflammation in vivo, and discuss ongoing clinical trials of therapies targeting the immune system. With validation in human patients, new evidence in this emerging field will serve to identify novel therapeutic targets and provide realistic hope for personalized treatment strategies.

Keywords: Amyotrophic lateral sclerosis; Biomarkers; Immunity; Inflammation; Target; Targeted therapies.

Figure 1.. The immune cell response in the CNS and periphery of SOD1^G93A rodent models during disease progression.

(A) Spinal cord: At the presymptomatic stage, CCL2 is activated by motor neurons and microglia to recruit neuroprotective CD4⁺ T cells (Th2 and Tregs), which together with microglia in an M2-activate state and with mildly activated astrocytes release neurotrophic (NTFs) and anti-inflammatory factors to preserve motor neurons. However, this phenomenon appears to be counterbalanced by infiltrating NK cells that injure motor neurons while inhibiting Tregs and M2 microglia through the expression of IFN-γ. During the disease course, a massive release of CCL2 enhances the recruitment of DCs alongside with CD8⁺ and CD4⁺ T cells (Th1). Proinflammatory T cells influence the activation status of astrocytes, which release pro-inflammatory factors and TGF-β1, which polarize microglia to a M1 phenotype. M1 microglia in turn release ROS and pro-inflammatory factors (IL-1β, TNF-α) detrimental to motor neurons. Peripheral monocyte infiltration in the spinal cord of SOD1^G93A rodent models is still controversial. (B) Sciatic nerve: At the presymptomatic stage, early production of CCL2 along with the complement-mediated opsonization of motor axons and IgM, IgG deposition elicit the infiltration of macrophages and mast cells. At onset, increased permeability of the blood-nerve barrier together with CCL2 overexpression and a massive IgM/IgG deposition promotes a further infiltration of mast cells, neutrophils, macrophages, and CD8⁺ T cells, which contribute to the massive degradation of peripheral motor axons and myelinating Schwann cells. (C) Skeletal muscle: At the presymptomatic stage, peripheral macrophages infiltrate the skeletal muscle of transgenic rodents alongside the increased expression of proinflammatory response initiator (Caspase1; C1q/C3) and byproducts (IL-1β). This likely is the response to neuromuscular junction (NMJ) alterations/denervation which precedes the motor neuron death according to the “dying back” hypothesis. Whether this response is an attempt to protect the myofibers or has a pathogenic role is still unknown. During disease progression, macrophages massively infiltrate the skeletal muscle together with mast cells, neutrophils, and T cells. This event is accompanied by increased inflammation due to IL-6, TNF-α, TGF-β1, TGF-β3, and C5a expression. Abbreviations: C-C Motif Chemokine Ligand 2 (CCL2), T helper (Th), regulatory T cell (Treg), neurotrophic factors (NTFs), natural killer (NK), interferon gamma (IFN-γ), dendritic cell (DC), transforming growth factor (TGF), reactive oxygen species (ROS), Interleukin (IL), tumor necrosis factor-α (TNF-α), immunoglobulin (Ig). Image created in Biorender.com

Figure 2.. The timeline of immune system involvement in ALS: evidence from animal models and patients.

The progression of the immune response in animal models (top) and human ALS patients (bottom) is depicted over time. Horizontal arrows mark the conversion of immune biomarkers when applicable, while vertical arrows mark non-immune milestones of disease. Monocyte infiltration is still controversial (*). Current studies reported no progression in PET tracing of microgliosis and astrogliosis but studies need to be expanded to include more patients. Abbreviations: cerebrospinal fluid (CSF), regulatory T cell (Treg), blood–brain barrier (BBB), central nervous system (CNS), natural killer (NK), peripheral blood mononuclear cell (PBMC), positron emission tomography (PET).