Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Abstract

Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

Microbiota‐Host Immunity Communication in Neurodegenerative Disorders: Bioengineering Challenges for In Vitro Modeling

“…More than 50 genes are associated with ALS development and code for proteins involved in several molecular and cellular mechanisms, such as dysregulation of protein aggregates degradation, mitochondrial dysfunction, and impairment of axonal signaling. [ 110 ] A common feature of various ALS forms is the systemic inflammation, which leads to neuronal death and ALS motor deficits. [ 111 ] Gut microbial imbalance contributes to increase the pro‐inflammatory state and the severity of the disease.…”

Some CSF Kynurenine Pathway Intermediates Associated with Disease Evolution in Amyotrophic Lateral Sclerosis

“…While neuroinflammation is uniformly present in end-stage pathology and is recognized as a major player in ALS progression [ 28 ], how and when it occurs remains unclear due to a lack of studies investigating this phenomenon in early disease and over the duration of the disease [ 29 ]. In fact, it was recently suggested that initial pre-symptomatic and early symptomatic phases are dominated by anti-inflammatory immune responses, whereas late symptomatic and terminal stages are dominated by proinflammatory immune responses [ 30 ]. This theory could actually explain the absence of KP modification found at early stages (diagnosis) in ALS patients, while most intermediates tend to be higher in ALS subjects with more severe evolution.…”

Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways

“…Our findings are in line with previous studies that identified higher ratios of neutrophils and/or granulocytes to lymphocytes in ALS patients 69,70 , elevated levels of inflammatory proteins 71 , and an association between higher neutrophil proportions and worse prognosis 72 . Although immune alterations could be part of a systemic aspect of ALS, there is evidence that suggests that the peripheral immune system contributes to neuroinflammation, the latter being an established phenomenon in ALS as well as other neurodegenerative diseases 73,74 . Especially interesting in this regard is that recent evidence shows that mast cells infiltrate skeletal muscles at the neuromuscular junction and degranulate to help recruit neutrophils 75,76 , which prevent reinnervation capacity and may thus be a potential mechanism causing worse prognosis.…”