Professor of Neurology and Neuroscience, Department of Neurology and the Brain and Mind Research Institute, Weill Cornell Medical College
Dr. Latov reports he is a consultant for Pfizer, receives grant/research support from Shire, and owns stock in Therapath LLC.
SYNOPSIS: Activation of the immune system has been recognized in patients with amyotrophic lateral sclerosis, and immune activation may influence the course of the disease and the speed of progression.
SOURCE: Murdock BJ, Zhou G, Kashian SR, et al. Correlation of peripheral immunity with rapid amyotrophic lateral sclerosis progression. JAMA Neurol 2017; Sept. 25.doi:10.1001/jamaneurol.2017.2255.
The number and types of circulating immune cells were assessed and tracked in 119 patients with amyotrophic lateral sclerosis (ALS) and 35 healthy controls to determine whether they are altered in and whether any alterations correlated with disease progression. Compared to controls, patients with ALS were found to have an increased numbers of total leukocytes, neutrophils, monocytes (CD16+ and CD16-), and natural killer cells, and an acute transient increase in CD11b+ myeloid cells expressing HLA-DR, CD11c, and CX3CR1. Changes in immune cell numbers, particularly neutrophils and CD4+ T cells, significantly correlated with disease progression as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. The authors speculated that changes in the immune system contribute to the pathogenic features of ALS and may influence its time course and progression.
In ALS, there is evidence for systemic immune activation, as evidenced by increased levels of autoantibodies,1 complement activation products,2 and pro-inflammatory cytokines.3 In this paper, the authors reported that patients with ALS also have increased numbers of circulating immune cells, and that the increase in neutrophils and CD4+ T cells correlated with disease severity and progression.
As with other disease associations, questions arise as to whether the association is a cause, contributory factor, consequence, or unrelated to the disease. The observation that the changes in cell numbers correlates with disease progression suggests that the two are related.
There is considerable evidence that neuroinflammation contributes to motor neuron degeneration. This process is thought to be mediated by microglia that secrete pro-inflammatory cytokines and neurotoxins. Studies of postmortem spinal cord samples from ALS cases reveal the presence of increased numbers of activated microglia and lymphocytes surrounding motor neurons, and the microglial activation occurs in the early stages of ALS.4 Activation of microglia might occur secondarily to the neuronal degeneration, possibly in response to misfolded protein aggregates, or be induced by other factors, such as autoimmunity5 or endogenous retroviruses.6 In either case, they would contribute to motor nerve degeneration.
In preclinical studies, inhibition of complement C5a-C5a1 receptor signaling ameliorated disease pathology in an SOD1 mouse model of ALS.7 Disruption of pathways involved in neuroinflammation offers potential therapeutic targets in patients with ALS.
- Thomas FP, Latov N. Motor neuron disease and autoimmunity. In: The Handbook of Amyotrophic Lateral Sclerosis. Smith RA, ed. Marcel Dekker: New York; 1992, Ch 20, pp 479-503.
- Mantovani S, Gordon R, Macmaw JK, et al. Elevation of the terminal complement activation products C5a and C5b-9 in ALS patient blood. J Neuroimmunol 2014;276:213-218. doi:10.1016/j.jneuroim.2014.09.005.
- Ehrhart J, Smith AJ, Kuzmin-Nichols N, et al. Humoral factors in ALS patients during disease progression. J Neuroinflammation 2015;12:127. doi:10.1186/s12974-015-0350-4.
- Liu J, Wang F. Role of neuroinflammation in amyotrophic lateral sclerosis: Cellular mechanisms and therapeutic implications. Front Immunol 2017;8:1005. doi:10.3389/fimmu.2017.01005.
- Gonzalez LE, Kotler ML, Vattino LG, et al. Amyotrophic lateral sclerosis-immunoglobulins selectively interact with neuromuscular junctions expressing P/Q-type calcium channels. J Neurochem 2011;119:826-838. doi:10.1111/j.1471-4159.2011.07462.x.
- Li W, Lee MH, Henderson L, et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med 2015;7:307ra153. doi:10.1126/scitranslmed.aac8201.
- Lee JD, Kumar V, Fung JN, et al. Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. Br J Pharmacol 2017;174:689-699. doi:10.1111/bph.13730.