Increased ratio of circulating neutrophils to monocytes in amyotrophic lateral sclerosis

Abstract

Objective:To elucidate amyotrophic lateral sclerosis (ALS) biomarkers and potential mechanisms of disease, we measured immune cell populations in whole blood from a large cohort of patients with ALS.Methods:Leukocytes were isolated from the blood of 44 control patients and 90 patients with ALS. The percentages and total numbers of each cell population were analyzed using flow cytometry and matched with patient ALS Functional Rating Scale–Revised (ALSFRS-R) score to correlate leukocyte metrics with disease progression.Results:We show a significant increase in the percentage of neutrophils and a significant decrease in the percentage of CD4 T cells and CD16− monocytes in the blood of patients with ALS compared to controls; however, only CD16− monocyte levels correlated with disease progression. We also examined the monocyte surface expression of CCRL2 and CCR3; CD16− monocytes displayed decreased percentages and total numbers expressing CCR3, but these numbers did not correlate with ALSFRS-R score. We found that combining multiple disease metrics yielded the most accurate predictor of disease progression: the ratio of neutrophils to CD16− monocytes (N:M ratio) is significantly increased in patients with ALS and better correlates with disease progression than any other single metric.Conclusions:These observations implicate neutrophils and monocytes as important factors in late disease progression.

Peripheral immune biomarkers and neurodegenerative diseases: A prospective cohort study with 20 years of follow‐up

“…Studies directed at mapping peripheral adaptive immune profiles in ALS and associating immune alterations to clinical disease phenotypes have been conducted . For example, ALS patients were shown to have altered levels of CD4+, CD8+, and natural killer T cells in the peripheral blood compared to healthy controls, and such alterations were shown to be associated with the progression rate of the disease .…”

“…Studies directed at mapping peripheral adaptive immune profiles in ALS and associating immune alterations to clinical disease phenotypes have been conducted. [30][31][32] For example, ALS patients were shown to have altered levels of CD4+, CD8+, and natural killer T cells in the peripheral blood compared to healthy controls, and such alterations were shown to be associated with the progression rate of the disease. 30,31,33 The present study did not, however, reveal different associations of specific cell types with the risk of ALS or different concentrations of specific cell types between ALS patients and individuals without ALS during the 20 years before ALS diagnosis.…”

“…[30][31][32] For example, ALS patients were shown to have altered levels of CD4+, CD8+, and natural killer T cells in the peripheral blood compared to healthy controls, and such alterations were shown to be associated with the progression rate of the disease. 30,31,33 The present study did not, however, reveal different associations of specific cell types with the risk of ALS or different concentrations of specific cell types between ALS patients and individuals without ALS during the 20 years before ALS diagnosis. The fact that previous studies compared leukocyte concentrations among clinical patients with ALS to healthy volunteers, whereas the present study examined leukocyte concentrations long before diagnosis of ALS patients to randomly selected population controls, might have contributed to part of the contrasting results pattern.…”

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

“…Neuroinflammation in ALS also involves the participation of blood-borne immune cells such as lymphocytes, monocytes, mast cells, and neutrophils, among others [92, 130-132]. These cells are known to permeate the BBB in specific regions and actively interact with the degenerative cellular microenvironment surrounding motor neurons and motor axons [81, 131, 133, 134].…”

“…Along this line, ALS patients display higher levels of circulating monocytes, neutrophils, and CD4 lymphocytes, with the increased number positively correlating with a more rapid progression of the disease [132, 138]. Mouse models as well as ALS patients also have high levels of cytotoxic CD8 lymphocytes and circulating natural killer cells [133, 139, 140].…”