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The Peripheral Immune System and Amyotrophic Lateral Sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

SUBMITTER: McCombe PA

PROVIDER: S-EPMC7186478 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Peripheral Immune System and Amyotrophic Lateral Sclerosis.

McCombe Pamela A PA Lee John D JD Woodruff Trent M TM Henderson Robert D RD

Frontiers in neurology 20200421

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spin ...[more]

PMID: 32373052

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Project description:ImportanceAmyotrophic lateral sclerosis (ALS) has an immune component, but previous human studies have not examined immune changes over time.ObjectivesTo assess peripheral inflammatory markers in participants with ALS and healthy control individuals and to track immune changes in ALS and determine whether these changes correlate with disease progression.Design, setting, and participantsIn this longitudinal cohort study, leukocytes were isolated from peripheral blood samples from 35 controls and 119 participants with ALS at the ALS Clinic of the University of Michigan, Ann Arbor, from June 18, 2014, through May 26, 2016. Follow-up visits occurred every 6 to 12 months. Fifty-one participants with ALS provided samples at multiple points. Immune cell populations were measured and compared between control and ALS groups. Surface marker expression of CD11b+ myeloid cells was also assessed. Changes over time were correlated with disease progression using multivariate regression.Main outcomes and measuresThe number of immune cells per milliliter of blood and the fold expression of cell surface markers. Multivariate regression models were used to correlate changes in immune metrics with changes on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).ResultsThirty-five controls (17 women [48.6%] and 18 men [51.4%]; mean [SD] age, 63.5 [9.9] years) and 119 participants with ALS (50 women [42.0%] and 69 men [68.0%]; mean [SD] age, 61.4 [11.5] years) were enrolled. Compared with controls, participants with ALS had increased mean (SEM) counts (?×?106/mL) of total leukocytes (4.57 [0.29; 95% CI, 3.94-5.11] vs 5.53 [0.16; 95% CI, 5.21-5.84]), neutrophils (2.87 [0.23; 95% CI, 2.40-3.35] vs 3.80 [0.12; 95% CI, 3.56-4.04]), CD16+ monocytes (0.03 [0.003; 95% CI, 0.02-0.04] vs 0.04 [0.002; 95% CI, 0.03-0.04]), CD16- monocytes (0.25 [0.02; 95% CI, 0.21-0.30] vs 0.29 [0.01; 95% CI, 0.27-0.31]), and natural killer cells (0.13 [0.02; 95% CI, 0.10-0.17] vs 0.18 [0.01; 95% CI, 0.16-0.21]). We also observed an acute, transient increase in a population of CD11b+ myeloid cells expressing HLA-DR, CD11c, and CX3CR1. Finally, early changes in immune cell numbers had a significant correlation with disease progression measured by change in ALSFRS-R score, particularly neutrophils (-4.37 [95% CI, -6.60 to -2.14] per 11.47?×?104/mL [SD, 58.04?×?104/mL] per year) and CD4 T cells (-30.47 [95% CI, -46.02 to -14.94] per -3.72?×?104/mL [SD, 26.21?×?104/mL] per year).Conclusions and relevanceChanges in the immune system occur during ALS and may contribute to the pathologic features of ALS.

Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a median lifespan of 2-3 years after diagnosis. There are few meaningful treatments that alter progression in this disease. Preclinical and clinical studies have demonstrated that neuroinflammation may play a key role in the progression rate of ALS. Despite this, there are no validated biomarkers of neuroinflammation for use in clinical practice or clinical trials. Biomarkers of neuroinflammation could improve patient management, provide new therapeutic targets, and possibly help stratify clinical trial selection and monitoring. However, attempts to identify a singular cause of neuroinflammation have not been successful. Here, we performed multi-parameter flow cytometry to comprehensively assess 116 leukocyte populations and phenotypes from lymphocytes, monocytes, and granulocytes in a cohort of 80 ALS patients. We identified 32 leukocyte phenotypes that were altered in ALS patients compared to age and gender matched healthy volunteers (HV) that included phenotypes of both inflammation and immune suppression. Unsupervised hierarchical clustering and principle component analysis of ALS and HV immunophenotypes revealed two distinct immune profiles of ALS patients. ALS patients were clustered into a profile distinct from HVs primarily due to differences in a multiple T cell phenotypes, CD3+CD56+ T cells and HLA-DR on monocytes. Patients clustered into an abnormal immune profile were younger, more likely to have a familial form of the disease, and survived longer than those patients who clustered similarly with healthy volunteers (344 weeks versus 184 weeks; p = 0.012). The data set generated from this study establishes an extensive accounting of immunophenotypic changes readily suitable for biomarker validation studies. The extensive immune system changes measured in this study indicate that normal immune homeostatic mechanisms are disrupted in ALS patients, and that multiple immune states likely exist within a population of patients with ALS.

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The Peripheral Immune System and Amyotrophic Lateral Sclerosis.

Publications

The Peripheral Immune System and Amyotrophic Lateral Sclerosis.

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