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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:Background: Nicotinamide adenine dinucleotide (NAD+) metabolism has drawn more attention on neurodegeneration research; however, the role in Amyotrophic Lateral Sclerosis (ALS) remains to be fully elucidated. Here, the purpose of this study was to investigate whether the circulating NAD+ metabolic-related gene signature could be identified as a reliable biomarker for ALS survival. Methods: A retrospective analysis of whole blood transcriptional profiles and clinical characteristics of 454 ALS patients was conducted in this study. A series of bioinformatics and machine-learning methods were combined to establish NAD+ metabolic-derived risk score (NPRS) to predict overall survival for ALS patients. The associations of clinical characteristic with NPRS were analyzed and compared. Receiver operating characteristic (ROC) and the calibration curve were utilized to assess the efficacy of prognostic model. Besides, the peripheral immune cell infiltration was assessed in different risk subgroups by applying the CIBERSORT algorithm. Results: Abnormal activation of the NAD+ metabolic pathway occurs in the peripheral blood of ALS patients. Four subtypes with distinct prognosis were constructed based on NAD+ metabolism-related gene expression patterns by using the consensus clustering method. A comparison of the expression profiles of genes related to NAD+ metabolism in different subtypes revealed that the synthase of NAD+ was closely associated with prognosis. Seventeen genes were selected to construct prognostic risk signature by LASSO regression. The NPRS exhibited stronger prognostic capacity compared to traditional clinic-pathological parameters. High NPRS was characterized by NAD+ metabolic exuberant with an unfavorable prognosis. The infiltration levels of several immune cells, such as CD4 naive T cells, CD8 T cells, neutrophils and macrophages, are significantly associated with NPRS. Further clinicopathological analysis revealed that NPRS is more appropriate for predicting the prognostic risk of patients with spinal onset. A prognostic nomogram exhibited more accurate survival prediction compared with other clinicopathological features. Conclusions: In conclusion, it was first proposed that the circulating NAD+ metabolism-derived gene signature is a promising biomarker to predict clinical outcomes, and ultimately facilitating the precise management of patients with ALS.

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.

Dataset Information

The Peripheral Immune System and Amyotrophic Lateral Sclerosis.

Publications

The Peripheral Immune System and Amyotrophic Lateral Sclerosis.

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