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Comprehensive immune profiling reveals substantial immune system alterations in a subset of patients with amyotrophic lateral sclerosis.

ABSTRACT: 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.

SUBMITTER: Gustafson MP

PROVIDER: S-EPMC5526569 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Comprehensive immune profiling reveals substantial immune system alterations in a subset of patients with amyotrophic lateral sclerosis.

Gustafson Michael P MP Staff Nathan P NP Bornschlegl Svetlana S Butler Greg W GW Maas Mary L ML Kazamel Mohamed M Zubair Adeel A Gastineau Dennis A DA Windebank Anthony J AJ Dietz Allan B AB

PloS one 20170725 7

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 ...[more]

PMID: 28742871

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Project description:Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.

Dataset Information

Comprehensive immune profiling reveals substantial immune system alterations in a subset of patients with amyotrophic lateral sclerosis.

Publications

Comprehensive immune profiling reveals substantial immune system alterations in a subset of patients with amyotrophic lateral sclerosis.

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