Amyotrophic lateral sclerosis patients show increased peripheral and intrathecal T-cell activation

Leoni Rolfes; Andreas Schulte-Mecklenbeck; Stefanie Schreiber; Stefan Vielhaber; Michael Herty; Anika Marten; Steffen Pfeuffer; Tobias Ruck; Heinz Wiendl; Catharina C Gross; Sven G Meuth; Matthias Boentert; Marc Pawlitzki

doi:10.1093/braincomms/fcab157

Amyotrophic lateral sclerosis patients show increased peripheral and intrathecal T-cell activation

Brain Commun. 2021 Jul 14;3(3):fcab157. doi: 10.1093/braincomms/fcab157. eCollection 2021.

Authors

Leoni Rolfes^{1

2}, Andreas Schulte-Mecklenbeck¹, Stefanie Schreiber^{3

4

5}, Stefan Vielhaber^{3

4

5}, Michael Herty⁶, Anika Marten¹, Steffen Pfeuffer¹, Tobias Ruck^{1

2}, Heinz Wiendl¹, Catharina C Gross¹, Sven G Meuth^{1

2}, Matthias Boentert¹, Marc Pawlitzki¹

Affiliations

¹ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany.
² Department of Neurology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf 40225, Germany.
³ Department of Neurology, Otto-von-Guericke University, Magdeburg 39120, Germany.
⁴ German Center for Neurodegenerative Diseases, Magdeburg 39120, Germany.
⁵ Center for Behavioral Brain Sciences (CBBS), Magdeburg 39106, Germany.
⁶ Institute of Geometry and Applied Mathematics, RWTH Aachen University, Aachen 52062, Germany.

Abstract

Several studies suggest a role for the peripheral immune system in the pathophysiology of amyotrophic lateral sclerosis. However, comprehensive studies investigating the intrathecal immune system in amyotrophic lateral sclerosis are rare. To elucidate whether compartment-specific inflammation contributes to amyotrophic lateral sclerosis pathophysiology, we here investigated intrathecal and peripheral immune profiles in amyotrophic lateral sclerosis patients and compared them with controls free of neurological disorders (controls) and patients with dementia or primary progressive multiple sclerosis. Routine CSF parameters were examined in 308 patients, including 132 amyotrophic lateral sclerosis patients. In a subgroup of 41 amyotrophic lateral sclerosis patients, extensive flow-cytometric immune cell profiling in peripheral blood and CSF was performed and compared with data from 26 controls, 25 dementia and 21 multiple sclerosis patients. Amyotrophic lateral sclerosis patients presented with significantly altered proportions of monocyte subsets in peripheral blood and increased frequencies of CD4⁺ and CD8⁺ T cells expressing the activation marker HLA-DR in peripheral blood (CD8⁺) and CSF (CD4⁺ and CD8⁺) compared with controls. While dementia and multiple sclerosis patients exhibited a comparable increase in intrathecal CD8⁺ T-cell activation, CD8⁺ T-cell activation in the peripheral blood in amyotrophic lateral sclerosis was higher than in multiple sclerosis patients. Furthermore, intrathecal CD4⁺ T-cell activation in amyotrophic lateral sclerosis surpassed levels in dementia patients. Intrathecal T-cell activation resulted from in situ activation rather than transmigration of activated T cells from the blood. While T-cell activation did not correlate with amyotrophic lateral sclerosis progression, patients with rapid disease progression showed reduced intrathecal levels of immune-regulatory CD56^bright natural killer cells. The integration of these parameters into a composite score facilitated the differentiation of amyotrophic lateral sclerosis patients from patients of all other cohorts. To conclude, alterations in peripheral monocyte subsets, as well as increased peripheral and intrathecal activation of CD4⁺ and CD8⁺ T cells concomitant with diminished immune regulation by CD56^bright natural killer cells, suggest an involvement of these immune cells in amyotrophic lateral sclerosis pathophysiology.

Keywords: amyotrophic lateral sclerosis; cerebrospinal fluid; immune phenotyping; immune system; neuroinflammation.