Peripheral proinflammatory Th1/Th17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis

Abstract

Neuroinflammation is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS), but only limited data are available on systematic peripheral and central immune cell profiles in ALS. We studied detailed immune profiles of 73 ALS patients and 48 healthy controls (controls) in peripheral blood by fluorescence-activated cell sorting as well as cytokine expression profiles in serum. In a subgroup of 16 ALS patients and 10 controls we additionally studied cerebrospinal fluid (CSF) samples. In peripheral blood, T cell subtypes presented a shift towards pro-inflammatory Th 1 and Th 17 cells whereas anti-inflammatory Th2 and T regulatory cells were decreased. Important players in innate immunity including distinct monocyte (Mo) and natural killer (NK) cell subtypes were changed in ALS patients compared to controls. Pro-inflammatory serum cytokines such as interleukin (IL)-1 beta, IL-6 and interferon-gamma (IFN-gamma) were increased and the anti-inflammatory cytokine IL-10 was decreased. Correlation analysis revealed moderate negative correlations between Th1 and Th17 to the ALS functional rating scale revised (ALSFRS-R) and to forced vital capacity. In CSF samples, no relevant alteration of the immune profile was found. In conclusion, the immune profile in ALS was shifted towards a Th1/Th17 cell-mediated pro-inflammatory immune response and correlated to disease severity and progression. Large prospective studies are needed to confirm these findings. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which affects the upper and lower motoneurons (MN) leading to progressive muscle weakness, paralysis and ultimately death due to respiratory failure. The pathophysiological mechanisms are still unresolved, although increasing knowledge gained in the last two decades. Multiple studies corroborated that numerous pathological processes are involved in MN degeneration and neuroinflammation gained increasing attention and had deemed as a pathological hallmark of ALS 1-3. It is commonly accepted that the non-neuronal neighbors play a significant role in the degenerative process of this vulnerable cell type 4. One of the most impressive pathohistological characteristics during disease progression is activation and increase abundance of microglial cells in the central nervous system (CNS) shown in animal models of ALS 5 as well as in human studies 6-8. Microglial cells are considered to be the resident mononuclear phagocytes in the CNS and can be renewed by bone marrow cells under special circumstances 9,10. It is supposable that specialized peripheral immune cell subsets are attracted to the central compartment to contribute and perpetuate the pathological processes in ALS disease by local inflammation or activation of resident cells. Therefore, neuroinflammation is not limited to the CNS, it needs a systemic inflammatory response to enable the local inflammation. In general, a systemic inflammatory response is very complex, a plethora of different immune cells are involved, diverse cytokines a...

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

“…low numbers are predictive for rapid disease progression and short survival ( Fig. 4 ) ( Henkel et al , 2013 ; Sheean et al , 2018 ), whereas there is moderate negative correlation between Th1 and Th17 T cells, ALSFRS-R and forced vital capacity ( Jin et al , 2020 ). Another study observed a positive correlation between high baseline neutrophil-to-lymphocyte ratio and shorter survival, proposing that it can reflect the degree of neuroinflammation in ALS patients ( Choi et al , 2020 ).…”

“…4A ). Data to support this neuroprotective to neurotoxic shift came largely from studies in mutant hSOD1 ALS models, in which the initial presymptomatic and early symptomatic phases are dominated by anti-inflammatory immune responses (anti-inflammatory microglia, Treg and Th2 CD4 T cells), whereas late symptomatic and terminal stages are dominated by proinflammatory immune responses (proinflammatory microglia and astrocytes, inflammatory monocytes, cytotoxic CD8 T cells, Th1 and Th17 CD4 T cells, NK cells and neutrophils) ( Henkel et al , 2013 ; Zhao et al , 2013 ; Murdock et al , 2017 ; Sheean et al , 2018 ; Choi et al , 2020 ; Garofalo et al , 2020 ; Jin et al , 2020 ). As previously discussed, once that a hyperinflammatory state of microglia or astrocytes is established, these glial cells directly become toxic and can kill motoneurons ( Roberts et al , 2013 ; Re et al , 2014 ; Zhao et al , 2015 ).…”

Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?

“…Infiltrated T lymphocytes were found in the post-mortem spinal cord of ALS patients ( Engelhardt et al, 1993 ). Studies evaluating immune cell profiles in the peripheral blood of healthy controls and ALS patients showed no differences in levels of total lymphocytes or CD3 + T lymphocytes, however, highlighted differences within specific T cell subsets ( Saresella et al, 2013 ; Shin et al, 2013 ; Chen et al, 2014 ; Jin et al, 2020 ). ALS patients have significantly lower proportions of CD4 + T cells with unchanged or elevated CD8 + T cell proportions ( Chen et al, 2014 ; Jin et al, 2020 ).…”

“…Studies evaluating immune cell profiles in the peripheral blood of healthy controls and ALS patients showed no differences in levels of total lymphocytes or CD3 + T lymphocytes, however, highlighted differences within specific T cell subsets ( Saresella et al, 2013 ; Shin et al, 2013 ; Chen et al, 2014 ; Jin et al, 2020 ). ALS patients have significantly lower proportions of CD4 + T cells with unchanged or elevated CD8 + T cell proportions ( Chen et al, 2014 ; Jin et al, 2020 ). Despite this decreased CD4:CD8 T cell ratio, only a higher CD4 + T cell percentage in ALS patients correlates with disease severity and progression ( Shi et al, 2007 ; Chen et al, 2014 ).…”

“…Despite this decreased CD4:CD8 T cell ratio, only a higher CD4 + T cell percentage in ALS patients correlates with disease severity and progression ( Shi et al, 2007 ; Chen et al, 2014 ). This correlation was associated with a shift toward a Th1/Th17 cell-mediated pro-inflammatory immune response ( Saresella et al, 2013 ; Jin et al, 2020 ). Even though the percentages of anti-inflammatory Th2 cells and Tregs were decreased ( Saresella et al, 2013 ; Jin et al, 2020 ), higher percentages of IL-13-producing CD4 + T cells, a Th2-related cytokine, were detected in ALS patients, correlating with disease severity ( Shi et al, 2007 ).…”