Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder that affects motor neurons in the brain and spinal cord, causing progressive loss of voluntary muscle control 1,2 . ALS heterogeneity includes the age of manifestation, the rate of progression, and the anatomical sites of symptom onset. In addition, disease-causing mutations in specific genes have been identified and are used to catalog different subtypes of ALS 3 . Interestingly, several ALS-associated genes have been shown to affect immune functions, and a variety of aberrant inflammatory events have been reported in patients and mouse models 4-11 , suggesting that specific immune features can also account for ALS heterogeneity. ALS4 is characterized by juvenile-onset and slow progression 12 . After experiencing mild symptoms during their childhood, ALS4 patients show motor difficulties by their 30s, and most of them require walkers or wheelchairs by their 50s. ALS4 is caused by dominant mutations in the gene SETX. Using Setx knock-in (KI) mice carrying the ALS4 causative L389S mutation, we discovered an immunological signature consisting of clonally activated CD8 T cells specifically in the central nervous system and blood of KI animals. Expansion of antigen-specific CD8 T cells mirrors disease progression. Bone marrow transplantation experiments indicate an essential role of the immune system in ALS4 neurodegeneration. Furthermore, we found that clonally expanded CD8 T cells circulate in the peripheral blood of ALS4 patients. Our results provide evidence of an antigen-specific CD8 T cell response linked to ALS4, and can serve not only to unravel specific disease mechanisms, but as a potential biomarker of disease activity. MainALS4 is caused by heterozygous mutation in the SETX gene, which encodes for the Senataxin protein, an ubiquitously expressed nuclear ATP-dependent DNA/RNA helicase [13][14][15][16] . Senataxin can resolve DNA/RNA hybrids and regulate RNA metabolism 14,17 . Also, we demonstrated that lack of Senataxin results in increased type I interferon (IFN-I) responses upon infection 16 ,

Single-cell transcriptional landscape of peripheral immunity and biomarkers for human sporadic amyotrophic lateral sclerosis patients

“…Compared to the Control group, the T cells from the ALS patients exhibited a slightly higher level of expansion. This observation is somewhat distinct from the significant clonal expansion of CD8 T EMRA cells recently reported for ALS4 13 . One possible explanation is that ALS4 patients are juvenile onset, where the age-matched controls are young people with very limited T cell clonal expansion, therefore diseased-related expansion can be more easily detected.…”

“…Clusters 4 was defined as naïve B cells (high in MS4A1, CD79A, HLA-DRA and TCL1A). Clusters 5,6,13,15,21,31 was regulatory T cells. Cluster 30 was assigned as mucosal-associated invariant T (MAIT) cells.…”

Early β-amyloid accumulation in the brain is associated with peripheral T cell alterations

“…Therefore, it is essential to analyze cohorts across the entire AD continuum. As for other neurodegenerative diseases, specific T cell responses have also been associated with amyotrophic lateral sclerosis (ALS) (Campisi et al, 2022) and early, preclinical stages of Parkinson’s disease (Lindestam Arlehamn et al, 2020) . Importantly, our findings on CD8 + TEMRA/Effector cells can be reproduced in a setup, in which diagnostic groups are assigned based on cognitive state and levels of plasma AD biomarker p-tau181.…”

Single channel properties of pannexin‐1 and connexin‐43 hemichannels and P2X7 receptors in astrocytes cultured from rodent spinal cords

“…In addition to modulate communication between neurons, astrocytes and myeloid cells, FGF-1 may be involved in other forms of neuroimmune interactions during inflammatory conditions, for example, providing a co-stimulatory signal for expansion and activation of CD8 T cells (Byrd et al, 1999). In this regard, antigen-specific CD8 T cells infiltrate in the spinal cord and contribute to pathogenesis in ALS-4, a juvenile form of ALS (Campisi et al, 2022). Future studies should determine whether FGFs modulate single channel activities of HCs and P2X7Rs and immune responses in disease-associated T cells.…”