T cell responses at diagnosis of amyotrophic lateral sclerosis predict disease progression

Yazdani, Solmaz; Seitz, Christina; Cui, Can; Lovik, Anikó; Pan, Lu; Piehl, Fredrik; Pawitan, Yudi; Kläppe, Ulf; Samuelsson, Kristin; Yin, Li; Vu, Trung Nghia; Joly, Anne-Laure; Westerberg, Lisa S.; Evertsson, Björn; Ingre, Caroline; Andersson, John; Fang, Fang

doi:10.1038/s41467-022-34526-9

Cited by 40 publications

(49 citation statements)

References 43 publications

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“…Importantly, CSF of ALS patients exhibits an expansion of a T cell subpopulation expressing eomesodermin, which drives IFN-𝝲 expression. 32 IFN-𝝲 is permeable to the blood spinal barrier, particularly in the cervical region, implying that T cells impacted by peripheral inflammation might expose motor neurons to IFN-𝝲. [33][34][35] Moreover, Bonney et al showed that IFN-𝝲 even promotes its permeability to the blood-brain barrier, implying that uncontrolled IFN-𝝲 secretion may broadly affect the physiology of the entire CNS.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ Elicits Pathological Hallmarks of ALS in Human Motor Neurons

Chun

Lee

Bothwell

et al. 2022

Preprint

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Neuroinflammation is an established factor contributing to amyotrophic lateral sclerosis (ALS) pathology, implicating the possible detrimental effects of inflammatory cytokines to motor neurons. The RNA/DNA-binding protein TDP-43 has emerged as a pivotal actor in ALS, because TDP-43 mutations cause familial ALS and loss of nuclear TDP-43, associated with its redistribution into cytoplasmic aggregates (TDP-43 proteinopathy), in motor neurons occurs in 97% of ALS cases. However, mechanisms linking neuroinflammation to TDP-43 mis-localization have not been described. Programmed death-ligand 1 (PD-L1) is an immune-modulatory protein, highly expressed on cell surfaces following acute inflammatory stress. To determine which inflammatory cytokines might impact motor neuron function, seven cytokines known to be elevated in ALS patients cerebrospinal fluid were tested for their effects on PD-L1 expression in human iPSC-derived motor neurons. Among the tested cytokines, only interferon-gamma (IFN-gamma) was found to strongly promote PD-L1 expression. Thus, we hypothesized that excessive exposure to IFN-gamma may contribute to motor neuron degeneration in ALS. We observed that neuronal populations exposed to IFN-gamma exhibited severe TDP-43 cytoplasmic aggregation and excitotoxic behavior correlated with impaired neural firing activity, hallmarks of ALS pathology, in both normal and ALS mutant (TARDBPQ331K+/-) neurons. Single-cell RNA sequencing revealed possible mechanisms for these effects. Motor neurons exposed to IFN-gamma exhibited an extensive shift of their gene expression profile toward a neurodegenerative phenotype. Notably, IFN-gamma treatment induced aberrant expression levels for 70 genes that are listed in the recent literature as being dysregulated in ALS. Additionally, we found that genes related to neuronal electrophysiology, protein aggregation, and TDP-43 mis-regulation were abnormally expressed in IFN-gamma-treated cells. Moreover, IFN-gamma induced a significant reduction in the expression of genes that encode indispensable proteins for neuromuscular synapse development and maintenance, implying that cytokine exposure could directly impair signal transmission between motor axons and muscle membranes. Our findings suggest that IFN-gamma could be a potent upstream pathogenic driver of ALS and provide potential candidates for future therapeutic targets to treat sporadic forms of ALS, which account for roughly 90% of reported cases.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ Elicits Pathological Hallmarks of ALS in Human Motor Neurons

Chun

Lee

Bothwell

et al. 2022

Preprint

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“…Recent studies have demonstrated that T-cell infiltration and clonal expansion is enhanced in neurodegenerative disorders such as AD, [126][127][128][129][130] PD, [131][132][133][134][135] ALS, 136,137 and MS. [138][139][140][141] Although some of these disorders have T-cell antigens that are more clearly defined such as in MS and PD, there is still a significant need for further investigating the antigenic source/breadth and the mechanisms in which they induce T-cell activation.…”

Section: Pathog Eni C-derived Anti G En S In N E U R O D E G E N E R ...mentioning

confidence: 99%

Antigen‐specific and cross‐reactive T cells in protection and disease

Jiang

Malone

Chizari

2023

Immunological Reviews

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Human T cells have a diverse T-cell receptor (TCR) repertoire that endows them with the ability to identify and defend against a broad spectrum of antigens. The universe of possible antigens that T cells may encounter, however, is even larger. To effectively surveil such a vast universe, the T-cell repertoire must adopt a high degree of crossreactivity. Likewise, antigen-specific and cross-reactive T-cell responses play pivotal roles in both protective and pathological immune responses in numerous diseases. In this review, we explore the implications of these antigen-driven T-cell responses, with a particular focus on CD8+ T cells, using infection, neurodegeneration, and cancer as examples. We also summarize recent technological advances that facilitate highthroughput profiling of antigen-specific and cross-reactive T-cell responses experimentally, as well as computational biology approaches that predict these interactions.

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“…They found that monocytes signal to clonal CD8 + T cells via CXCL16-CXCR6 in patients with cognitive impairment. Yazdani et al [ 82 ] have used the same technique to examine the CSF of patients with amyotrophic lateral sclerosis (ALS) and described clonally expanded CD4 + and CD8 + T cells with characteristic patterns of gene expression.…”

Section: Elements Of the Blood-csf Barrier And The Csf And Glymphatic...mentioning

confidence: 99%

“…In ALS, Yazdani et al [ 82 ] have found that T cell phenotypes in blood and CSF are good predictors of disease progression with high CD4 + FOXP3 − effector T cell expression being associated with poor survival, whereas a high frequency of Treg cells was associated with better survival. They also found evidence of clonally expanded CD4 + and CD8 + cells in CSF and propose that modulating adaptive immunity is a therapeutic option for ALS.…”

Section: Neurological Disordersmentioning

confidence: 99%

A year in review: brain barriers and brain fluids research in 2022

Keep

Jones

Hamilton

et al. 2023

Fluids Barriers CNS

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This aim of this editorial is to highlight progress made in brain barrier and brain fluid research in 2022. It covers studies on the blood-brain, blood-retina and blood-CSF barriers (choroid plexus and meninges), signaling within the neurovascular unit and elements of the brain fluid systems. It further discusses how brain barriers and brain fluid systems are impacted in CNS diseases, their role in disease progression and progress being made in treating such diseases.

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T cell responses at diagnosis of amyotrophic lateral sclerosis predict disease progression

Cited by 40 publications

References 43 publications

Interferon-γ Elicits Pathological Hallmarks of ALS in Human Motor Neurons

Interferon-γ Elicits Pathological Hallmarks of ALS in Human Motor Neurons

Antigen‐specific and cross‐reactive T cells in protection and disease

A year in review: brain barriers and brain fluids research in 2022

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