Can we continue to ignore the evidence that T-cells are fundamental to MS?
Can we continue to ignore the evidence that T-cells are fundamental to MS?
Is it not time to take off the B-cell blinkers? Do you think MS-Selfie is the appropriate platform for highlighting key research findings in MS?
I have had many debates about whether or not MS is a T-cell or B-cell-mediated disease. The emergence of B-cell-depleting (anti-CD20) and B-cell inhibiting (BTKIs) therapies as a treatment for MS means the pendulum has swung into the B-cell camp. However, this ignores the solid circumstantial data that puts T-cells as the orchestrator of MS pathology. Surely, finding mainly CD8+ T-cells in MS lesions is telling us something? CD8+ effector cells are usually involved with viral infections and are one clue I use to support the viral hypothesis of MS. I suspect B-cells may be downstream of the T-cell and B-cells may simply be involved as antigen-presenting cells or, dare I say as the source of EBV, which is driving MS disease activity.
I was, therefore, very excited to see the study below that examined CD8+ T cells in people with multiple sclerosis (pwMS) and their identical twins to identify immunological and metabolic changes associated with the disease. In short, the findings
Key findings
CD8+ T cells in pwMS and their twins with subclinical neuroinflammation (SCNI) or arguably asymptomatic MS showed signs of being more activated, proinflammatory, and migratory than healthy individuals. These changes were evident in CD8+ T cells from the blood and cerebrospinal fluid (CSF).
Specific gene expression patterns in CD8+ T cells, including several markers (CD27, CD69, COTL1, and ANXA5), are associated with increased T cell activation capacity.
Using an analysis gene set enrichment analysis (GSEA), they revealed that pathways related to interferon-γ response, i.e. IL-2/STAT5 signalling and oxidative phosphorylation, were enriched in both SCNI and MS groups.
CD8+ T cells from MS-affected individuals showed higher expression of genes involved in proteasomal degradation and HLA class II antigen presentation than those with SCNI.
The study identified several immunological modules linked to increased activation, antigen presentation, central nervous system (CNS) migration, and production of effector molecules in MS disease-associated CD8+ T cells.
Metabolic module analysis revealed up-regulated energy metabolism, specifically oxidative phosphorylation, in SCNI and MS groups. This was evidenced by the high expression of genes involved in glucose intake (SLC2A3), glycolysis or glucose metabolism (GAPDH, LDHB), the citric acid cycle (MDH2, IDH2), and the mitochondrial respiratory complex I (NDUFA13).
They confirmed the immunological and metabolic alterations observed in the twin study in an independent validation cohort of untreated patients with relapsing-remitting MS (RRMS).
Single-cell analysis of brain tissue from MS patients showed that T cells in MS lesions also express key elements of the identified immunological and metabolic modules, supporting the sustained activation of CD8+ T cells in these areas.
In summary, this study identified specific immunological and metabolic alterations in CD8+ T cells that are associated with both the prodromal or asymptomatic and manifest stages of MS. These findings suggest that CD8+ T cells play a key role in MS pathogenesis and highlight potential targets for diagnostic and therapeutic approaches.
What are the implications of these findings for clinical practice?
The findings offer several potential implications for clinical practice, highlighting potential avenues for diagnosis, monitoring, and treatment of the disease:
Early Diagnosis and Monitoring: The study identified immunological and metabolic alterations in CD8+ T cells present even in individuals with SCNI, suggesting that these changes occur in the early, prodromal or asymptomatic stages of MS. This raises the possibility of using these alterations as biomarkers for early diagnosis and monitoring disease progression, potentially allowing for earlier intervention. This could involve monitoring the expression of specific genes or proteins in CD8+ T cells or assessing the metabolic activity of these cells.
Therapeutic Targets: Identifying specific immunological and metabolic pathways dysregulated in MS-associated CD8+ T cells opens up potential therapeutic avenues.
For instance, targeting the IL-2 signalling pathway, particularly IL2RB, which is upregulated in SCNI, could be beneficial in the early stages of the disease.
Inhibiting CXCR3, a chemokine receptor involved in T cell migration to the CNS, could be another approach to modulate T cell trafficking and reduce neuroinflammation.
Targeting CD6, which mediates interactions between T cells and antigen-presenting cells and is highly expressed in MS-associated CD8+ T cells, might also be explored.
The study's findings also suggest that JAK inhibitors, already used in other autoimmune diseases, could hold promise for treating MS due to JAK3's involvement in T-cell activation.
The potential of targeting metabolic pathways, particularly oxidative phosphorylation, for therapeutic intervention is also highlighted.
Understanding Disease Mechanisms: The in-depth characterisation of CD8+ T cell alterations in MS provides valuable insights into the underlying disease mechanisms. The study demonstrates the critical role of CD8+ T cells in driving inflammation. It highlights their complex interplay with other immune cells, such as dendritic cells and macrophages, by releasing chemokines like CCL5 and FLT3L. This more profound understanding of disease pathogenesis can guide the development of more targeted and effective treatments.
Overall, the study underscores the importance of CD8+ T cells in MS pathogenesis and offers a rich source of potential targets for developing novel diagnostic and therapeutic strategies. Further research is necessary to translate these findings into clinical applications, link them to EBV biology and determine the most effective ways to manipulate these pathways as a treatment for MS.
I suspect that this newsletter will be confusing and too scientific for many of you. This begs the question of whether you think MS-Selfie is the appropriate platform for highlighting key research findings in MS and related disorders.
Paper
Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8+ T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8+ T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8+ T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8+ T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.
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General Disclaimer
Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
You're right - I don't understand it. However, it's really important for me to read this level of information because it gives me an appreciation of how complex it all is and a general picture of what the known unknowns are. This in turn helps me ask more informed questions about my own treatment and to understand that my neurologist doesn't have all the answers yet.
I would really like it if there was a basic guide/text book aimed at patients to teach us the biology needed to understand more. I find it all fascinating and am one of those people for whom the more information I have, the less scary it all is because it is just so interesting
I think its good for pwms and their loved ones to be able to access this information and research so thankyou