Multiple sclerosis pathway

Multiple sclerosis (MS) is an autoimmune disease that often leads to significant neurological disability due to damage to the myelinated tracts in the central nervous system (CNS). MS is a complex condition influenced by various factors. Many genes contribute modestly to an individual's susceptibility to the disease, alongside several well-defined environmental factors, including vitamin D levels, exposure to ultraviolet B (UVB) light, infection with the Epstein–Barr virus (EBV), obesity, and smoking¹. In most patients, the disease initially presents as an episodic disorder and progressively evolves.

MS can be classified into four types based on the clinical course of the disease. The most common type, especially among young individuals, is relapsing-remitting MS (RRMS). This type is characterized by episodes of attacks followed by periods of partial or complete remission. Initially, some recovery occurs after each attack; however, with multiple episodes, nerve damage may accumulate, and full recovery becomes less likely. The second type is primary progressive MS (PPMS), where symptoms worsen continuously without any periods of remission. There may be occasional plateau phases, but the condition progressively deteriorates overall. The third type is secondary progressive MS (SPMS), which evolves from relapsing-remitting MS. SPMS is marked by a gradual progression of symptoms that become more severe over time. Finally, there is progressive-relapsing MS (PRMS), the least common form of the disease, which features a steady progression of symptoms from the outset, along with intermittent periods of remission.

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Lifestyle factors can majorly impact the frequency and intensity of MS attacks. For example, smoking can aggravate symptoms and accelerate the progression of disability compared to non-smokers. In addition, stress, poor diet, and inadequate sleep can worsen MS symptoms. Consequently, adopting a healthy lifestyle, such as quitting smoking, maintaining a balanced diet, and engaging in regular exercise, may help alleviate some symptoms.

Contemporary models of pathogenesis support the existence of two interconnected and overlapping effector arms: inflammatory and neurodegenerative². Focal inflammation bursts are believed to cause the episodic relapsing-remitting phase of MS, while axonal loss and neurodegeneration contribute to progressive symptoms, which are the primary source of disability. Multiple sclerosis has traditionally been categorized as an organ-specific autoimmune disease mediated by T-cells. However, the effectiveness of B-cell-targeted therapies challenges this standard view of T-cell involvement³. Indeed, anti-CD20 therapies have been a game changer in the MS field as CD20-depleting antibodies effectively reduce relapses and progression in MS⁴. Moreover, recent advancements in treating autoimmune diseases like MS involve chimeric antigen receptor (CAR)-T cell therapies^5,6.

One of the key routes involved in MS is the Toll-like receptor (TLR)/MyD88 pathway. TLRs are part of the pattern recognition receptor family, which operates in innate and adaptive immune responses by identifying microbes, viruses, and abnormal cells. Particularly, TLR2 and TLR4 are expressed at higher levels in patients with MS, revealing their potential contribution to the disease's pathogenesis. In addition, a large study from Harvard University has found strong evidence that the Epstein-Barr virus (EBV) is a major cause of MS⁷. Th1 and Th17 cells are also critical in the development of MS and are employed to distinguish between several clinical phenotypes of the disease. Th1 cells produce cytokines essential for cellular immunity and autoimmune diseases, but are not the main pathogenic cell subset in MS. In contrast, Th17 cells play a key role in the progression of MS. IL-17A, a cytokine produced by Th17 cells, is closely associated with the breakdown of the blood-brain barrier and the growth of neutrophils in the cerebrospinal fluid. Furthermore, it can promote the calcium-dependent release of glutamate, contributing to glutamate excitotoxicity in developing MS⁸.

Multiple sclerosis is a chronic progressive neurological disorder composed of numerous molecular pathways. This illustration presents a general overview of the MS process, which entails intricate and comprehensive exchanges and collaborations at the molecular level.

References

1. Ascherio, A. Environmental factors in multiple sclerosis.  Expert Rev. Neurother.  13, 3–9 (2013).

2. Oksenberg, J. R., Baranzini, S. E., Sawcer, S. & Hauser, S. L. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis.  Nat. Rev. Genet.  9, 516–526 (2008).

3. Dobson, R. & Giovannoni, G. Multiple sclerosis - a review.  Eur. J. Neurol.  26, 27–40 (2019).

4. de Sèze, J. et al. Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.  Front. Immunol.  14, 1004795 (2023).

5. Mullard, A. CAR-T therapy for multiple sclerosis enters US trials for the first time.  Nature  (2024).

6. Fischbach, F. et al. CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis.  Med.  5, 550–558.e2 (2024).

7. Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis.  Science  375, 296–301 (2022).

8. Kosa, P. et al. Molecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms.  Nat. Commun.  13, 7670 (2022).