Introduction

Multiple sclerosis (MS) is an inflammatory, autoimmune-mediated neurological disease that affects the central nervous system (CNS). MS leads to severe cognitive, physical, and neurological issues in approximately 2.5 million young adults worldwide (Jelcic, I. et al., 2018). In addition, 15-30% of adults suffering from MS develop a relapsing-remitting (RR) course, manifested in neurological, physiological, sensory, and motor impairments which progress with intervals of acute recovery and remission (Kunkl et al., 2020). Current research suggests that

50 % of patients with RRMS progress into chronic secondary disability over a vacillating period. Though the exact mechanism of MS development is unknown, research focuses on determining potential MS causes and triggers of its progression (Kunkl et al., 2020).

Generally, MS targets the CNS by destroying the myelinated axons. Due to axon demyelination, patients develop a variety of visual, motor, sensory, autonomic, and neurocognitive impairments (Jelcic, I. et al., 2018). Although the pathogenesis of MS is still unclear, many studies support a conjugated effect in its progression. Both environmental and genetic predisposition contribute to developing its degenerative course (Ghasemi N. et al., 2017).) Potential exposure to environmental pathogens, infectious agents, viruses, smoking, and other factors stimulates the initiation of a negative cascade of events in the immune system resulting in myelin sheath demyelination and, ultimately, neuronal failure (Ghasemi, N. et al., 2017). In addition, studies suggest the intervention of T helper (CD4+ T) cells in conjugation with viral antigens initiate and progress inflammatory cytokine signaling (Fransen NL et al., 2020). Initiation of specific cytokines such as (IL)-12, IL-23, and IL-4 induce T cell phenotype differentiation which triggers additional innate and adaptive immunity proinflammatory cytokines (IFNγ) to promote neuronal inflammation by suppressing Th2 differentiation (Ghasemi N et al.,2017). This literature review will focus on understanding the mechanism of MS progression through the T helper cell differentiation pathway and investigating an effective therapeutic for individuals suffering from RRMS.

The role of T helper cells in initiating cytokine signaling

Extensive research shows T helper (Th) cells play a crucial role in the pathophysiology of MS. Specifically, CD4+T recruitment across the blood-brain barrier (BBB) into the CNS releases specific cytokines that trigger progressive inflammation throughout the brain (Ghasemi, N. et al., 2017). T helper cells are white blood cells that are crucial in sustaining adaptive immunity. Helper T cells function when activated by antigen-presenting cells, which promote differentiation into effector helper subclasses such as Th1 or Th2 cells, further allowing recognition by cytokines (Alberts B et al., 2002). Cell differentiation into Th1 cells initiates interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) secretion, which triggers macrophages to attack oligodendrocytes. Thus, promoting myelin destruction, apoptosis of infected cells, cellular debris, lesions, and inflammation in the CNS (Alberts B et al., 2002). However, differentiation into Th2 cells initiates activation of anti-inflammatory interleukins (IL-4 and IL-13) that combat inflammation caused by cell death thus, resulting in restoration and initiation of new oligodendrocytes to induce remyelination of damaged axons (Alberts B et al., 2002).

T helper cell differentiation promotes inflammation in MS patients

Studies suggest that increased levels of Th cells and cytokines found in CNS lesions and cerebrospinal fluid (CSF) of MS patients confirm lymphocyte extravasation across the BBB leading to exacerbated progression of MS (Kunkl et al., 2020) (Alberts B et al., 2002). These signaling factors influence astrocyte and microglial activation leading to BBB destruction, resulting in neuroinflammation and myelin damage (Alberts B et al., 2002). Several current hypotheses mention specific T lymphocyte interactions with antigen-presenting cells (APCs) at the beginning and further progression of MS (Ghasemi N et al., 2017). The predicted mechanism of action includes binding of pathogen molecules such as viral infections, bacterial lipopolysaccharides, and metabolic stress with toll receptors present on APCs, triggering interleukin (IL)-12, IL-23, and IL-4) cytokines (Ghasemi N et al.,2017). Such cytokines further induce differentiation of CD4+ T cells into different Th phenotypes (Th1, Th2/Th17), able to initiate the release of additional pro-inflammatory cytokines. This cytokine cascade includes Th1-produced pro-inflammatory cytokines responsive to innate and adaptive immunity (Ghasemi N et al., 2017). Pro-inflammatory cytokines such as Interferon-gamma (IFNγ) or type II interferon (TNF-α) suppress Th2 cell differentiation, encouraging inflammation. Furthermore, research suggests Th2 cells’ role in pathological inflammation is controlled by releasing IL-4 cytokines, which reduces inflammation by increasing M2 macrophage (Ghasemi N et al.,2017). In conclusion, CD4+T differentiation into subsets such as Th1, Th2, and Th17 induces cytokine release that further triggers inflammation. Recruitment of CD4+ T lymphocytes across the BBB into the CNS develops inflammation and oligodendrocyte damage throughout the brain by activating several proinflammatory cytokines (Ghasemi N et al., 2017).

The cytokine IFN-γ produced by the T cells and natural killer cells plays a critical role in autoimmune demyelination. Although the molecular mechanisms of how cytokines mediate destruction of oligodendrocytes, demyelination is believed to be facilitated by cell-mediated cytotoxicity and apoptosis (Balabanov et al., 2006, Traugott et al., 2001). Studies have shown that upon activation of IFN-γ, oligodendrocytes upregulate the expression of surface ligands and and major histocompatibility (MHC) class I molecules that promote cytotoxicity and ultimately cell death (Balabanov et al., 2006).  Research on autoimmune-mediated demyelination has also illustrated the effect of IFN-γ on failed remyelination in RRMS. Studies have attributed inability of oligodendrocytes to remyelinate in demyelinated lesions is due in part to endoplasmic reticulum (ER) stress (Wensheng et al., 2006, Lin et al., 2005). Mediating ER stress could be a potential target in facilitating remyelination in demyelinated lesions of MS patients to reduce relapse of symptoms. Meanwhile, one effective MS treatment that decreases inflammation and thus reduces symptoms in RRMS patients is Natalizumab.

Natalizumab (NAT) short term treatment reduces inflammation in RRMS patients

Natalizumab (NAT) is an effective treatment in active relapsing-remitting multiple sclerosis (RRMS) patients. NAT inhibits the migration and extravasation of leukocytes across the CNS by binding to α4-integrin (Lakritz et al., 2016) (Mellergård et al., 2013). This treatment is encouraged for RRMS patients that maintain non-responsive nor effective reactions to current effective therapy such as first-line disease-modifying therapies (DMT) (Kappos et al., 2011). Therefore, allowing individuals with no-responsive behavior is an alternative option in combating RRMS and improving their quality of life. A study observed the effects of short-term NAT treatment on lymphocyte circulation in 40 RRMS patients taking a drug dosage of 30 mg weekly (Mellergård et al., 2013). The results showed an increased expression of NK cells and B cells, including improved T cell (CD4+/CD8+) sensitivity to antigens (Mellergård et al., 2013). NAT treatment showed decreased migration of harmful lymphocytes across the BBB into the CNS and reduced intrathecal inflammation (Lakritz et al., 2016) (Mellergård et al., 2013). Similar results are observed in a study performed over two years that tested the effects of Natalizumab treatment in 596 patients (Polman et al., 2006). The study compared the annual relapse rate (ARR) after NAT treatment and placebo administration of one year. The results found a significant reduction following NAT treatment compared to the placebo.

Moreover, the study observed a 59% reduction in relapse following a two-year NAT treatment (Polman et al., 2006). Ultimately, the study aligns with other studies suggesting a decrease of RRMS and a decrease in disease progression and lesion formation in MS patients. These findings indicate that NAT could be used as an effective long-term treatment in RRMS patients.  

Natalizumab (NAT) long term treatment reduces relapse remission in MS patients

Long-term treatment focuses on determining the efficacy, safety, and life quality of RRMS patients prescribed NAT. Furthermore, MS research shows the effectiveness of NAT treatment in reducing RR rates in MS patients in long-term use. A study performed by an observational program (TOP) analyzed ARRs of MS patients following the NAT treatment over ten years (Butzkueven et al., 2019). Results suggest a significant reduction of ARR across all subjects despite initial baseline, age, or category classification. Individuals with an initial lower baseline (less recorded relapse in the year before treatment) experience significant lower ARRs when on NAT treatment (Butzkueven et al., 2019). Additionally, during the first year of treatment, ARR significantly decreased from an initial baseline score of 1.99 to 0.24 and remained at this rate for the duration of the 10-year treatment (Butzkueven et al., 2019).

A similar study observed treatment annualized relapse rates in RRMS patients also revealed significantly reduced ARR over five years of treatment (Butzkueven et al., 2014). Besides efficient decreased annual relapse rates, researchers noted progressive multifocal leukoencephalopathy (PML) as a common side effect in multiple MS patients, increasing with yearly NAT treatment exposure (Kleinschmidt-DeMasters et al., 2005, Butzkueven et al., 2019). PML is a progressive disorder that maintains a rapid degenerative course, leading to the destruction of the white matter, manifested as extensive lesions throughout the brain (Kleinschmidt-DeMasters et al., 2005). Although the mechanism of PML development in MS patients is unknown, research has indicated that PML develops in individuals with autoimmune disorders such as MS and with other immunosuppressive diseases such as HIV and lymphomas (Major et al., 2018). PML is caused by the reactivation of the John Cunningham (JC) virus that is unharmful in its dormant stages (Major et al., 2018). However, in MS patients taking long-term immunosuppressive medication such as Natalizumab leads to the reactivation of the virus. Consequently, the virus leads to severe inflammation and damage to oligodendrocytes in various parts of the brain. The development of PML in MS patients suggests further research is needed on the effects of NAT treatment in MS patients that receive long-term NAT treatment. In addition, studies should investigate the impact of α4-integrin inhibition in RRMS patients and how it might play a role in developing PML.

Conclusion

Multiple sclerosis is a severe, progressive disease that affects millions worldwide. MS progression results in inflammation, axon demyelination, and relapse-remission stages resulting in various progressive autonomic and neurocognitive impairments. Although the exact mechanism of disease initiation and development remains unclear, scientists suggest factors such as T helper cell differentiation, pathogens, and cytokine signaling participate in MS advancement. Although current MS treatment involves first-line disease-modifying therapies (DMT) to reduce relapse frequency and severity, DMTs are not effective in all RRMS patients. However, Natalizumab is a potential short and long-term treatment, showing effective potency in reducing yearly relapse rates and increasing life quality. Despite its effectiveness and efficiency in reducing relapse remission rates, NAT progresses with detrimental side effects such as PML disease, leading to progressive deterioration, extensive lesions, and destruction of white matter in RRMS patients. Therefore, further research is needed to investigate the progression of PML as a significant side effect of NAT long-term treatment. Furthermore, current research indicates additional long-term NAT treatment conduction to acquire further data on annual disease relapse rates, safety, efficiency, and life quality during and after treatment. Since MS involves several cell types that trigger an array of specific immune responses, future research should also investigate the interaction of glial and immune cell types and their role in the progression of MS. Specifically, the interaction between oligodendrocytes, pro-inflammatory and anti-inflammatory cytokines released by natural killer cells and T cells such as IFN-γ and other cytokines involved in demyelination should be further investigated. Since, studies have shown the effect of IFN-γ on reduced remyelination in response to ER stress, further research should explore how oligodendrocytes can mediate ER stress to remyelinate lesions in the brain.

[+] References

[+] Other Work By Virginia Buracioc