The Role of T Helper Cells and Brain Barriers in Multiple Sclerosis: Unveiling Key Mechanisms of CNS Inflammation

The article "The interplay between T helper cells and brain barriers in the pathogenesis of multiple sclerosis" (Angelini et al., 2023) explores how the interactions between T helper (Th) cells and the brain's protective barriers contribute to the development and progression of multiple sclerosis (MS). In MS, the immune system mistakenly attacks the central nervous system (CNS), leading to inflammation, demyelination, and neurodegeneration. This review provides a detailed analysis of the role of two key CNS barriers—the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB)—and their interactions with Th cells during neuroinflammation.

Blood-Brain Barrier (BBB) Breakdown in MS
The BBB is a critical structure composed of endothelial cells, astrocytes, and other components, which tightly regulate the movement of immune cells and molecules between the bloodstream and the CNS. In MS, this barrier becomes compromised, leading to increased permeability and allowing immune cells, particularly T cells, to infiltrate the CNS. Two subsets of Th cells, Th1 and Th17, are considered key drivers of MS pathology. These cells release pro-inflammatory cytokines, including interferon-gamma (IFN-γ) and interleukin-17 (IL-17), which exacerbate the inflammatory response, further disrupting BBB integrity.

Th1 cells, known for secreting IFN-γ, have a dual role in MS. While IFN-γ can destabilize the BBB by promoting the expression of adhesion molecules such as VCAM-1 and ICAM-1, facilitating leukocyte infiltration, recent studies suggest that it may also help restore BBB integrity under certain conditions. Conversely, Th17 cells secrete IL-17, which directly damages the BBB by disrupting tight junctions between endothelial cells, promoting CNS invasion by leukocytes. This breakdown of the BBB is an early event in MS and is detectable in relapsing-remitting MS (RRMS) through imaging techniques such as gadolinium-enhanced MRI, which highlights areas of BBB disruption.

Blood-Cerebrospinal Fluid Barrier (BCSFB) and Immune Cell Trafficking
The BCSFB is another critical barrier that protects the CNS by regulating the movement of immune cells and solutes from the blood into the cerebrospinal fluid (CSF). This barrier is located at the choroid plexus and leptomeninges. The choroid plexus, in particular, becomes a site of immune cell trafficking in MS. Under normal conditions, immune surveillance at the BCSFB is minimal, but during neuroinflammation, immune cells, including Th cells, migrate through the choroid plexus into the CNS. The review highlights the role of the CCL20-CCR6 axis, which recruits Th17 cells to the CNS via the BCSFB.

Additionally, the leptomeninges, a compartment within the BCSFB, are identified as sites where Th cells can be reactivated, contributing to the local immune response. The discovery of organized lymphoid follicles within the leptomeninges of MS patients emphasizes their role as immune interfaces that drive chronic inflammation in secondary progressive MS (SPMS). These follicles serve as hubs for continuous T cell activation and proliferation, sustaining neuroinflammation and promoting disease progression.

The Role of Adhesion Molecules and Cytokines in CNS Invasion
A key aspect of Th cell-mediated CNS invasion is their ability to adhere to and migrate across endothelial cells in the BBB and BCSFB. This process is regulated by various adhesion molecules, including integrins (e.g., VLA-4) and members of the immunoglobulin superfamily (e.g., VCAM-1, ICAM-1). Th1 cells primarily rely on VLA-4-mediated interactions to infiltrate the CNS, while Th17 cells use a combination of VLA-4 and LFA-1 integrins to cross the BBB. In MS patients, therapies such as natalizumab, which block VLA-4, have proven effective in reducing T cell migration and disease activity.

Cytokines produced by Th cells also play a crucial role in modulating BBB and BCSFB permeability. While IFN-γ from Th1 cells can both disrupt and restore BBB integrity, depending on the context, IL-17 from Th17 cells consistently weakens the BBB by downregulating tight junction proteins and promoting endothelial cell contraction. IL-17 also increases the expression of pro-inflammatory cytokines and chemokines, amplifying the immune response and further damaging the CNS.

Emerging Role of the Dura Mater as a Neuroimmune Interface
Recent studies have identified the dura mater, the outermost meningeal layer, as a potential immune interface that may regulate immune cell migration in MS. The dura mater contains lymphatic vessels that drain CSF and immune cells to cervical lymph nodes, suggesting that it plays a role in immune surveillance and antigen presentation. Although the dura's involvement in MS is less well understood than the BBB and BCSFB, emerging evidence suggests that it may act as a secondary route for immune cell trafficking into the CNS during neuroinflammation.

Conclusion
The review by Angelini et al. (2023) provides a comprehensive overview of the complex interactions between Th cells and brain barriers in MS. The BBB and BCSFB are key gateways for immune cell infiltration into the CNS, and their dysfunction plays a central role in the pathogenesis of MS. Th1 and Th17 cells, through their adhesion molecules and cytokines, drive the inflammatory process that leads to BBB breakdown, CNS invasion, and neurodegeneration. While therapies targeting these mechanisms, such as natalizumab, have shown promise in MS treatment, further research is needed to fully understand the role of other CNS interfaces, such as the dura mater, in disease progression.

References:
Angelini, G., Bani, A., Constantin, G., & Rossi, B. (2023). The interplay between T helper cells and brain barriers in the pathogenesis of multiple sclerosis. Frontiers in cellular neuroscience, 17, 1101379.