B cells play a multifaceted and crucial role in the development and progression of multiple sclerosis (MS), a chronic autoimmune disease that affects the central nervous system (CNS). Their involvement goes beyond merely producing antibodies; they actively participate in immune regulation, antigen presentation, and inflammatory processes that drive MS pathology.
At the core, B cells contribute to MS by interacting with other immune cells, especially T cells, to amplify and sustain neuroinflammation. One of the key mechanisms is through antigen presentation. B cells can capture and present CNS-derived antigens on their surface via MHC class II molecules to CD4+ T helper cells. This interaction activates pathogenic T cells, which then infiltrate the CNS and cause damage to myelin, the protective sheath around nerve fibers. This antigen presentation by B cells is particularly important in the meninges, the membranes surrounding the brain and spinal cord, where local B cells form aggregates that promote inflammation independently of peripheral immune organs. These meningeal B cells create a localized environment that accelerates disease progression by sustaining T cell activation and recruitment.
In addition to antigen presentation, B cells produce pro-inflammatory cytokines such as interleukin-23 (IL-23), which further stimulate T cells and other immune cells, creating an inflammatory amplification loop. This loop involves not only B and T cells but also neutrophils and endothelial cells, perpetuating chronic inflammation within the CNS. This sustained immune activation leads to the characteristic demyelination and neurodegeneration seen in MS.
Memory B cells, a subset of B cells that have previously encountered antigens, are particularly implicated in MS. These cells can migrate into the CNS, where they differentiate into antibody-secreting cells. Although the exact target antigens of these antibodies remain unclear, locally produced antibodies are thought to contribute to tissue damage. The presence of these B cells and antibodies within the CNS distinguishes MS from some other autoimmune diseases of the nervous system.
Therapeutically, targeting B cells has proven effective in managing MS. Treatments such as anti-CD20 monoclonal antibodies rapidly deplete B cells, leading to a reduction in disease activity. Interestingly, while B cell depletion occurs quickly, changes in T cell behavior and inflammatory pathways emerge more gradually over months, suggesting that B cells influence T cells indirectly over time. This delayed effect includes the reprogramming of regulatory T cells, which become more active and resilient, helping to maintain long-term immune balance and reduce MS progression.
Beyond their role in adaptive immunity, B cells also interact with myeloid cells like microglia and macrophages within the CNS. These interactions contribute to the activation of innate immune responses that exacerbate neuroinflammation. Molecules such as SLAMF5 on myeloid cells modulate these processes, and their blockade has shown promise in reducing disease severity, highlighting the complex network of immune cells involved in MS.
In summary, B cells in MS are not just antibody factories but are central players in orchestrating the autoimmune attack on the CNS. They present antigens to T cells, produce inflammatory cytokines, form meningeal aggregates that sustain local inflammation, and influence other immune cells to perpetuate the disease. Understanding these diverse roles has been key to developing effective B cell-targeted therapies that have transformed MS treatment and continue to be a focus of research for better disease control.
