Inflammation plays a central and complex role in the progression of multiple sclerosis (MS), acting as both a driver of early disease activity and a contributor to ongoing neurological damage over time. MS is fundamentally an autoimmune disorder where the immune system mistakenly attacks components of the central nervous system (CNS), particularly myelin—the protective sheath around nerve fibers—and sometimes the nerve fibers themselves. This immune attack triggers inflammation, which is crucial in shaping how MS develops and worsens.
At its core, inflammation in MS involves various immune cells, including T cells, B cells, and myeloid cells such as microglia and macrophages. These cells infiltrate or become activated within the CNS, releasing inflammatory molecules like cytokines that promote tissue damage. Early in MS, this inflammatory response causes relapses—episodes of new or worsening neurological symptoms—by damaging myelin and disrupting nerve signaling. The adaptive immune system’s T cells recognize specific antigens on myelin proteins and orchestrate attacks that lead to focal areas of demyelination visible as lesions on MRI scans.
However, inflammation’s role extends beyond these acute flare-ups. Even when clinical symptoms are not apparent—a phase sometimes called “silent” or asymptomatic disease activity—inflammation continues at low levels inside the brain tissue itself. This smoldering or chronic inflammation is driven by resident brain immune cells like microglia that remain activated for long periods. It contributes to gradual neurodegeneration by producing oxidative stress and releasing toxic substances that harm neurons directly or impair their ability to repair damaged myelin.
One important aspect is how certain receptors on these brain-resident immune cells regulate their activation state during neuroinflammation. For example, molecules like SLAMF5 expressed on myeloid-lineage cells can enhance their inflammatory activity within the CNS environment, promoting further infiltration of harmful lymphocytes such as CD4+ T cells into brain tissue. This amplifies local inflammation leading to more severe neurological dysfunction over time.
Iron dysregulation also intersects with inflammation in MS progression. Iron is essential for many cellular processes but must be tightly controlled because excess free iron can catalyze harmful oxidative reactions causing cell injury. In MS patients’ brains, disrupted iron homeostasis has been observed alongside chronic neuroinflammation; this imbalance exacerbates demyelination and neuronal loss by fueling oxidative stress pathways linked with inflammatory responses.
As MS advances from early stages characterized mainly by relapses toward progressive phases marked by steady disability accumulation without clear relapses (secondary progressive MS), underlying pathology shifts somewhat but remains heavily influenced by persistent compartmentalized inflammation inside the CNS compartments such as meninges or perivascular spaces where adaptive immunity may be less prominent but innate immunity persists strongly.
Recent research using advanced imaging techniques combined with artificial intelligence has revealed that dynamic episodes of CNS inflammation—whether clinically evident or silent—drive cumulative damage leading to physical disability progression and cognitive decline across all forms of MS rather than distinct separate disease types being responsible at different times.
In addition to direct tissue injury caused by inflammatory mediators damaging oligodendrocytes (myelin-producing glial cells) and neurons themselves, chronic neuroinflammation disrupts normal glial cell function including astrocytes which normally support neuron health but under prolonged activation contribute further to pathological changes through release of pro-inflammatory factors.
Neurotrophic factors—which normally help protect neurons from damage—are often overwhelmed during ongoing inflammatory states seen in progressive phases; thus smoldering intraparenchymal immune activation perpetuates a vicious cycle where insufficient repair mechanisms fail against continuous low-grade destructive processes fueled largely by sustained microglial activation combined with infiltrating lymphocytes when present.
Moreover, volumetric changes detected via MRI studies correlate with clinical progression: regions such as thalamus show atrophy linked closely with advancing disability scores while other areas like amygdala may exhibit volume increases associated specifically with certain patterns of progression without overt relapse activity indicating complex regional differences influenced partly by localized inflammatory states within neural circuit
