Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that culminates in inflammation, neuronal degeneration and loss of nerve functioning. While there is no specific cause of MS, there are factors that can influence disease progression, in particular tobacco smoke exposure (smoking). Smoking has been shown to increase inflammation, disease activity, and disability progression – herein we aim to connect this to both early inflammation and late-stage neurodegeneration. We propose that smoking enhances immune cell aging (immunosenescence) and examine evidence showing that this induces immune cell phenotypes that mirror physiological aging, specifically the depletion of naïve T-cell pools and the expansion of terminally differentiated, senescent CD8+ populations. We also review literature that suggests potential mechanism(s), including oxidative stress, cholenergic signaling, and epigenetic remodeling. By integrating clinical and mechanistic studies, we provide a framework that suggests smoking-associated immune aging shifts the MS profile from acute relapses toward sustained, treatment-resistant disability – and that smoking cigarettes is an active driver of disease, not just an environmental risk factor.

The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS) represents an ambiguous transition period characterized by diagnostic delays and a shifting therapeutic window. While inflammatory relapses are well-managed, the underlying neurodegeneration often remains undetected until substantial disability has accrued. This review evaluated the shift from traditional metrics, such as the Expanded Disability Status Scale (EDSS), toward more sensitive, multimodal monitoring strategies. We described characteristic MRI findings in SPMS and addressed the impact of comorbidities that frequently confound the diagnosis of disease transition. Furthermore, we evaluated the predictive potential of emerging fluid biomarkers and gut microbial signatures in identifying the early RRMS-to-SPMS transition. Finally, we described the current therapeutic landscape and emerging immunomodulatory interventions. Diagnosing SPMS remains a clinical challenge due to comorbidities and the lack of a singular definitive marker. Moving toward high-sensitivity imaging and molecular biomarkers is essential for the early initiation of treatments and improved patient outcomes.

The transition from relapsing–remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS) represents an ambiguous transition period characterized by diagnostic delays and a shifting therapeutic window. While inflammatory relapses are well-managed, the underlying neurodegeneration often remains undetected until substantial disability has accrued. This review evaluated the shift from traditional metrics, such as the Expanded Disability Status Scale (EDSS), toward more sensitive, multimodal monitoring strategies. We described characteristic MRI findings in SPMS and addressed the impact of comorbidities that frequently confound the diagnosis of disease transition. Furthermore, we evaluated the predictive potential of emerging fluid biomarkers and gut microbial signatures in identifying the early RRMS-to-SPMS transition. Finally, we described the current therapeutic landscape and emerging immunomodulatory interventions. Diagnosing SPMS remains a clinical challenge due to comorbidities and the lack of a singular definitive marker. Moving toward high-sensitivity imaging and molecular biomarkers is essential for the early initiation of treatments and improved patient outcomes.

Costimulatory signaling is essential for T-cell activation, tolerance, and immune homeostasis. Dysregulation of these pathways contributes to autoimmune diseases, including multiple sclerosis. Therapeutic targeting of costimulatory molecules, particularly the CD40–CD40L axis, has demonstrated clinical success in several autoimmune conditions, including multiple sclerosis. This review integrates mechanistic insights from experimental models with clinical data to examine the effects of CD40L blockade across diverse immune and central nervous system–resident cell populations. Preclinical models highlight the complex interplay between immune cells and central nervous system–resident cells beyond costimulatory signaling alone. Clinical mechanistic studies support CD40L blockade as a promising therapeutic strategy for multiple sclerosis.

Multiple sclerosis (MS) remains a leading cause of neurological disability, primarily due to the limited efficacy of current disease-modifying therapies in arresting progressive neurodegeneration. While peripheral lymphocyte depletion effectively manages relapsing activity, it fails to address the compartmentalized, smoldering inflammation driven by interactions between adaptive and innate immune systems within the central nervous system (CNS). The CD40–CD40L costimulatory pathway has emerged as a central regulator of these immune interactions, positioning it as a unique therapeutic target capable of addressing the full spectrum of MS pathology. This review examines the multimodal effects of CD40L blockade across peripheral and CNS-resident cell populations. Preclinical and genetic models demonstrate that inhibiting this axis suppresses pathogenic T-cell and B-cell responses while modulating innate immune activation, including macrophages, microglia, and astrocytes, and disrupting pro-inflammatory glial crosstalk. Early clinical data from second-generation, non-thromboembolic CD40L inhibitors, such as frexalimab, demonstrate reductions in markers of neuroaxonal injury and inflammatory disease activity. By simultaneously modulating systemic lymphocyte responses and CNS-resident innate immune processes, CD40L blockade represents a promising strategy to address both relapsing disease activity and progressive disability accumulation, thereby overcoming key therapeutic barriers in multiple sclerosis.