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.

In 334 people with multiple sclerosis, a backward stepwise regression analysis was conducted to identify clinical characteristics that predict who declines neurocognitive testing (p < 0.05), from demographics, disease-related variables, psychiatric diagnoses, and self-reported cognitive concerns. The mean age was 44.1 years (standard deviation = 11.4), the median Expanded Disability Status Scale was 2.5 (1.5-4.0), 79.8% had relapsing-remitting MS, and 14.7% declined testing. Independent correlates of declining neurocognitive testing included progressive MS (odds ratio = 2.1, 95% confidence interval = [1.0, 4.4], p = 0.046), anxiety-related disorders (odds ratio = 2.5, 95% confidence interval = [1.3, 4.9], p = 0.007), and the absence of self-reported cognitive concerns (odds ratio = 0.3, 95% confidence interval = [0.2, 0.7], p = 0.004). People with multiple sclerosis with these clinical characteristics are more likely to decline neurocognitive testing.

Myelin oligodendrocyte glycoprotein antibody-associated disease is a demyelinating disorder affecting the central nervous system. Autoimmune regulator mutations disrupt central tolerance and cause immunodeficiency and autoimmune manifestations. We report the case of a 49-year-old Asian male with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease and a heterozygous dominant-negative autoimmune regulator mutation (c.901G > A, p.Val301Met), alongside vitiligo, cryptococcal disease and nasopharyngeal carcinoma. This case raises a potential link between negative selection failure and myelin oligodendrocyte glycoprotein antibody-associated disease and suggests that autoreactive T cells may be primary pathogenetic drivers, implying that restoring immune tolerance could inform future therapeutic approaches.

Kabuki syndrome, caused by KMT2D or KDM6A mutations, is a multisystem disorder with immune dysregulation. Its association with aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder has not been reported. A 17-year-old male with autoimmune hypothyroidism presented with acute visual loss and was diagnosed with AQP4-IgG-positive optic neuritis. He received corticosteroids, plasma exchange, and rituximab, achieving full recovery and remaining relapse-free during follow-up. Genetic testing showed a likely pathogenic KMT2D variant. This case documents the first association between these conditions, where immune dysregulation, including FOXP3-dependent regulatory T-cell dysfunction and Th17-skewed inflammation, suggests a mechanistic link with implications for diagnosis and management.

There is an increasing number of people experiencing housing insecurity and forcible displacement globally. We perform a scoping review, searching PubMed (1 January 1990-30 June 2026) for the key terms "housing insecurity," "inadequate housing," "houselessness," "homelessness," "housing," "forcible displacement," "refugee," "asylum seeker," and "internal displacement," focusing on the outcomes of persons with multiple sclerosis. We estimate the approximate number of persons with multiple sclerosis in these situations. The number of reports from persons with multiple sclerosis who experience housing insecurity, homelessness, or forcible displacement remains very limited compared to the high number of estimated persons with multiple sclerosis living in these circumstances. Among US veterans, homelessness was not significantly more common among those with multiple sclerosis than matched veterans without multiple sclerosis. Refugees with multiple sclerosis experience inaffordability of care. A larger, but distinct, literature examining exposure to armed conflict (war) finds increased relapse and magnetic resonance imaging disease activity in subsets of persons with multiple sclerosis during conflict as well as disruptions in access to multiple sclerosis care and treatment. Global geographic representation of these reports is limited. We recommend health systems-based and clinical approaches for persons with multiple sclerosis in times of vulnerability. More data are needed to understand the defined risks to persons with multiple sclerosis as well as inform and monitor a durable humanitarian approach to their care.