Immune-inflammatory conditions in the central nervous system (CNS) rely on molecular and cellular interactions which are homeostatically maintained to protect neural tissue from harm. The CD40–CD40L interaction upregulates key proinflammatory molecules, a function best understood in the context of infection, during which B-cells are activated via CD40 signaling to produce antibodies. However, the role of CD40 in neurological disease of non-infectious etiology is unclear. We review the role of CD40–CD40L in traumatic brain injury, Alzheimer’s Disease, Parkinson’s Disease, stroke, epilepsy, nerve injury, multiple sclerosis, ALS, myasthenia gravis and brain tumors. We also highlight therapeutic advancements targeting the CD40 system to either attenuate the neuroinflammatory response or leverage the downstream effects of CD40 signaling for direct tumor cell lysis.

SARS-CoV-2 has an impact on the nervous system as a result of pathological cellular and molecular events at the level of vascular and neural tissue. Severe neurologic manifestations including stroke, ataxia, seizure, and depressed level of consciousness are prevalent in patients with SARS-CoV-2 infection. Although the mechanism is still unclear, SARS-CoV-2 has been associated with the pathogenesis of intravascular coagulation and angiotensin-converting enzyme-I, both exacerbating systemic inflammation and contributing to hypercoagulation or blood–brain barrier leakage, resulting in ischemic or hemorrhagic stroke. On the other hand, the SARS-CoV-2 spike protein in neural tissue and within the cerebrospinal fluid may induce neural dysfunction, resulting in neuroinflammation, which is exacerbated by peripheral and neural hypercytokinemia that can lead to neuronal damage and subsequent neuroinflammation. A deeper understanding of the fundamental biological mechanisms of neurologic manifestations in SARS-CoV-2 infection can pave the way to identifying a single biomarker or network of biomarkers to help target neuroprotective therapy in patients at risk for developing neurological complications.