CD40-CD40L in Neurological Disease

Abstract

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.

Keywords: CD40; CD40 ligand; immunotherapy; neuroinflammation.

Figure 1

Effects of CD40–CD40L ligation in neurology. Proposed downstream expression of cytokines, chemokines, and cell-adhesion molecules following CD40–CD40L activation that contribute to neuroinflammation and damage to the blood–brain barrier (BBB) and neural tissue in traumatic brain injury (TBI), Alzheimer’s disease (AD), stroke, epilepsy, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Upon CD40–CD40L ligation, soluble CD40 is released, which can bind to membrane CD40L to inhibit further CD40–CD40L-mediated immune responses.

Figure 2

CD40–CD40L in neuroinflammation. Proposed mechanism for cytokine-mediated neuronal damage, disruption of the blood brain barrier, and microthrombi formation.

Figure 3

CD40–CD40L activation promoting glioblastoma (GBM) cell lysis. GBM is unique from other neurological diseases of noninfectious etiology in that CD40 signaling is downregulated rather than amplified by tumor cells as they evade the immune response.