Abstract
The CD40–CD40L dyad is an immune checkpoint regulator that promotes both innate and adaptive immune responses and has therefore an essential role in the development of inflammatory diseases, including multiple sclerosis (MS). In MS, CD40 and CD40L are expressed on immune cells present in blood and lymphoid organs, affected resident central nervous system (CNS) cells, and inflammatory cells that have infiltrated the CNS. CD40–CD40L interactions fuel the inflammatory response underlying MS, and both genetic deficiency and antibody-mediated inhibition of the CD40–CD40L dyad reduce disease severity in experimental autoimmune encephalomyelitis (EAE). Both proteins are therefore attractive therapeutic candidates to modulate aberrant inflammatory responses in MS. Here, we discuss the genetic, experimental and clinical studies on the role of CD40 and CD40L interactions in EAE and MS and we explore novel approaches to therapeutically target this dyad to combat neuroinflammatory diseases.
Highlights
Multiple sclerosis (MS), a chronic inflammatory, demyelinating disease of the central nervous system (CNS), affects approximately 2.5 million people worldwide and is the most common cause of nontraumatic neurological disability in young adults [1]
This review emphasizes that besides the classical adaptive immunity-related CD40 ligand (CD40L)–CD40 signaling, this dyad has an essential role in the establishment and pathogenesis of multiple sclerosis (MS) in multiple ways
CD40 and CD40L are widely expressed on both resident and CNS-infiltrated cells in MS lesions and CD40 gene SNPs associate with MS incidence
Summary
Multiple sclerosis (MS), a chronic inflammatory, demyelinating disease of the central nervous system (CNS), affects approximately 2.5 million people worldwide and is the most common cause of nontraumatic neurological disability in young adults [1]. In RRMS, reduced frequency of relapses and inhibition of disease progression is observed upon treatment with disease modifying drugs, including interferons, The CD40–CD40L Dyad in MS glatiramer acetate, sphingosine-1-phosphate receptor modulators and monoclonal antibodies directed against α4-integrin (natalizumab), CD52 (alemtuzumab), CD25 (daclizumab), and CD20 (ocrelizumab, ofatumumab) [7]. Differences in blood sample handling may affect serum sCD40L levels, as low temperatures limit the ex vivo release of sCD40L from platelets [29] Monitoring of these factors in future studies is required to fully elucidate the role of sCD40L in MS
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