The Role of Semaphorins and their Receptors in the Immune System and their Relation to Multiple Sclerosis

Semaphorins are large family of secretory and membrane-bound proteins that first were recognized in the nervous system as axon guidance molecules. Semaphorins family has more than 30 members and has been classified into eight subclasses. Different classes of these molecules involved in various phases of immune responses are considered as immune semaphorins. Main receptors for semaphorins are plexins and neuropilins. Moreover, other types of molecules can act as receptor for semaphorins, such as TIM-2 (T cell, immunoglobulin, and mucin domain protein 2), CD72 that bind to Sema 4A (Semaphorin 4A), and Sema 4D. Both forms of semaphorins, namely secretory and membrane-bound semaphorins, play important roles in the immune system. Multiple sclerosis (MS), a chronic inflammatory autoimmune disease, is characterized by infiltration of lymphocytes into the central nervous system and demyelination. Recent investigations have shown that increased serum level or increased expression of some immune semaphorins is associated with severity of MS disease. Moreover, immune semaphorins-deficient mice are resistant to experimental autoimmune encephalomyelitis, which is attributed to impaired production of myelin basic protein-specific T cells. Identification of specific expression patterns of semaphorins and their receptors in the nervous system and a comprehensive understanding of their function in autoimmune brain disorders could provide a novel biomarker and therapeutic target for these disorders. The present study reviews the role of semaphorins and their receptors in the development and differentiation of immune cells and their relation to MS