Novel mechanisms of chronic inflammation in secondary progressive multiple sclerosis

Abstract

Genome wide-association studies have clearly shown the key roles of helper T (Th) cells and cellular immune responses for development of multiple sclerosis (MS). Novel medication for a “relapsing–remitting” form of MS (RR-MS) including natalizumab and fingolimod that targets immune cells, such as Th cells, is now available in clinics. However, a significant proportion of RR-MS patients subsequently develop a chronic progressive disease without obvious signs of relapses known as secondary progressive MS (SP-MS). Therapeutic agents for SP-MS are limited and pathogenesis of SP-MS remains elusive, partly because of the lack of experimental animal models that enable comprehensive and deep analysis of the disease. We have previously reported that an orphan nuclear receptor, NR4A2, plays critical roles in Th17 cells, a key Th cell subset associated with the pathogenesis of RR-MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Although EAE induced in mice lacking the NR4A2 gene in Th cells showed significantly milder signs of acute EAE, they unexpectedly developed a late/chronic EAE, in which atypical Th cells expressing Eomesodermin (Eomes) with cytotoxic properties were involved. Functional analysis revealed that Eomes+ Th cells are critically associated with the development of late/chronic EAE. Interestingly, similar Eomes+ Th cells were remarkably increased in the peripheral blood and cerebrospinal fluid from SP-MS patients, but not from RR-MS patients, implying that Eomes+ Th cells are selectively involved in the pathogenesis of SP-MS. Therefore, elimination or functional inhibition of Eomes+ Th cells could be considered as novel therapeutic strategies for SP-MS.