Immunopathological patterns from EAE and Theiler's virus infection: Is multiple sclerosis a homogenous 1-stage or heterogenous 2-stage disease?

► Relapsing-remitting (RR) MS transitions to secondary progressive (SP) MS. ► “1-stage” and “2-stage” disease theories explain the transition from RRMS to SPMS. ► 1-stage theory: the effector mechanism remains the same during the disease course. ► 2-stage theory: pathogenesis shifts (e.g. from inflammation to neurodegeneration). ► Animal models are either homogenous 1 stage or heterogenous 2-stage diseases. Multiple sclerosis (MS) is a disease which can presents in different clinical courses. The most common form of MS is the relapsing-remitting (RR) course, which in many cases evolves into secondary progressive (SP) disease. Autoimmune models such as experimental autoimmune encephalomyelitis (EAE) have been developed to represent the various clinical forms of MS. These models along with clinico-pathological evidence obtained from MS patients have allowed us to propose ‘1-stage’ and ‘2-stage’ disease theories to explain the transition in the clinical course of MS from RR to SP. Relapses in MS are associated with pro-inflammatory T helper (Th) 1/Th17 immune responses, while remissions are associated with anti-inflammatory Th2/regulatory T (Treg) immune responses. Based on the ‘1-stage disease’ theory, the transition from RR to SP disease occurs when the inflammatory immune response overwhelms the anti-inflammatory immune response. The ‘2-stage disease’ theory proposes that the transition from RR to SP-MS occurs when the Th2 response or some other responses overwhelm the inflammatory response resulting in the sustained production of anti-myelin antibodies, which cause continuing demyelination, neurodegeneration, and axonal loss. The Theiler's virus model is also a 2-stage disease, where axonal degeneration precedes demyelination during the first stage, followed by inflammatory demyelination during the second stage.