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

Abstract

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.

Fig. 1

The 1-stage (a, b) and 2-stage (c, d) disease theories of MS. (a) Classical EAE and RR-EAE are 1-stage diseases where the relapses and remissions of disease courses are due to the balance between inflammatory (Th1 and Th17 cells) versus regulatory (Th2, Treg, and NKT cells) cells. In this scheme, Th1/Th17 cells contribute to relapse and Th2, Treg, and NKT cells support remission. During the SP phase of the 1-stage disease theory, immune responses are skewed toward inflammatory responses. Here, the pathomechanisms of SP-MS remain the same during the disease course (intra-individual homogeneity); excessive anti-myelin inflammatory responses result in secondary axonal degeneration. (b) PP-EAE can be a 1-stage disease, which is mediated by anti-myelin antibody with the participation of Th2 cells. (c) Ataxic SP-EAE could be a 2-stage disease, where the central effector mechanisms change and the RR disease course shifts to the SP course. Here, a new effector mechanism, such as increased autoantibody production, is promoted by Th2 cells, leading to disease progression (intra-individual heterogeneity). (d) TMEV-induced demyelination is also a 2-stage disease. During the first stage, axonal damage, oligodendrocyte apoptosis, and macrophage activation leads to demyelination. During the second stage, epitope spreading results in generation of anti-myelin immune responses, contributing to disease progression. EAE: experimental autoimmune encephalomyelitis; PP: primary progressive; RR: relapsing-remitting; SP: secondary progressive; TMEV: Theiler’s murine encephalomyelitis virus

Fig. 2

Stage-dependent pathology of EAE induced with MOG_92-106. (a, c) In RR-EAE, intense CD3⁺ T cell infiltration was observed around vessels (v) with mild demyelination. (b, d) In progressive EAE, T cell infiltration was sparse around vessels (v), despite large areas of demyelination (arrowheads). UV irradiation can alter the disease course from RR-EAE to SP-EAE in SJL/J mice sensitized with MOG_92-106. PP-EAE was induced in A.SW mice sensitized with MOG_92-106. (a, b) Luxol fast blue stain. (c, d) CD3 immunohistochemistry. Magnification × 70.

Fig. 3

Inter-individual heterogeneity of pathology in animal models for PP-MS. TMEV infection and PP-EAE induced with MOG_92-106. (a, b) Both in TMEV infection and PP-EAE, demyelination was observed in the spinal cord (arrowheads, Luxol fast blue stain). (c, d) Although a few oligodendrocytes survived in the lesions in TMEV infection (arrows), many oligodendrocytes were detected in PP-EAE (carbonic anhydrase II immunohistochemistry for oligodendrocytes). Magnification: × 70.