Modeling the heterogeneity of multiple sclerosis in animals

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) manifested with varying clinical course, pathology, and inflammatory patterns. There are multiple animal models that reflect different aspects of this heterogeneity. Collectively, these models reveal a balance between pathogenic and regulatory CD4(+) T cells, CD8(+) T cells, and B cells that influences the incidence, timing, and severity of CNS autoimmunity. In this review we discuss experimental autoimmune encephalomyelitis (EAE) models that have been used to study the pathogenic and regulatory roles of these immune cells; models that recapitulate different aspects of the disease seen in patients with MS, and questions remaining for future studies.

Keywords: animal models; autoimmunity; experimental autoimmune encephalomyelitis; multiple sclerosis; neuroimmunology.

Figure 1. Model of CD4⁺ T cell-initiated CNS autoimmunity

The sequential steps proposed for the pathogenesis of CD4⁺ T cell-initiated disease are indicated by numbers. CD8⁺ T cell initiated autoimmunity may occur, but is not included in this schematic. (a) Genetic and environmental factors both promote myelin-specific CD4⁺ T cell activation and influence the type and efficacy of the corresponding immunoregulatory response mediated by regulatory (reg) CD4⁺ and CD8⁺ T cells and B cells. (b) Activated CD4⁺ T cells enter the CNS and are re-activated by resident APCs, triggering production of inflammatory mediators. (c) These mediators promote (i) localized inflammation of the blood brain barrier (BBB) that facilitates recruitment of naïve CD4⁺ and CD8⁺ T cells, B cells, and monocytes to the CNS, and (ii) may directly damage myelin and/or oligodendrocytes. (c) Determinant spreading occurs as APCs presenting epitopes derived from myelin debris activate newly recruited T cells with different myelin specificities. (d) Newly activated CD8⁺ T cells may gain the ability to lyse both (a) APCs presenting myelin antigen and (e) oligodendrocytes. Dashed lines indicate pathways not yet verified with experimental evidence.