Genetics of Experimental Autoimmune Encephalomyelitis

Abstract

The genetic basis for susceptibility to experimental autoimmune encephalomyelitis (EAE) has been the subject of intense study for several decades. In spite of this long history, however, the effort has only yielded small hints and contradictory leads to which genes influence susceptibility to this autoimmune disease. EAE is a prototypical model of autoimmunity that differs from other autoimmune diseases since it is relatively easily induced and quickly diagnosed in a wide range of strains and species. It also typically shows what looks, at first glance, to be a simple autosomal dominant inheritance pattern, making it appear to be an ideal disease to be solved genetically. In reality, however, the underlying genetics of EAE are much more complex than they appear on the surface, and the disease itself has a complex pathology that is only just beginning to be understood. With the advent in the last few years of transgene and knockout technologies and progress on the mapping and sequencing of genomes, strides are finally being made that promise to make an understanding of the genetics of EAE susceptibility a realizable goal. EAE is well established as a model for the human disease multiple sclerosis (MS), with resemblance in both its clinical and pathological features. Unlike MS, however, which is a spontaneous disease of unknown etiology, EAE is induced by driving the immune system to attack the brain and spinal cord through an immunization with any of several well-described central nervous system (CNS) myelin proteins. The disease that ensues begins with an inflammatory reaction in the white matter of the brain and spinal cord, causing both edema and myelin damage. As the inflammation progresses, damage to the myelin, which normally forms an insulating sheath around axons, leads to a disruption in the transmission of nerve signals along the spinal cord. This disruption typically manifests outwardly as paralysis in the tail and limbs.

Cutting Edge: TheIdd3Genetic Interval Determines Regulatory T Cell Function through CD11b+CD11c− APC

“…Among these, Il2 is an obvious candidate gene because of its established role in regulating T cell growth (6), death (7) (8) and the generation/maintenance of CD4 + CD25 + FoxP3 + regulatory T cells (Tregs) (9). The fact that there are Il2 gene polymorphisms that are shared among autoimmune susceptible strains (10) and the recent identification of IL-2Ralpha (CD25) as a susceptibility gene for multiple human autoimmune diseases (11) (12) (13) support the hypothesis that Il2 is an important determinant of autoimmune disease susceptibility.…”

Polymorphisms in the IL2, IL2RA and IL2RB genes in multiple sclerosis risk

“…19 A decade later, treatment with an IL2-caspase3 chimeric protein of experimental autoimmune encephalitis EAE-induced mice caused a significant delay in disease onset by controlling lymphocyte reactivity through targeted apoptosis. 20 Moreover, the cytokine profile of myelin crossreactive vs monospecific Epstein-Barr virus nuclear antigen 1-specific T cells differed in their capability to produce IL-2.…”

IL-2 as a therapeutic target for the restoration of Foxp3+ regulatory T cell function in organ-specific autoimmunity: implications in pathophysiology and translation to human disease

“…Fine mapping studies show that the Idd3 locus encompasses several genes of potential immune relevance, notably: Il-2 , testis nuclear RNA-binding protein ( Tenr ), Il-21 , Centrin 4 ( Cetn4 ) and Fibroblast growth factor 2 ( Fgf2 )[20], although the IL-2 gene is the strongest and primary candidate gene for protection in NOD mice congenic for the C57BL/6 Idd3 locus[20,22]. NOD mice introgressed with the protective Idd3 allele from C57BL/6 display a reduced onset and severity of T1 D, as well as reduced susceptibility to other organ-specific autoimmune disorders, such as experimental autoimmune encephalomyelitis (EAE) and autoimmune ovarian dysgenesis[23]. Yamanouchi et al .…”