New EAE Models More Accurately Reflect MS

Multiple Sclerosis (MS) affects about 400,000 people in the United States. In MS, the myelin sheath that coats our neuronal axons is degraded, as are the cells that produce myelin (also known as oligodendrocytes). MS is considered an autoimmune disease because the attack is facilitated by our body’s own immune system. This degradation of the myelin sheath affects the ability of our neurons to transmit electrical signals to each other. This manifests itself in the symptoms often associated with MS: numbness in limbs, paralysis and vision impairment.

In order to study MS, researchers often employ the use of animal models. Specifically, Experimental Autoimmune Encephalomyelitis (EAE) is a well recognized mice model that mimics the progression of MS. EAE is considered a Th1 focused disease with T cells secreting primarily IFNϒ. T cells are immune cells in the body that participate in cell-mediated killing of foreign pathogens (1). In MS, they recognize our myelin as a foreign substance and proceed to destroy it. One way they do this is by secreting cytotoxic cytokines, such as the aforementioned IFNϒ. When inducing EAE in mice, this Th1 response is ensured by injecting a myelin peptide(to mount an immune response against) along with complete Freunds adjuvant (CFA), which contains a bacterium called M. Tuberculosis (CFA).

Aside from IFNϒ, IL-23 has emerged as a notable cytokine because mice deficient for it remained protected against EAE pathology. Furthermore, IL-23 promotes the differentiation of inflammatory Th17 cells (2). Numerous EAE models currently exist; some more representative of MS in certain clinical regards (e.g., onset, clinical progression, and remission). Therefore, it’s vital to always explore new EAE models in an effort to find one that best represents human MS. In a recent study by Smith et al. 2011, researchers replaced M. tuberculosis with C. rodentium (CRA)in the injected adjuvant. CRA is a bacteria known to induce an IL-23 dependent Th17 response (as opposed to the aforementioned M.tuberculosis-mediated Th1 response) to find out whether different EAE phenotypes would emerge.

Multiple Sclerosis: the Good, the Bad, and the Ugly of TNF

Multiple sclerosis (MS) is a disease that affects over 2.5 million people worldwide. It is typically first diagnosed in patients in their 20s and 30s and is most common among women (Trapp and Nave, 2008). MS is characterized by areas in which myelin, a collection of lipids and proteins that forms a protective and insulating layer around portions of neurons, is destroyed (also known as demyelination). This damage occurs most often in the brain and spinal cord, impairing the transmission of signals among nerve fibers. MS is considered to be an autoimmune disease because a person’s immune system attacks self tissues, in this case myelin and myelin-producing cells. A large amount of this damage it is thought to stem from the activation of autoreactive CD4+ T cells that recognize peptides from the myelin sheath. (In healthy patients, these CD4+ T cells - also known as “helper” T cells - are not autoreactive and help B cells produce antibody.) As the disease course of MS progresses, symptoms increase in severity and include dizziness, impaired thinking, tremors, and difficulty walking.

Tumor Necrosis Factor (TNF) is a cytokine (a subset of small cell-signalling proteins) that has been linked to MS and is expressed by many cell types (Grivennikov et al., 2005). This protein can trigger either cell death or cell survival and can it also mediate inflammation. Inflammation is a local response at a site of infection caused by the influx of leukocytes, which are cells that attempt to combat infection; infiltration of inflammatory cells is common in the brains and spinal cords of MS patients. High levels of TNF have also been observed in MS and other autoimmune disorders (Hohnoki et al., 1998); blockade of TNF is actually an approved treatment for some of these diseases, including rheumatoid arthritis (Feldmann and Maini, 2001). Nevertheless, the role that TNF plays in MS is still controversial.

A model called Experimental Autoimmune Encephalomyelitis (EAE) can be used among mice to study multiple sclerosis. EAE is induced by injecting mice with proteins that comprise myelin. In a recent study, published in the Journal of Immunology, Kruglov and colleagues (et al., 2011) used an EAE model to assess the roles of different cellular sources of TNF during EAE. The mice were scored daily on the basis of their clinical symptoms on a scale ranging from 0 to 6, where 0 = no disease and 6 = moribund.