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.
EAE was induced in mice by subcutaneously injecting them with incomplete Freund’s adjuvant, Mog35-55/MBP Ac1-11 (a myelin fragment that induces the autoimmune attack), and either CRA or CFA. Mice were subsequently scored on a daily basis using a scale that gave points (between 0-6) depending on the symptoms displayed. For example, a score of 1 equates with a limp tail and a score of 4 corresponds with hind limb paralysis. Furthermore, by draining the lymph node, researchers were able to isolate periphery CD4+ T cells that they could then analyze further. To analyze the activity in the central nervous system (CNS), brains and spinal cord were homogenized and then isolated in microscope slides for analysis.
Interestingly, researchers found that the CRA still developed the classical EAE phenotype, but that overall the course of the disease was less severe, had a later onset, and exhibited a much slower progression. 54% of mice developed EAE within a 25 day span. In contrast, mice immunized with CFA experienced a rapid-onset chronic disease with only a slight reduction in clinical severity near the end of the study.
Researchers then observed that CD4+T cells from the lymph node (periphery) demonstrated patterns of IFNϒ and IL-17 in both the CFA and CRA mice. The similarity of cytokine response was unexpected; researchers had expected a dominant IL-17 response from the Th17 cells. However, researchers were able to detect a difference in the profile of CNS infiltrating cells. The CRA mice exhibited a higher number of activated T cells by the end of the study, consistent with the delayed progression of their disease. However, at early and late time points, the CFA-immunized mice had an overall increased amount of IFNϒ and IL-17 producing Th1 and Th17 cells.
The results of the study were enlightening in several ways. For one, it was demonstrated that different bacterium alter the progression of EAE. So in this regard, their initial expectations of witnessing a different phenotype was fulfilled. Interestingly, the different roles of bacterium-adjuvant combinations are consistent with the role of infections in the development of MS. The suggestion that infections may trigger autoimmune disease is still controversial, but at the very least they have been shown to affect the disease development such as incidence of relapse (3).
Ultimately, the CRA model provides researchers an alternative tool to studying MS. Bacterium other than M. tuberculosis is capable of eliciting an inflammatory immune response in animals that is different than anything observed before. In fact, the slower progression observed is more representative of the most prevalent form of MS: relapsing remitting with slow progression. Additionally, the slower course of the disease allows novel therapeutic drugs a larger window to exert its effects before severe neuropathic damage is induced that could impede any type of recovery. Gaining a more accurate model is crucial to finding therapeutic agents that could help those afflicted with MS.
Smith AJ, Liu Y, Peng H, Beers R, Racke MK, Lovett-Racke AE.(2011). Comparison of a classical Th1 bacteria versus a Th17 bacteria as adjuvant in the induction of experimental autoimmune encephalomyelitis. The Journal of Neuroimmunology. 237(1-2):33-8
(1) Mal, Tak & Saunders, Mary. Primer to the Immune Response. California. Elsevier, 2011. Print.
(2) Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. The Journal of Experimental Medicine. 201(2):233-40.
(3) Confavreux C. (2002).Infections and the risk of relapse in multiple sclerosis. Brain. 125(Pt 5):933-4