**3. Autoimmune disease**

Inflammation as a response of the body to infection or cell injury is a well-known concept that dates back to the beginning of medicine. However, Metchnikoff pointed out that although normally a method of protection, inflammation that exceeds normal bounds can cause disease [27]. Even with this knowledge, it was not until the 1950s that inflammation was recognised as inducing an autoimmune reaction responsible for disease. Autoimmune disease is characterised by an excessive immune response against self, often resulting in inflammation and tissue destruction, in the absence of a threat to the organism [50, 51]. Aberrant immune responses have been associated with over 80 disorders, including multiple sclerosis, and affects 5–7% of the population [52]. Clinical observations over the past decade have suggested that the prevalence of all autoimmune disease, not just MS, is increasing, bringing the issue to the forefront of scientific interest [53, 54]. Successful treatment of autoimmune disease is also of great societal interest, as they are commonly characterised by

#### *Cellular Cytotoxicity and Multiple Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.105681*

chronic natures, ongoing health care costs, and debilitating issues resulting in loss of productivity.

Immunological self-tolerance is maintained in part by Tregs. Tregs are CD4 T cells that actively and dominantly supress lymphocytes, particularly self-reactive T cells in the normal periphery that exist despite the deletion mechanisms in the thymus [43]. Natural CD25+ CD4 Tregs utilise several modes of suppression, including cell contact dependent mechanisms, such as the killing of APCs or responder T cells by granzyme and perforin, and by mediation of soluble factors, such as the secretion of immunosuppressive cytokines like IL-10, TGF-β or IL-35, or deprivation of cytokines necessary for expansion and survival of responder T cells (reviewed in [55, 56]).

Optimal T cell function relies on a carefully maintained state of equilibrium. When one subpopulation of T helper cells is activated, others are modulated or inhibited to promote the most specific effector response to the threat [57]. The cellular development of Tregs shares a common cytokine with Th17 cells, TGF-β [41, 42]. Th17 cells are the opposing force to Tregs, serving as an effector lymphocyte population that plays a key role in autoimmunity [41, 42]. At homeostasis, Th17 cells promote gut barrier defence, granulopoiesis, granulocyte chemotaxis and immunity against extracellular pathogen [58]. IL-17 induces granulopoesis indirectly through the stimulation of fibroblasts, epithelial and endothelial cells to secrete GM-CSF, IL-6, IL-8 and MIP-2, with IL-8 and MIP-2 enhancing chemotaxis of neutrophils [59, 60]. While Th17 cell mediated immunity is crucial for maintaining mucosal and haematopoietic homeostasis, too strong a response can induce autoimmunity. The relationship between Tregs and effector Th17 must remain balanced to provide the optimal functional immunity and health of an organism.

Another theory of immune regulation is the hypothesis of homeostasis between Th1 and Th2 cells. The subpopulations can be distinguished by the cytokines they produce and the expression of difference cell surface molecules. Th1 cells are responsible for cell mediated immunity, phagocyte dependent protective responses, B cell activation and production of opsonising antibodies such as IgG1, whereas Th2 cells produce cytokines that are responsible for strong antibody production, eosinophil activation and inhibition of several macrophage functions, thus providing phagocyte independent protective responses [61]. Th2 cells are also responsible for the general activation of B cells. When the Th1/Th2 paradigm is thrown out of balance by failure of central or peripheral tolerance, immunological disorders can occur due to uncontrolled responses [61].
