**1. Introduction**

Multiple sclerosis (MS) is the most prevalent neurological disease among young adults in developed countries, with approximately 2.8 million people being affected worldwide [1]. It principally affects women in their prime, with diagnosis typically occurring between the ages of 20 and 40. The disease is debilitating due to central nervous system (CNS) damage resulting from activated lymphocytes migrating across the blood brain barrier (BBB) and engaging in a proinflammatory response. This causes cells to attack and destroy the myelin sheaths that coat the axons of neurons of the brain, spinal cord and optic nerve, as well as the myelinating cells or oligodendrocytes, and the axons themselves [2]. As neurons receive sensory input from external sources and send motor commands to the muscles by relaying interneuron electrical impulses, breakdown causes interruption to the signals being sent around the body, and dependent on where the damage occurs, results in different signs and symptoms. These can include vision impairment, muscle spasms and numbness, bladder and bowel issues, fatigue and difficulty walking [3]. Most people with MS have progressive neurological disability which, though not usual, can culminate in death [4]. The area of damage or scarring caused by the immune system attack is

called a lesion or plaque, and can be visualised by magnetic resonance imaging (MRI). A definitive diagnosis of MS is made when these plaques are shown to be reoccurring and when there is the clear presence of clinical symptoms [3].

Two major types of MS have been recognised, primary progressive multiple sclerosis (PPMS), diagnosed in approximately 15% of patients and which results in steady progression of disease from onset, and relapsing remitting multiple sclerosis (RRMS), which affects approximately 80% of patients and is characterised by periods of relapse separated by periods of remit without worsening of symptoms [5–7]. Most patients with an initial diagnosis of RRMS will, within 20 years of diagnosis, progress to secondary progressive multiple sclerosis (SPMS) where the stages between relapse and remit shorten and there is a steady decline with an increase in symptoms and disease progression [8]. Up to approximately 5% of MS patients have progressive relapsing multiple sclerosis (PRMS) and this characterised by steady disease progression with occasional relapses [9].

The exact cause of MS is still unknown, however research has determined that it is an autoimmune disease, arising from complex interactions between environmental and genetic influences. There is a latitude incidence variance, with prevalence of MS increased the further one is from the equator; sunlight and vitamin D are therefore being investigated as disease triggers [1, 10–12]. Childhood exposure to bacteria and viruses have also been investigated, due to a person's disease risk being set as the incidence of the region they moved to prior to puberty [13, 14]. Of note, every patient with MS have previously been exposed to Epstein–Barr virus (EBV) [15, 16]. Smoking also increases a person's risk and worsens symptoms following diagnosis [17].

Although the disease is not inherited, it has a genetic component, with those having an affected first degree relative exhibiting an increased incidence of disease [18], and twin studies indicate that there is a 30% chance of developing disease in the second twin if the first has been diagnosed with MS [19]. Genome wide association studies (GWAS) have identified more than 230 genes associated with a person's MS risk, several being immune genes, particularly those of T cells, B cells, natural killer (NK) cells, monocytes and microglia, implicating involvement of both major branches of the immune system, the innate and adaptive immune responses, in initiation and progression of disease [20–23]. These studies are supported by several human and animal model functional studies [24–26].

Cellular toxicity, or the ability to kill other cells, is an important effector mechanisms of the immune system to protect us from infections, cancer or autoimmune diseases. There is a close association between inflammation and neurodegeneration, and cellular toxicity has been implicated as a having a major role in MS [27]. The main players are CD8, or cytotoxic, T cells and NK cells. Cellular toxicity can operate by many mechanisms including NK cell release of lytic granules containing perforin or granzymes to kill directly, or by inducing death receptor-mediated apoptosis via tumour necrosis factor (ligand) superfamily member 10 (TRAIL) or Fas Ligand (FasL) expression on CD8 T cells [28]. There are also antibody-dependent cell-mediated cytotoxic mechanisms (ADCC), where B cells produce antigen specific antibodies or immunoglobulins, that will coat a pathogen or foreign body, marking them for killing or destruction through cell to cell cytoloysis by effector immune cells expressing FcγRIIIA (CD16A), including classical NK cells, monocytes/macrophages, neutrophils, eosinophils, NKT cells, or γδT cells (reviewed in [29]).
