**4. Pathogenesis**

Multiple sclerosis is a neuroimmunologic disorder characterized pathologically by inflamma‐ tion, demyelination, and axonal loss. Neuropathological findings and animal models such as experimental allergic encephalomyelitis support the immunopathogenesis in multiple sclerosis. HLA Class II genes which are associated with MS risk are also related to the immune system.

The first step in the immunopathogenesis of MS is peripheral activation of CD4+ T lymphocytes in response to an antigen. This antigen is unknown. It has been suggested that

molecular mimicry between this antigen and central nervous system antigens causes cross reactivity. Subsequently, activated T lymphocytes migrate through the blood-brain barrier into the central nervous system [10, 11]. Lymphocyte migration represents an important step in MS pathogenesis. This multistep process includes adhesion, chemoattraction, and active infiltration into the central nervous system. Adhesion molecules, chemokines, and cyto‐ kines play an important role in these steps [10]. α4β1 integrin (VLA-4, very late activating antigen) is an adhesion molecule which is expressed on the lymphocyte surface and binds to the vascular cell adhesion molecule-1 (VICAM-1) located on the endothelium. As a result of this interaction, lymphocytes adhere to the endothelium and transmigrate across the endothelial cell layer into the central nervous system [12]. Chemokines regulate migration of immune cells into the brain; they also manipulate the lymphocyte transendothelial migration and locomotion within the tissue along chemoattractant gradients. Reactivation of infiltrating immune cells within the central nervous system leads to perivascular inflammation and injury. This injury results in the release of additional central nervous system antigens such as myelin proteins and leads to immune responses to these selfantigens (antigen spreading/epitope spreading). T cells reactive to myelin proteins includ‐ ing myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and myelin proteolipid protein (PLP) are involved in the central nervous system inflammatory re‐ sponse of MS patients [10]. Myelin-reactive T cells have differences in MS patients as compared with healthy controls. In MS patients myelin-reactive T cells differ by having memory phenotype. Memory T cells play an important role in MS pathogenesis. Other immune cells including proinflammatory and anti-inflammatory/regulatory CD4+ T cells (helper T lymphocytes), CD8+ T cells (cytotoxic T lymphocytes), myeloid cell subsets, B cells, and natural killer cells contribute to the pathogenesis of MS in adults. After activation by antigen-presenting cells such as dendritic cells, naïve T cells differentiate into one of the several subsets with different effector functions. Th1 lymphocytes secrete proinflammato‐ ry cytokines such as interferon gamma, while Th2 lymphocytes produce anti-inflammato‐ ry cytokines such as interleukin 4, interleukin 10. The imbalance between proinflammatory and anti-inflammatory cytokines has been invoked in MS pathogenesis. Proinflammatory cytokines play crucial roles in MS pathogenesis including peripheral immune activation, enhancement of trafficking of activated immune cells into the CNS, and direct damage to oligodendrocytes, myelin, and axons [10, 12]. Th17 lymphocytes are also a subgroup of CD4+ T cells that produce the proinflammatory cytokines interleukin 17A and interleukin 17F. Th17 lymphocytes are developmentally distinct from Th1 and Th2 lineages. Interleukin 23 produced by macrophages and dendritic cells contributes to development of Th17. High Th17 to Th1 ratios are associated with T cell infiltration and inflammation in the brain parenchyma [13]. The presence of interleukin 17 in MS lesions and increased interleukin 17 expression in both blood and CSF of MS patients have been demonstrated [14, 15]. Other subgroups of T cells also have been implicated in the immunopathogenesis of MS. Regula‐ tory T (Treg) cells control potentially pathogenic autoreactive T cells. Studies demonstrat‐ ed that regulatory T cell functions are altered in MS. In a study, similar T cell responses to myelin basic protein and myelin oligodendrocyte glycoprotein epitopes have been found in both adult and pediatric MS patients [16]. Vargas Lowy demonstrated increased CD4+ T

in MRI as compared to adult MS patients. These differences are more marked in prepuberal children [3]. The still developing central nervous and immune systems may be responsible for these differences. However, studies on pathogenesis and pathology of pediatric MS are limited.

The incidence of pediatric MS is unknown, but its estimated prevalence has been reported to be 1.35–2.5 per 100,000 children [4]. The gender ratio varies with the age of onset: in patients older than 10 years, the female-to-male ratio is similar to adults; there is female dominance. In children younger than 10 years old, the female-to-male ratio decreases. This difference may be due to hormonal influence or gender-specific genetic influence on immunological reactivity

Pediatric MS has a complex etiology related to both genetic and environmental factors. Vitamin D deficiency has been implicated as a risk factor for MS in children, as it is in adults. Mowry et al. have demonstrated an association between relapse rate and vitamin D level in pediatric MS patients [6]. Smoking has been considered as a risk factor in adults, whereas passive smoke exposure has been recognized as a risk factor in children [7]. One of the most studied envi‐ ronmental risk factors is viral exposure and studies have found that viral exposure in child‐ hood may predispose some individuals to the development of MS. Epstein-Barr seropositivity and serum anti-EBV antibody titers tend to be higher in MS patients than they are in normal individuals. The relationship between the Epstein-Barr virus and MS has also been shown in pediatric MS [8]. Another risk factor is obesity. Childhood and adolescent obesity has been suggested as a risk factor for the development of MS in both adults and children [9]. Genetic susceptibility is also a risk factor for MS. HLA-DRB1 locus has been associated with multiple sclerosis in children. Twin studies have demonstrated a concordance rate of 27% in monozy‐ gotic twins. The incidence for first-degree relatives of patients with MS is 2–5%, whereas the

Multiple sclerosis is a neuroimmunologic disorder characterized pathologically by inflamma‐ tion, demyelination, and axonal loss. Neuropathological findings and animal models such as experimental allergic encephalomyelitis support the immunopathogenesis in multiple sclerosis. HLA Class II genes which are associated with MS risk are also related to the immune

The first step in the immunopathogenesis of MS is peripheral activation of CD4+ T lymphocytes in response to an antigen. This antigen is unknown. It has been suggested that

**2. Epidemiology**

170 Trending Topics in Multiple Sclerosis

**4. Pathogenesis**

system.

**3. Etiology and risk factors**

incidence for the general population is under 0.1% [10].

[5].

cell proliferation to myelin peptides in children with MS and also found an increased proportion of dividing CD4+ T cell to myelin peptides with a memory phenotype which produced interleukin 17 [10].

Humoral immunity has also been implicated in MS pathogenesis. B lymphocytes, plasma cells, immunoglobulins, and complement deposition have been shown in MS lesions. Anti-myelin oligodendrocyte glycoprotein antibodies (anti-MOG) have been reported in pediatric cases with inflammatory demyelinating diseases, predominantly in children with ADEM-like first episodes and in pediatric MS patients younger than 10 years of age at disease onset. Anti-MOG antibodies have also been observed in pediatric patients with recurrent optic neuritis and seronegative NMO [10, 17]. The presence of anti-MOG antibodies has been reported in a subgroup of adults with seronegative NMO but only rarely in adults with MS [18]. Moreover, antibody-independent functions of B lymphocytes such as cytokine production play a role in MS immunopathogenesis.

Neurodegeneration and axonal damage are other processes in the pathogenesis of MS. Mechanisms of axonal damage in multiple sclerosis include a specific immunologic attack on axons; the presence of soluble mediators such as proteases, cytokines, and free radicals released during the inflammatory process and lack of neurotrophic factors provided to the axon by oligodendrocytes as a result of chronic demyelination [10, 19].

### **5. Pathology**

The cellular content of MS lesions includes primarily T lymphocytes (CD4+ and CD8+) and macrophages. Lucchinetti et al. have described four distinct pathological patterns of demye‐ lination in autopsy and biopsy samples from adult MS patients. Patterns I and II showed T cell/macrophage inflammation and there was also T cell plus antibody-mediated autoim‐ mune damage in pattern II. Patterns III and IV were suggestive of a primary oligodendro‐ cyte dystrophy. Oligodendrocyte apoptosis or death and lesser macrophage-T cell inflammation were observed in patterns III and IV [20]. In another study, Trapp et al. demonstrated axonal damage in normal appearing white matter [21]. Additionally, subpial cortical, intracortical, and leukocortical lesions were found in adult-onset multiple sclerosis patients' biopsy specimens. Immune cells were also identified within the pia-arachnoid in adult-onset multiple sclerosis and ectopic B-cell follicles with germinal centers were detect‐ ed in the meninges of patients with secondary progressive multiple sclerosis. All these pathological findings were identified in adult patients [10, 22, 23]. Neuropathological studies are limited in pediatric multiple sclerosis [10]. Tumefactive demyelinating lesions have been investigated in pediatric patients with MS [24]. The pathological characteristics of tumefac‐ tive demyelinating lesions include relative axonal preservation, perivascular and parenchy‐ mal lymphocyte and macrophage inflammation [25].
