# Targeting Antigen-Presenting Cells in Multiple Sclerosis Treatment
## 2 The Role of Antigen-Presenting Cells in MS Pathogenesis  
The pathobiology of MS is complex, and despite intense studies, the initial events leading to autoimmunity development have still not been unraveled. However, it is known that peripheral self-antigen-specific immune cells are activated during the antigen presentation process and they enter the CNS through the disrupted blood-brain barrier (BBB), the subarachnoid space, or the blood-CSF barrier [8; 9; 10; 11]. The route of entry depends on the phenotype and activation state of T-cells [12]. After transmigration into the CNS, myelin-specific T-cells are re-activated by CNS-resident APCs (dendritic cells, microglia), which results in the development and/or exacerbation of inflammatory reaction and demyelination [13; 14].  
Antigen-presenting cells convert myelin antigens to various epitopes and present them with MHC class I and/or II molecules to the T-cell receptors (TCRs) of CD4 and CD8 cells. The activation of protease synthesis and antigen processing as well as synthesis of functional MHC molecules are indispensable signal mechanisms [15]. Additionally, for successful antigen presentation during T-cell priming and re-activation, other co-stimulatory molecules such as CD40, CD80, CD86, and integrins are required [16; 17].  
Myelin-reactive CD4+ T-cells are activated by dendritic cells, microglia cells, infiltrating macrophages, and B-cells--all expressing MHC class II molecules. CD8+ T-cells, which are highly present in the acute lesions of MS, mediate inflammation and demyelination after their activation by myelin peptide presentation with APCs expressing MHC class I molecules. All nucleated cells, including oligodendrocytes, astrocytes, and neurons, expressed MHC I [18; 19; 20].  
The antigen-priming of T-cells is an important process in chronic and acute inflammation. In animal models of MS, infiltrating auto-reactive CD4+ T-cells are re-activated within CNS by APCs, which results in monocyte recruitment into the CNS, as well as in naive CD4+ T-cells priming through epitope spreading, which boosts disease inflammatory reaction.  
In autoimmune diseases, epitope spreading contributes to chronicity of inflammation and to diversification of the ongoing immune response. Epitope spreading is a process in which immune responses are directed to epitopes that vary from the initial ones [9]. In EAE, it has been shown that initial immune response is focused on a certain epitope and, then, during disease progression, spreads to others [21; 22]. Spreading of epitopes may be intramolecular--within one molecule, e.g., various epitopes of MBP, or intermolecular, e.g., from PLP to MOG [21; 23; 24]. Various EAE models suggested that this process may begin within CNS, and that it was associated with clinical relapses [24; 25]. Both intramolecular and intermolecular epitope spreading has also been observed in patients with MS [26; 27; 28]. However, what is the exact role of such process on disease course requires further analyses, as some studies were not able to detect any associations with disease exacerbations [26; 29].  
Numerous studies emphasize the importance of microglia and infiltrated dendritic cells/macrophages as an antigen-presenting cells in the CNS. Recently, it was speculated that B-cells may also act as professional APCs.