# Targeting Antigen-Presenting Cells in Multiple Sclerosis Treatment
## 3 Dendritic Cells
Microglia express MHC class I and II molecules and secrete many pro- and anti-inflammatory cytokines, as well as co-stimulatory molecules, such as intercellular adhesion molecule-1 (ICAM-1), CD80, and CD86 [59, 60]. As APCs, microglia interact with other immune cells, which leads to the activation of various T-cell subsets during demyelination and remyelination [59, 61]. Microglia can interact with CD28 or CTLA4 expressed on T-cells, which results in different outcomes. microglial co-stimulatory molecules CD80 and CD86 bind CD28 to stimulate T-cells proliferation, differentiation, and cytokine production. Conversely, binding to CTLA4 leads to T-cell anergy or apoptosis [62]. Results from a number of studies indicated that microglia are not effective as APCs, DCs, or macrophages [8, 63, 64]. However, contradictory results exist. [PERSON] et al. have shown that DC and microglia sorted from CNS of mice with EAE have similar expression levels of MHC class I and II, CD80, and CD86. Moreover, it was shown that both cell populations were able to induce an antigen-specific proliferative response in primed T-cells. However, CD11c+ microglia were weak inducers of Th1 and Th17 differentiation, due to the lack of expression of necessary cytokines, conversely to infiltrating CD11c+ cells that strongly induced such cytokines [65]. Interestingly, CD11c\(-\) microglia have been shown to be poor inducers of T-cells proliferation, but this subset has the capability to produce Th1- and Th17-inducing cytokines, pointing to the synergized mode of action of both microglia subpopulations [65]. Thus, it is speculated that CD11c\({}^{+}\) and CD11c\(-\) microglia may function as CNS-resident APCs being as effective as infiltrating CD11c\({}^{+}\) cells. B-cells, despite their function in antibodies production, may also act as antigen-presenting cells. It has been demonstrated that in the subset of MS patients, B-cells supported proliferation and/or IFN-\(\gamma\) production by autologous T-cells in response to neuroimaging, such as MOG and MBP [66]. Additionally, B-cells from MS patients, but not from healthy donors (HD), were able to induce proliferation and IL-17 production by Th17 cells in response to neuroimaging [67]. Similar results were obtained in the EAE model, where B-cells also promoted MOG-specific Th1 and Th17 cell differentiation [68]. Additionally, animals with MHC class II molecules deficiencies were resistant to disease induction and have attenuated Th1 and Th17 responses [69]. Several studies have shown that CD40-activated B-cells from HD and MS patients induce T-cell responses specific to myelin antigens [70, 71]. However, [PERSON] et al. have indicated that B-cells from MS patients may support myelin antigen-specific T-cell priming without previous in vitro activation [67]. Thus, B-cells are efficient APCs, capturing antigens through a membrane-bound B-cell receptor, processing them, and presenting via MHC class II molecules [72]. Moreover, it has been reported that B-cells from the peripheral blood of MS patients have increased the expression of co-stimulatory CD40 and CD80 molecules compared to HD [73]. Immunomodulatory treatment decreased B-cell co-stimulatory molecules expression, resulting in reduced T-cell responses induced by B-cells [74, 75]. The increased expression level of co-stimulatory molecules CD80, CD86, and HLA-A/B/C was also observed on B-cells isolated from CSF [73]. Clonal expansion of B-cells allows them to activate many T-cells, thus leading to an exacerbation of inflammation. In an animal model of MS depending on B- and T-cells, it was shown that B-cell function as APCs is necessary for disease induction, instead of their ability to produce antibodies [69; 72]. The vascular endothelial cells separating the blood stream from the brain parenchyma are referred to as a blood-brain barrier. This barrier regulates the entry of various substances and myeloid cells into the CNS, thus providing anatomical and physiological protection.