**5.5 Monocytes and macrophages**

Besides imbalances in cytokine levels in the CNS and cerebrospinal fluid (CSF), immune imbalances also occur in the blood of MS patients, as reflected by altered levels of cytokines and cytokine producing cells (reviewed in [139]). The cause of these imbalances are thought to be due to circulating monocytes, with monocytes and macrophages influencing early MS, mediating both pro and anti-inflammatory responses [140, 141].

Surface expression of CD14 and CD16 are used to distinguish three distinct monocyte subsets: classical (CD14++CD16−), intermediate (CD14++CD16+ ) and nonclassical (CD14<sup>+</sup> CD16++) [142]. Monocytes and macrophages perform the key functions of antigen presentation and co-stimulation vital to the body's immune response, with important roles in T and B cell activation and differentiation via the CD40-CD154 interaction (reviewed in [143]). Macrophages are primarily derived from blood borne monocytes, are present at sites of active demyelination in MS, and are assumed to be a part of the demyelinating process [144]. These inflammatory cells produce a range of toxic oxygen metabolites which mediate host tissue destruction. During MS progression, there is a significant expansion of the CD16<sup>+</sup> monocyte population, which can primarily be attributed to nonclassical monocytes [145]. Depletion of these nonclassical monocytes may be an alternative to T and B cell depletion with the advantage of leaving the major classical monocyte population untouched. Selective subset depletion of monocytes may also supplement existing therapies to increase efficacy [145].
