Nonclassical monocytes: are they the next therapeutic targets in multiple sclerosis?

Innate immunity is the first line of defense and is rapidly responsive to danger signals from microbial pathogens and tissue injury. The mononuclear phagocyte system encompasses the nongranulocyte population of myeloid cells, which includes circulating blood monocytes, tissue macrophages and dendritic cells. In this issue, Gjelstrup et al. investigate the involvement of various monocyte subsets, particularly the nonclassical monocytes in multiple sclerosis (MS). In a landmark study in 1968, van Furth and Cohen labeled circulating cells in the blood and established monocytes as the precursors for tissue macrophages. Monocytes are a heterogeneous cell population. Human monocytes have been classified by flow cytometry into three distinct subsets using antibodies against the receptor for lipopolysaccharide (CD14) and the low affinity receptor for IgG (CD16). CD14CD16 cells are called classic monocytes; CD14CD16 that resemble tissue macrophages are called nonclassical monocyte subsets; and CD14CD16 represent an intermediate monocyte subset. In various inflammatory situations, such as asthma, colorectal cancer, psoriasis and rheumatoid arthritis, the frequency of distinct monocyte subpopulations increases during different phases of disease. For instance, in patients with rheumatoid arthritis or cardiovascular diseases, the frequency of intermediate monocytes is associated with a decreased response to specific therapies and can serve as a predictor of poor outcome. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS disease, a correlation has been shown between monocyte infiltration into the central nervous system (CNS) and progression to the paralytic stage of the disease. Depletion of monocytes was shown to significantly inhibit both disease initiation and progression in EAE mice. Understanding the pathological cascade of MS has been helpful in tailoring more specific therapies. For instance, blockade of the homing of T lymphocytes as well as B cells to the CNS with an antibody to the key adhesion molecule, a4 integrin (natalizumab), or the specific depletion of CD20 B cells (ocrelizumab) are both currently the most potent approved therapeutics for MS. Natalizumab, although a powerful drug in reducing relapses and halting progression of MS disease, has significant side effects, including leaving individuals at risk for opportunistic infection. Patients on natalizumab are at risk for developing a devastating viral infection of the brain, called progressive multifocal leukoencephalopathy. These issues highlight the need for investigating other potential targets. The different monocyte populations in MS patients represent a potential therapeutic target. These subsets may serve as sensitive biomarkers that could be used in drug development to help predict the response in individual patients, thereby guiding treatment decisions. Gjelstrup and colleagues examined the composition of monocyte subsets and other inflammation-related cellsurface markers in a broad spectrum of MS patients, both treated and nontreated, compared to healthy individuals. The patient cohort included patients diagnosed with relapsing-remitting MS and primary progressive MS as well as patients with clinically isolated syndrome (CIS). Flow cytometric analysis of peripheral blood mononuclear cells demonstrated a significant expansion of the nonclassical monocyte population (CD14CD16) in patients with MS compared to healthy controls. Interestingly, a comparison between patients with MS and CIS, or between males and females with MS, or between patients with different degrees of disease activity demonstrated no significant differences in expansion of this nonclassical monocyte population. Correspondence Lawrence Steinman, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. E-mail: steinman@stanford.edu