The Immune Response in the Central Nervous System

It had long been held as a traditional view that there was little interplay between the immune system and the “immunoprivileged” central nervous system (CNS).  However, by the early 1990s there had been studies showing that immune system cells (ie, T cells) patrolled the healthy brain via specialized regions of the CNS (Svenningsson 1995, Hickey 1991), and over the past decade many advances have been made in our understanding of neuro-immune interactions.

In the recent August edition of Nature Neuroscience, much attention was focused on the role of the immune system in surveying the CNS, not only during pathological and injurious circumstances, but during normal health as well.  Many articles in this particular issue glean insight on situations where there is considerable interaction between resident sentinels of the CNS and circulating immune cells.  Immense in scope and insight was a wonderful review entitled Immune Surveillance in the Central Nervous System by Shalina Ousman and Paul Kubes, which is the focus of this blog post.

I highly recommend anyone interested in neuro-immune interactions to check this review out.  Given the topic, it is dense with information and packs in quite a hefty amount of citations for good measure (100 exactly for a 4+ page review).  It would be difficult to condense all of the themes of this review; I will attempt to cover some of the major themes as illustrated by the most recent findings that have contributed to the information contained in this review.

1) Microglia are the first-responders to CNS immune responses.  Microglia, in addition to playing important supporting roles in the development, homeostasis, and function of neurons, are the mediators of immune responses in the CNS.  Microglia share surface markers with hematoenously-derived macrophages (Prinz 2011) and fate-mapping has revealed microglia derive from primitive macrophages (Ginhoux 2010).  In mice, microglial progenitors can invade the CNS as early as ten days into development (Schulz 2012) and a subset have been shown to be derived from the bone marrow and enter the brain after birth (Chen 2010).  It has been well-documented over the last decade that microglia possess all the necessary tools to detect noxious stimuli and can release a plethora of cytokines, interleukins, interferons, etc, which are vital to mounting a potent inflammatory response.

2) Immune cells can travel into and out of the CNS.  Regions characterized by a less stringently-controlled blood-brain barrier (BBB) have been hypothesized to be entry sites for circulating immune cells, including specialized zones of the choroid plexus (CP), the perivascular (Virchow-Robin) space, and even directly though postcapillary venules.  A subset of CD4⁺ T cells have been implicated to target Epithelial V-like Antigen in CP epithelial cells (Wojcik 2011) while another subset of CD4⁺ T cells have been shown to enter the CNS at the 5^th lumbar level of the spinal cord in multiple sclerosis models (Arima 2012).  However, there is controversy as to which types of immune cells regularly enter the CNS, with various subtypes of lymphocytes having been implicated (Loeffler 2011).  While their entry into the CNS can be fervently discussed, it has also been shown that CNS-derived antigens can drain to deep cervical lymph nodes, with one group finding that monocytes injected into the brain reach lymphatic organs via the cribroid plate (Kaminski 2012).

3) Viral infections reveal the overall neuro-immune response.  When viral antigen is detected by microglia, various antiviral responses can be initiated to activate the innate and adaptive immune systems.  Recognition of herpes simplex virus 1 (HSV-1) by microglia cells via TLR2 or TLR9 results in secretion of type I interferons, TNF, IL-15, and the chemokine CCL2, which recruits macrophages (Conrady 2010).  Other viral infections, such as West Nile Virus (WNV), are recognized by microglia via TLR7 and results in secretion of IL-23; this promotes the infiltration of monocytes and macrophages, plus CD4⁺ T cells (Sitati 2006), CD8⁺ T cells (Shrestha 2006), and δγ T cells (Wang 2003).  CXCL12-CXCR4 interactions have been shown to further mediate CD8⁺ T cell entry (McCandless 2008, Zhang 2008), while it is believed that CCR5 also mediates the traffic of leukocytes in WNV infection (Glass 2005).

In summation, I apologize for the length of this post, but do yourself a favor and read the review!

-All citations taken from the review

SS Ousman and P Kubes. Immune surveillance in the central nervous system. 15(8):1096-1101, Nat Neurosci. August 2012.

http://www.nature.com/neuro/journal/v15/n8/full/nn0812-1055.html