**The Gateway Reflex, a Novel Neuro‐immune Interaction, is Critical for the Development of Mouse Multiple Sclerosis (MS) Models**

Daisuke Kamimura, Yasunobu Arima, Andrea Stofkova, Naoki Nishikawa, Kotaro Higuchi, Takuto Ohki and Masaaki Murakami

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/62938

#### **Abstract**

The central nervous system (CNS) is an immune‐privileged tissue protected by the brain– blood barrier (BBB), which limits the absorption of substances and cells from blood flow. In the case ofinflammatorydiseases in the CNS, such as multiple sclerosis (MS),however, autoreactive T cells that attack brain autoantigens, including myelin proteins, circum‐ vent the BBB. Despite the wide distribution of brain autoantigens, demyelination often occurs as discrete foci. This fact suggests that there might be a certain cue that guides autoreactive T cells to particular site(s) in the CNS. In other words, there exists a mechanism that facilitates a site‐specific accumulation of autoreactive T cells in the CNS. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we identi‐ fied dorsal vessels of the fifth lumbar (L5) spinal cord as the initial entry site of immune cells. The formation of a gateway for immune cells is defined by local neural stimula‐ tions. For example, neural stimulation by gravity creates this gateway by increasing the expression of chemokines that attract autoreactive T cells. Regional neural activation by the other stimuli, such as electric pulses or painsensation, also inducesgatewayformation, but at different blood vessels via chemokine expression. These neuro‐immune interac‐ tions are examples of the gateway reflex and are extensively reviewed in this chapter.

**Keywords:** gateway reflex, inflammation amplifier, NF‐κB, STAT, multiple sclerosis

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

Multiple sclerosis (MS) is a common neurological disease that is estimated to inflict more than 2.5 million patients worldwide [1–4]. MS is associated with chronic inflammation of the central nervous system (CNS) with myelin antigens as the immune target during the inflammation processes. The clinical manifestations of MS are variable and often include both symptoms of upper motor neurons, such as hyperreflexia, ataxia, spasticity, and visual defects, and lower motor neuron symptoms, such as sensory neuron defects and paralysis [5]. Given the uniform presence of myelin antigens in the CNS, however, variable local, rather than systemic clinical symptoms raise the possibility that there exists specific sites in the CNS that are vulnerable to immune cells thus triggering auto‐reactivity. As discussed below, we observed using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), that regional neural stimulations permit entry of immune cells into the CNS, which may explain the variable MS symptoms among patients.

Genetic susceptibility of MS is well studied, and major histocompatibility complex (MHC) genes and genes associated with CD4+ helper T‐cell activation and homeostasis are identified as susceptible genes. The strongest genetic linkage was found at certain alleles of MHC class II, which suggests a relationship between autoreactive CD4+ T cells and MS development in humans [6]. Consistently, autoreactive CD4+ T cells have important roles in the development and relapse of animal models of MS [4, 7–13]. In addition to MHC genes, several genome‐wide association studies (GWAS) of MS patients have identified addition‐ al genetic loci including interleukin (IL)‐17, IL‐2 receptor (CD25), and IL‐7 receptor (CD127), which are important for CD4+ T‐cell effector function, activation, and survival [14–16]. These lines of genetic evidence suggest that blocking CD4+ T‐cell entry into the CNS, thereby blocking subsequent inflammation in the CNS, would be an effective way for the treat‐ ment of MS. Indeed, drugs that target T‐cell migration such as fingolimod (FTY720) and natalizumab (anti‐VLA4 antibody) have shown clinical success in the treatment of MS. Fingolimod is an orally available sphingosine‐1‐phosphate receptor modulator, which reduces CD4+ T‐cell invasion to the CNS due to the inhibition of lymphocyte egress from lymph nodes [17]. Natalizumab, on the other hand, targets alpha4 integrin (a subunit of VLA4), which is required for the migration of CD4+ T cells to inflamed CNS [4, 18]. The prominent clinical effects of these drugs provide a proof of concept for therapeutic strat‐ egies to suppress the invasion of autoreactive CD4+ T cells into the CNS. Because side effects such as progressive multifocal leukoencephalopathy warrant caution for the use of fingoli‐ mod and natalizumab [19, 20], a novel strategy including a blockade of the entry site, or gateway, of immune cells to the CNS is desired.

It is widely known that the CNS is an immune‐privileged site, protected by the blood– brain barrier (BBB), which restricts the exchange of substances and cell migration into and out of the organ. However, CNS invasion by immune cells occurs in not only neuropatho‐ logic conditions including MS, but also normal healthy conditions. We have been studying where and how immune cells can enter the CNS using EAE models. In this chapter, our recent findings about these gateways, a mechanism to operate them, and perspectives are discussed.
