Chapter 1

Sex Differences in Immunity and Inflammation: Implications for Brain and Behavior

Gretchen N. Neigh Christina L. Nemeth Sydney A. Rowson    Emory University, Department of Physiology, Department of Psychiatry & Behavioral Sciences, Atlanta, GA, USA

Abstract

The immune system is the body's defense against disease; however, inherent differences in how the male and female immune systems detect and respond to immune threats dictate susceptibility to illness and immune-related diseases. Sex differences in the immune system begin during development and continue throughout life, with males and females showing different periods of immune susceptibility and resilience. Given that these differences likely stem from sex-dependent requirements for species survival, this chapter discusses how this evolutionary "need" for sex differences in immune function carries with it far reaching effects on both the periphery and the brain. This chapter highlights basic immune-related differences between men and women, describes how these differences translate into sex-dependent risk for immune-related diseases, discusses the implications for brain function, and outlines potential mechanisms to explain these differences. Finally, we conclude by discussing sex-dependent immune effects on behavior and how differential immune function drives the manifestation of comorbid disease states.

Keywords

immune system sex differences brain inflammation immune disorder immune development

1. Introduction

Are sex differences in the immune system evolutionary in nature? Sir Peter Medawar was the first to address the question of how a mother is able to immunologically tolerate her fetus (Trowsdale and Betz, 2006). This complex issue where a fetus, up to 50% immunologically foreign, is able to pass inert has been discussed since the 1950s (Abrams and Miller, 2011; Trowsdale and Betz, 2006). The necessity for a mother to have an immune system that can fluctuate in order to prevent the rejection of the foreign fetus is one explanation for the baseline differences we observe in the male and female immune systems (Van Lunzen and Altfeld, 2014; Abrams and Miller, 2011). Sex differences in the immune response and susceptibility to immune-related diseases cannot be disputed. The exact nature of these differences and how these differences contribute to sickness and disease incidence is quite complex, depending on a multitude of factors including age, genetics, and environment. The evolutionary "need" brought on by these factors carries with it far reaching effects on both peripheral and central functions of the immune system. The sections within this chapter highlight the basic immune-related differences between men and women, citing studies of both human disease and model animal systems. Differences in disease incidence and baseline immune activity will be outlined, followed by potential mechanisms to explain these differences, and finally, sex-dependent immune effects on behavior and the manifestation of comorbid disease states will be discussed.

1.1. Immune mediators

A vast array of inflammatory cells mediates peripheral and central immune responses. The immune response is divided into two component systems, the innate and adaptive systems, which differ in their ability to recognize and remember specific pathogens and antigens. While the innate system mounts a generalized and nonspecific response, the adaptive system triggers a response that is both pathogen/antigen specific and based on an immunological memory of previous responses. Despite this major difference, both the innate and adaptive immune responses are composed of cell-mediated and humoral components. It is important to note that while these immunological components may originate peripherally, the brain is not unaffected - or immune privileged. Macrophages and dendritic cells are located within the brain and respond to inflammatory stimuli (Dantzer et al., 2008), and furthermore, activation of microglial cells, the brain's resident macrophages, occurs readily following infection. In addition to resident immune cells in the brain, several different routes of immune-to-brain access are possible including humoral access through circumventricular organs (Rivest, 2009), primary afferent nerve activation (vagal and trigeminal nerves; Goehler et al., 2000; Dantzer et al., 2008), cytokine trafficking through increased permeability of the blood-brain barrier, and activation of macrophage or endothelial cell interleukin-1 (IL-1) receptors, which cause a local increase of cytokine and prostaglandin release (Kubera et al., 2011; Rivest, 2009; Dantzer et al., 2008). Within the body, lymphoid tissues and immune-relevant organs house the immunological system. Four major organs of the immunological system are bone marrow, thymus, spleen, and lymph nodes. All cells of the body are derived from the bone marrow. Here, stem cells develop into mature red blood cells, platelets, lymphocytes, and granulocytes while some migrate out of the bone marrow to mature. The following is a brief review of inflammatory mediators to aid in the understanding of how basic sex differences affect these cell populations and the immune response (Figure 1.1). T-cells: They derive from immature lymphocytes, mature in the thymus and are released into the blood stream. In action, T-cells have two very different functions. T helper (Th) cells coordinate the immune response and activate other necessary immune cells. There are two distinct types of Th cells, Th1 and Th2, which are differentiated by the inflammatory cytokines that they release. Th1 cells release inflammatory cytokines that promote phagocytosis while Th2 cells release cytokines that stimulate the production of antibodies. Cytotoxic T lymphocytes (Tc cells) are important for the downregulation or destruction of parasites, tumor cells, and virus-infected cells. Like many other immune cells, T-cell recruitment to the brain occurs following injury and in many immune-related disorders (Engelhardt and Ransohoff, 2012). B-cells: They originate in the spleen and are important for the development of specific antigens against foreign bacteria, viruses, and tumor cells. B-cells respond to inflammation within the brain and are thought to be one of the main effector cells in multiple sclerosis pathogenesis, promoting inflammatory activity on both sides of the blood-brain barrier (Büdingen et al., 2012). Natural killer (NK) cells: These cells, similar to T- and B-cells, derive from lymphocytes. NK cells are the most effective killer cells and are similar to Tc cells. NK cells destroy parasitic or infected foreign targets. Unlike Tc cells, NK cells do not require target recognition prior to killing infected cells, and therefore work more efficiently than Tc cells. Because NK cells act in a general fashion, they are one of the quickest responders to cerebral injury and are recruited to sites of injury within the brain. NK cells have been shown to have detrimental effects following injury, such as stroke (Gan et al., 2014). Neutrophils: These are the most abundant white blood cells, and are produced in the bone marrow. Neutrophils are one of the first responders to the site of injury where they promote secretion of anti-inflammatory molecules while reducing cell death and the release of toxic substances. In the brain, neutrophils migrate to the site of injury within hours and can contribute to neurotoxicity in response to injury (Allen et al., 2012). Macrophages: These are essential to the immune response. Activation of the immune system is triggered when macrophages and/or dendritic cells present antigens to T- or B-cells within the spleen. Macrophages also participate in phagocytosis and release cytokines that modulate the immunological response. Macrophages stem from perivascular monocytes, which are derived from blood-borne monocytes, and reside just outside of the basement membrane of the brain. These cells cycle in and out of blood vessels and play an important role in immune responses within the brain. Microglia: They serve as the brain's resident macrophages and are highly involved in the central immune response and the release of inflammatory signaling proteins. These cells are derived from hematopoietic stem cells and enter the brain early in gestation to mature. Though similar in nature, recent evidence suggests microglia to be very different from macrophages in both origin and function (Prinz and Priller, 2014). Microglial involvement is implicated in a variety of immune-related disorders as discussed throughout this chapter. Dendritic cells: Similar to macrophages, dendritic cells originate in the bone marrow and are capable of presenting antigens. Dendritic cells, due to their vast presence, are more efficient antigen-presenting cells than macrophages and work to reduce cytokine release while increasing cell death pathways. Derived from monocytes, dendritic cells also infiltrate to the brain and participate in localized increases in inflammation (Prinz and Priller, 2014). Figure 1.1 Immune cells originate from hematopoietic stem cells in the bone marrow.
A number of these cells then mature within the bone marrow while other...