17.1 Cells and Messengers of the Immune System

Innate immune system

The innate immune system consists of physical barriers of the body including the skin (epithelium) and mucosal surfaces of the gut, lungs, and other exposed areas, as well as several critical cell types: neutrophils, macrophages, and monocytes (Figure 17.3).

Figure 17.3 Innate immune structures and cells

All three types of innate immune cells respond broadly to multiple pathogens, which they can detect using a number of pattern recognition receptors on their cell surface (Figure 17.4). These receptors can detect evolutionarily conserved pathogen-associated-molecular-patterns (PAMPs) present on bacteria, viruses, fungi, or other foreign invaders.

Figure 17.4 Pathogen-associated molecular patterns Pathogen associated molecular patterns (PAMPs) are structures common across classes of microbes. Innate immune cells express receptors that recognize PAMPs.

How each of these cellular components of the innate immune system functions once they detect these PAMPs is diagrammed in Figure 17.5, using the case of a penetrating skin wound that introduces some bacterial pathogens as an example. We will discuss what each cell type does in more detail below.

Figure 17.5 Innate immune cells in action

Neutrophils are a type of white blood cell that are affectionately known as the soldiers or footmen of the immune system. These cells react exquisitely fast and pour into infected or injured areas and unleash a battery of potent pathogen killing defenses—these cells largely create the oozing “pus” in wounds, which is basically an accumulation of dead neutrophils that have finished doing their thing. Neutrophils can also quite literally spit out their DNA in nets (called extracellular traps) to capture pathogens and pull them back in for elimination (Papayannopoulos, 2018)!

A second major player in innate immunity and in repair mechanisms is the macrophage (Greek for “big eater”), which is a type of phagocyte (phagocytic cell) meaning that they are good at eating and digesting things. These cells eat pathogens, as well as dead cells and debris, and thus are critical for overall tissue homeostasis and wound healing. They are also one of the primary antigen presenting cells (APC) along with B cells and dendritic cells. An antigen is a tiny portion of a cell or pathogen that gets processed after an APC chews it up and it gets “presented” to an adaptive immune cell like a T cell, which we cover in the next section, in order to activate that cell and mobilize a full immune response. A critical part of innate defense involves activation of the complement cascade, a series of proteins that have diverse functions including opsonization or “tagging” of pathogens for removal/phagocytosis by an APC (usually a macrophage). Complement proteins can also directly kill pathogens via punching holes in their cell membranes, as well as activate some adaptive immune cells.

A final cell type within the innate immune system important for our study of neuroimmunology is the monocyte, which is a cousin of the macrophage. Monocytes circulate freely within the blood and lymphatic system (e.g. lymph nodes) where they constantly scan for any sign of trouble. Once a pathogen or chemotactic signal (basically a “come help” signal) from another immune cell is detected, monocytes can extravasate (crawl) into tissues like the skin or adipose and thereby become macrophages (or “tissue-resident” monocytes).

Innate immune responses are rapid and stereotyped, meaning that they occur with the same time course and magnitude each time and somewhat regardless of the specific pathogen detected. One major consequence of the innate immune cell response is inflammation. Inflammation is the term we use to describe how tissues become red, swollen and hot after an injury or pathogen exposure of some kind. When inflammation happens in tissues in your body, it is also often painful (see Chapter 9 Touch and Pain).

Inflammation is quite a buzz word these days as it is implicated in many different diseases ranging from heart disease to depression to Alzheimer’s disease (Figure 17.6). There is good reason for this attention, as inflammatory processes that last too long, especially within the brain, can be very harmful. It is important to remember however that inflammation is classically defined in immunology by heat, swelling, pain, and importantly, repair. Thus, inflammation is helpful when properly controlled and only becomes harmful when it fails to resolve, which is a theme that we will visit repeatedly throughout this chapter.

Figure 17.6 Inflammation-associated diseases

Taken together the role of innate immune cells is to quickly neutralize or contain pathogens and to mobilize the entire immune system, including the brain, in immune defense. Their parallel function is to notify the adaptive immune system which begins to generate a more specific and enduring response via the generation of memory cells.

Adaptive immune system

The adaptive immune system consists primarily of another class of white blood cells called lymphocytes, which consists of B cells and T cells. B cells are so-called because they are born in the bone marrow (like all blood cells). B cells make antibodies which are soluble (secreted) proteins produced in response to antigen stimulation and which make up the humoral immune response. This humoral immune response is generated within the extracellular spaces (the “humors” of the body, e.g. blood and lymph) and is important for neutralizing pathogens before they enter cells. Each antibody recognizes a single antigen, and each B cell generates a single type of antibody (Figure 17.7).

Figure 17.7 B cell function

There is a tremendous diversity of B cell receptors in your body which ensures maximal recognition of dangerous things that might make us sick. These cells are fairly sophisticated as well: B cell receptors get thoroughly “fit tested” early in their life to ensure they are not responding to your own cells (which is critical to prevent autoimmunity). If they do respond to so-called “self-antigens”, they are immediately eliminated. Indeed, most B cells will die a quiet dignified death without ever finding their non-self antigen match (this again is a good thing, as otherwise our bodies would be overrun with B cells). However, a small subset will find their match! Once a match between antibody and antigen occurs, that particular B cell will start to make many copies of itself. This process takes time; by the end of about a week, around 20,000 clones of that original B cell will be produced. This creates an army of antibody-producing soldiers—each one of which can then produce an astounding number of antibodies—about 2000 per second!

What do antibodies do? Interestingly, they don’t directly kill anything. Rather, they tag (label) pathogens for recognition and removal by a macrophage. Antibodies can also bind to viruses and prevent them from entering cells, in a process called neutralization. Memory B cells are also produced during this process, which are very long-lived cells that can much more rapidly begin to replicate themselves and produce antibodies if they encounter the same antigen again. Remember vaccines? The production of memory B cells in response to vaccination is crucial to confer long-term protection.

T cells are called T cells because, while they are born in the bone marrow like all blood cells, they grow up and attend primary school in the thymus. T cells are responsible for cell-mediated immunity (which is concerned with the killing of pathogens inside of cells, see Figure 17.8) and they come in several flavors:

• Helper T cells which “help” or amplify other immune cell activities
• Cytotoxic or “Killer” T cells which, as the name suggests directly kill infected cells and thus the pathogens within them
• Regulatory T cells, which again as the name suggests, regulate the activities of other T cells
• Memory T cells which get generated in response to specific infections and mediate long-term immunity to these same pathogens in collaboration with Memory B cells, and several other types which we won’t discuss.

Suffice to say, it’s complicated and beyond the scope of this chapter to understand them all. The most important bit for our topic is that T cells generate receptors on their cell surface during their development in the thymus to precisely respond to a single pathogen via a very similar process to B cells. They form a primary arm of the adaptive immune response and the loss or dysfunction of these cells can be devastating. Acquired immunodeficiency syndrome (AIDS) in humans is due to a loss of helper T cells after infection with human immunodeficiency virus (HIV), which highlights their importance.

Figure 17.8 B vs T cells

T cells are called into action to attack infected cells following their activation by professional APCs like macrophages, which “present” antigen to the T cell using a molecule called the major histocompatibility complex, or MHC, also known as human leukocyte antigen (HLA) in humans. T cell attacks are very specifically targeted to only infected cells with the epitope (a small fragment of an antigen) the T cells have learned to recognize, not healthy cells and not even the APCs displaying that pathogen epitope. The MHC is critical to this selectivity. MHC comes in two forms: class I and class II. All APCs have class II, and all cells of the body have class I. Whether an epitope is displayed to a T cell using MHC class I or class II will help determine whether a T cell decides to try to kill that cell, leave it alone or learn from it.

Under healthy conditions, host cells (i.e. your own cells) use MHC I to display a tiny bit of themselves, a self-antigen, on its cell surface (step 1 of Figure 17.9). This tells the T cell “I’m you! Don’t kill me!”. This presentation of a bit of “self” by MHC I is a crucial step because it prevents T cells from killing any healthy cells. MHC/HLA molecules are the reason that organ transplantation in humans is a bit tricky—you can’t just take any liver and give it to someone that needs it, unfortunately—it has to be a close match in terms of HLA type (sort of like blood type) or the receiving person’s immune cells (and antibodies) will rapidly detect and attack it, leading to organ failure. In contrast to all other cells in our body, APCs use MHC class II to package and display epitopes on their cell surface for the purpose of activating T cells (step 2 of Figure 17.9). The T cell learns about the pathogen epitope that the APC displays, and it also knows not to kill the APC because it is displayed with MHC II. This again prevents the T cell from going rogue and killing things without permission. They are pretty potent cells! However, if a normal cell, say a kidney cell, gets infected with a virus, it will use MHC class I to package part of that virus into a small digestible form and wave it like a flag on its cell surface. This tells any passing T cell (with a receptor that recognizes that specific antigen) that the cell has been invaded and the T cell will then kill and remove the cell and its virus (step 3 of Figure 17.9). We will learn in a subsequent section about a subset of T cells that are important for inflammatory bidirectional communication between the brain and the immune system. We will also further discuss how T cells seem to be critical for normal behavior, specifically learning and memory.

Figure 17.9 MHC complexes and self vs pathogen recognition

Interestingly, MHC is another source of diversity building for the immune system (meaning the ability to respond to a vast number of potential antigens), as the genes that encode MHC (and HLA in humans) are some of the most diverse in the entire genome. There is fascinating literature showing that animals like mice, other mammals, birds, and even fish may choose their mates based on their detection of MHC gene polymorphisms, likely via pheromonal cues contained in urine. Specifically, animals choose mates that have MHC genes least like their own, ensuring that their offspring will inherit the largest possible diversity of genes important for building a robust immune defense. Whereas this has been shown for many species (Grob et al., 1998; Roth et al., 2014; Rymešová et al., 2017), the possibility in humans remains tantalizing but controversial (Havlicek and Roberts, 2009; Havlíček et al., 2020).

Cytokines and chemokines

All cells need good communication. Immune cells, and many other cell types in the body, use cytokines and small “chemotactic” cytokines called chemokines to signal over long distances. Cells of both the innate and adaptive immune systems secrete cytokines and chemokines as a part of their response to pathogens. Immune cells in the brain, which we will learn about shortly, also produce these potent signaling molecules. Among cytokines are several “families”, including tumor necrosis factors (TNF), interferons (IFN), interleukins ([IL]-1 through IL-36 and counting), and others. Cytokines serve a wide variety of functions including signaling between cells and coordinating inflammation. They are produced by and affect a wide variety of cells in the brain and body. Chemokines are a type of cytokine that induce cell movement via chemical signals or gradients. An equally lengthy list of chemokines from several structural families has been described, which mediate diverse functions including cell adhesion, chemotaxis (or directed cell movement towards a signal source), and leukocyte (white blood cell) trafficking.

The naming conventions of cytokines and chemokines are based on their chemical structure rather than their functions which is a bit unfortunate when you are trying to remember what different cytokines do! However, cytokines can be roughly divided into having pro-inflammatory (inflammation promoting) vs. anti-inflammatory (inflammation resolving) functions, although these outcomes are highly context-dependent. That is, sometimes they induce inflammation and sometimes they prevent it, and the impact often depends on the receiving cell. While acute and local inflammation/immune activation caused by the pro-inflammatory cytokines is necessary for responding to insult or injury, homeostasis and health are restored and tissue repair is elicited by regulatory anti-inflammatory processes. Cytokines released by innate immune cell response to pathogens also mediate the activation of T and B lymphocytes, which play a critical role in the adaptive immune response later in the time course of an infection.

Cytokines can induce the production of other cytokines, chemokines and inflammatory mediators, and rarely work alone, but rather in a cascade with other cytokines. You may have heard the term “cytokine storm,” which is more or less what it sounds like: when one cytokine induces the production of another, which induces another, and so on, until you have a whole storm of swirling cytokines within a given organ or tissue. Figure 17.10 shows an example of the cytokine storm process as it happens following SARS-CoV2 infections in the lungs. This is one of the major causes of death with Covid-19; the cytokine storm causes excess inflammation that damages lung cells and restricts airflow. Cytokine storms can occur in multiple kinds of severe infection and are generally bad news as it can lead to organ failure or death.

Figure 17.10 Cytokine storm

For the purposes of this chapter, the important thing about cytokines is that they have neuromodulatory (i.e. “neuron modulating”) properties within the brain during infectious and inflammatory processes by acting directly on neurons and glia. For example, one well characterized PAMP used widely in neuroimmunology research is lipopolysaccharide, or LPS, which is the cell wall component of bacteria that induces a robust immune response if injected into experimental animals (or humans!). LPS induces a suite of changes in physiology, including white blood cell (e.g. monocytes, T cells, B cells) replication (proliferation), fever, and cytokine production. Cytokines released in response to LPS signal to the brain to induce rapid changes in behavior, including fatigue, loss of interest in eating and normal behaviors, e.g. social interactions, and maybe even a form of depression (called anhedonia). These behavioral changes are not caused by the pathogens themselves, but rather by cytokine signaling in the brain. They are widely regarded as adaptive because they help you to rapidly shift motivation to prioritize rest and recovery and help to overcome illness more quickly. We will learn more about these roles of cytokines in the next section. Cytokines are also constitutively expressed in healthy brain tissue and regulate such homeostatic mechanisms and behaviors as sleep, metabolism, and even cognition. Cytokine receptors in mammals have been characterized throughout the central nervous system (CNS), with high concentrations within brain regions important for these functions, including the hypothalamus, hippocampus, striatum, amygdala, and thalamus (Hopkins and Rothwell, 1995; Rothwell and Hopkins, 1995).