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Vaccine Development I: Overview of the Immune System

When we read about deadly infectious diseases, we often feel life is unfair. After all, why can’t our body fight of the invading microorganisms and keep us safe? In reality, however, our body possesses amazing defense capabilities: our immune system routinely protects us from a vast army of pathogens—the organisms that can cause diseases. While our immune system excels at eliminating a previously-encountered pathogen, it also tries its best when it does encounter a novel pathogen. In this essay, I will provide a brief overview of how our immune system works and how it relates to vaccine development.1 


Elimination of pathogens (Courtesy: 
https://www.britannica.com/)

Our immune system can be broadly classified into two systems: the innate/general resistance system and the adaptive system. The innate system may be able to eliminate a pathogen on its own or it can stimulate the adaptive immune system to become involved in eliminating the pathogen. 

Let’s see how the innate/general resistance system works as this is the first line of defense we have against pathogens. Our skin, for example, forms an anatomic barrier against pathogens as well as toxic agents. The skin also has an acidic environment that prohibits microorganism growth. Furthermore, mucous membranes line various body cavities that are exposed to the external environment and internal organs, and these membranes can aid in getting rid of pathogens by trapping and expunging them.

Our body also has physiologic barriers that inhibit a variety of pathogens. Our body temperature—especially when we have a fever—and the acidic environment in our stomach can inhibit and/or destroy many pathogens. Moreover, special enzymes from tears and mucous secretions, as well as some surfactant proteins that are present in serum, lung secretions, and mucosal surfaces, are capable of destroying many pathogens.  Finally, infected viral cells can produce and secrete special proteins that can bind to non-infected cells to heighten their anti-viral defenses. 

Our innate immune system also relies on the inflammatory response to keep us safe. Through the inflammatory response, our body responds to foreign dangers like pathogens or physical damages, and these responses can manifest as redness, heat, pain, or swelling in the affected area.   

Three complement pathways are also a part of the innate immune system. These pathways are important in eliciting localized inflammatory responses and can facilitate phagocytosis. Phagocytosis (from Greek phagein and kytos which means “to eat” and “cell”, respectively) is a process by which a cell engulfs a large particle, such as a virus or bacteria, and eliminates it.  

As one of the processes that can destroy pathogens, phagocytosis is an important part of the innate immune system. Cells that are specialized in phagocytosis are collectively called phagocytes and can act as the bridge between the innate immune response and the adaptive immune response (more on this later). 

But how does our body detect when a pathogen has entered our body? One way our body can detect a pathogen entry is via pattern recognition receptors. Acting as molecular sensors, these proteins can recognize some general molecular patterns that can be found on most pathogens. But this line of defense has a limited capability as it has a limited repertoire, which can’t be expanded because these instructions are set by our genetic code.

Hence, we need a system that can expand and evolve to fight off when we encounter novel pathogens. This is where the adaptive immune system comes into play, and vaccine development aims to modulate this system to protect us from novel pathogens. 

Schematics of an antibody (courtesy: Wikipedia)

The adaptive immune system has two arms: the cell-mediated immunity and antibody-mediated immunity. Two distinct cell types of adaptive immune system—the T cells and B cells—are responsible for each arm.

Let’s focus on the cell-mediated immunity first. There are two main types of T cells: CD4 or T-helper cells and CD8 or T-cytotoxic cells. The CD8 cells, along with a subtype of CD4 cells, promote cell-mediated immunity. This immunity does not involve antibodies; instead, the immunity depends on the actions of some phagocytes and other cells types,

Conversely, the antibody-mediated immunity does depend on antibodies, and the B cells are the main players here. Here, antibodies produced by the B cells can travel in the blood to establish immunity to a particular pathogen. Interestingly, both the immune response and memory induction in the B cells remain weak when the T-helper cells are not involved. 

To understand why that happens, let’s consider the scenario when our body encounters a novel pathogen. When B cell receptors come into contact with the specific molecular pattern or antigen that is present on the pathogen, part of the receptor—the part that contacts the antigen—underdoes excessive mutation or hypermutation. This only happens when signaling cues from the helper T cells are also present. The hypermutation creates many combinations until the best combination or key that best fits the novel antigen is found. This stimulates the B cells to mature into plasma cells, and these plasma cells then begin antibody production based on the previously-determined combination. Like a lock and key mechanism, each antibody is capable of binding only to a specific antigen.

Around the same time, our body will also start making clones of these stimulated B cells to create more cells. Some of these cloned cells will become plasma cells and produce the necessary antibodies while others will become memory cells that can be used to create more antibody-producing B cells if the same pathogen invades again.2  

This process takes several days, and the initial type of antibodies produced during this period are called immunoglobin M or IgM (the term immunoglobin and antibody are often used interchangeably). In other words, IgM is the first antibody that is produced during the primary immune response. As the immune response progresses and our body keeps fighting the pathogen, activated plasma B cells will begin producing a different type of antibody called IgG. Although IgM is the first antibody our body produces, IgG does a better job: IgG binds more effectively to the antigen, and hence, pathogens can be eliminated faster.

While binding of an antibody to an antigen can inactive some pathogens, antibody binding also “marks” the pathogen. These marked pathogens then can be eliminated by components of the innate immune system, such as phagocytes. Furthermore, the classical pathway, one of the complement pathways, gets triggered when some antibodies bind to their antigens.

When our body reencounters a pathogen, the reaction to that pathogen will be quicker and more effective. Thanks to the memory cells that were produced during the primary immune response, our body can quickly ramp up the production of antibodies—especially IgG—to eliminate the pathogen as soon as possible. Now, if we can somehow elicit this response without getting sick, won’t that be wonderful? And that is the idea that led to vaccine discovery, which I will cover in another essay.

1. This essay was mostly based on a great review article, Fundamentals of Vaccine Immunology, by Angela S Clem. 
2. Clonal expansion can also occur for activated T cells, and special T cells called effector T cells (to fight off the current infection) and memory T cells are created as well.

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