Introduction to the immune system

Despite being surrounded by harmful microorganisms, toxins, and the threat of our own cells turning into tumor cells, humans manage to survive; thanks largely to our immune system. The immune system is made up of organs, tissues, cells, and molecules that all work together to generate an immune response that protects us from microorganisms, removes toxins, and destroys tumor cells - hopefully, though, not all at once! The immune response can identify a threat, mount an attack, eliminate a pathogen, and develop mechanisms to remember the offender in case you encounter it again - all within 10 days. In some cases, like if the pathogen is particularly stubborn or if the immune system starts attacking something it shouldn’t like your own tissue, it can last much longer, for months to years, and that leads to chronic inflammation.

Your immune system is like the military - with two main branches, the innate immune response and the adaptive immune response. The innate immune response includes cells that are non-specific, meaning that although they distinguish an invader from a human cell, they don’t distinguish one invader from another invader. The innate response is also feverishly fast - working within minutes to hours. Get it? “Feverishly” - that’s ‘cause it’s responsible for causing fevers. The trade-off for that speed is that there’s no memory associated with innate responses. In other words, the innate response will respond to the same pathogen in the exact same way no matter how many times it sees the pathogen. The innate immune response includes things that you might not even think of as being part of the immune system. Things like chemical barriers, like lysozymes in the tears and a low pH in the stomach, as well as physical barriers like the epithelium in the skin and gut, and the cilia that line the airways to keep invaders out.

In contrast, the adaptive immune response is highly specific for each invader. The cells of the adaptive immune response have receptors that differentiate one pathogen from another by their unique parts - called antigens. Adaptive immunity is also diverse, meaning it can recognize almost an infinite number of specific antigens and mount a specific response against each of them. The trade off is that the adaptive response relies on cells being primed or activated, so they can fully differentiate into the right kind of fighter to kill that pathogen, and that can take a few weeks. But the great advantage of the adaptive immune response is immunologic memory. The cells that are activated in the adaptive immune response undergo clonal expansion which means that they massively proliferate. And each time the adaptive cells see that same pathogen, they massively proliferate again, resulting in a stronger and faster response each time that pathogen comes around. Once the pathogen is destroyed, most of the clonally expanded cells die off, and that’s called clonal deletion. But some of the clonally expanded cells live on as memory cells and they’re ready to expand once more if the pathogen ever resurfaces.

Now, it’s time to meet the soldiers - which are the white blood cells or leukocytes. Hematopoiesis is the process of forming white blood cells, as well as red blood cells, and platelets, and it primarily takes place in the bone marrow. Hematopoiesis starts with a multipotent hematopoietic stem cell which can develop into various cell types - its future is undecided. Some become myeloid progenitor cells whereas others become lymphoid progenitor cells.

The myeloid progenitor cells develop into myeloid cells which include neutrophils, eosinophils, basophils, mast cells, dendritic cells, macrophages, and monocytes, all of which are part of the innate immune response and can be found in the blood as well as in the tissues. The neutrophils, eosinophils, and basophils are considered granulocytes, because they contain granules in their cytoplasm, and neutrophils in particular are also referred to as polymorphonuclear cells, or PMNs, because their nuclei contain multiple lobes instead of being round.

During an immune response, the bone marrow produces lots of cells, many of which are neutrophils. Neutrophils use a process called phagocytosis - that’s where they get near a pathogen and reach around it with their cytoplasm to “swallow” it whole, so that it ends up in a phagosome.

From there, the neutrophils can destroy the pathogen using two methods - they can use their cytoplasmic granules or oxidative burst. First, the cytoplasmic granules fuse with the phagosome to form the phagolysosome. The granules contain molecules that lower the pH of the phagolysosome, making it very acidic, and that kills about 2% of the pathogens. Now, the neutrophil doesn’t stop there. It keeps swallowing up more and more pathogens until it’s full of pathogens, and at that point, it unleashes the oxidative burst. During an oxidative burst, the neutrophil produces lots of highly reactive oxygen species like hydrogen peroxide. These molecules start to destroy nearby proteins and nucleic acids within the phagolysosomes, which are the components of the pathogen that has been ingested. The net result is that the pathogen is eliminated.

Now, in comparison to neutrophils, eosinophils and basophils are far less common. They both contain granules that contain histamine and other proinflammatory molecules. Eosinophils stain pink with the dye eosin - which is where they get their name. They are phagocytic cells even though it's not their primary mechanism of attack. They are best known for fighting large and unwieldy helminthic parasites, or “worms,” by releasing molecules that can poke holes in the outer layer of helminths. These cells are also involved in allergic reactions, such as atopic dermatitis and allergic rhinitis, also known as hay fever. When involved in allergic reactions, eosinophils degranulate, meaning they release various enzymes and proteins within their granules, and this causes an inflammatory reaction.

Next you have basophils, and they stain blue with the dye hematoxylin, and unlike neutrophils, basophils are non-phagocytic. On the flip side, they have granules that contain histamine and other proinflammatory molecules; therefore, they are important in initiating allergic responses. Finally, there are the mast cells, which live in tissues (not in the blood), and are very similar to basophils. They are also non-phagocytic and are involved in allergic responses.

Next up are the monocytes, macrophages, and dendritic cells which are also phagocytic cells - they gobble up pathogens, present antigens, and release cytokines - which are tiny molecules that attract other immune cells to the area. Monocytes only circulate in the blood. Some monocytes migrate into tissues and differentiate into macrophages, which remain in tissues and aren’t found in the blood. Dendritic cells are the prototypical antigen presenting cell. Dendritic cells are usually found in sites that are in contact with most external antigens - like the skin epithelium, or the gastrointestinal mucosa.

When dendritic cells are young and immature they’re excellent at phagocytosis, constantly eating large amounts of protein found in the interstitial fluid. But when a dendritic cell phagocytoses a pathogen - it’s a life-changing, coming of age moment. Mature dendritic cells will destroy the pathogen and break up its proteins into short amino acid chains. Dendritic cells will then move through the lymph to the nearest lymph node, and they’ll perform an antigen presentation, which is where they present those amino acid chains - which are antigens - to T cells.

Antigen presentation is what connects the innate and adaptive immune systems. Antigen presentation is something that can be done by dendritic cells, macrophages, as well as monocytes - which is why all of these cells are referred to as antigen presenting cells. Dendritic cells are the best at this process because they are the only cells that live where pathogens enter (through epithelia like the skin, gut and airways) and they are the only cells that can traffic from these tissues to lymph nodes, where T cells circulate. Now, only T cells with a receptor that can bind to the specific shape of the antigen will be activated - and that’s called priming. It’s similar to how a lock will only snap open when a key with a very specific shape goes in. However, T cells can only see their antigen if it is presented to them on a silver platter - and on a molecular level that platter is the Major Histocompatibility complex or MHC for short. So the antigen presenting cell will load the antigen on an MHC molecule and display it to T cells - and when the right T cell comes along - it binds!