Despite being surrounded by harmful microorganisms, toxins, and the threat of our own cells turning into tumor cells, humans manage to survive, largely thanks 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.
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.
Our immune system is of two types
1. Innate immune response
2. Adaptive immune response.
1. Innate 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. 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 may 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.
2. Adaptive Immune Response
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.
These receptors can distinguish between friendly bacteria and potentially deadly ones. 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. 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, 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 that pathogen ever resurfaces.
Immune Cells and it's function
White blood cells or leukocytes are the key cell of Immune system. Hematopoiesis is the process of forming white blood cells, as well as red blood cells, and platelets and it takes place in the bone marrow.
Hematopoiesis starts with a multipotent hematopoietic stem cell which can develop into various cell types - it’s 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, basophils, and mast cells are considered granulocytes, because they contain granules in their cytoplasm,and the trio of neutrophils, eosinophils, and basophils are also referred to as Polymorphonuclear cells, or PMNs, because they’re nuclei contain multiple lobes instead of being round.
The mast cells, aren’t considered PMNs because their nucleus is round. During an immune response, the bone marrow produces lots of PMNs, most 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 withthe 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 molecules like hydrogen peroxide. These molecules start to destroy nearby proteins and nucleic acids - a bit like the neutrophil dumping bleach on itself and then lighting itself on fire. This process kills the neutrophil - a bitof a suicide mission. but each neutrophil takes out a lot of pathogens with it. 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. Eosinophils are also phagocytic, and they’re best known for fighting large and unwieldy parasites because eosinophils are much larger than neutrophils and have receptors that are specific for parasites.
Unlike neutrophils and eosinophils, basophils are non-phagocytic. They stain blue with the dye hematoxylin,and like eosinophils they can be helpful at combating large parasites but also cause inflammation in asthma and allergy responses.
Finally, there are the mast cells which are also non-phagocytic and they’re involved in asthma and allergic responses. Next up are the monocytes, macrophages, and dendritic cells, which are phagocytic cells - they gobble up pathogens, present antigens,and release cytokines a tiny molecules that help 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. Other monocytes differentiate into dendritic cells, the prototypical antigen presenting cell, which roam around in the lymph, blood,and tissue.
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 for the first time. it’s a life-changing, coming of age moment.
Mature dendritic cells will destroy the pathogenand break up it’s proteins into short amino acid chains. Dendritic cells will then move through the lymph to the nearest lymph node and they will perform 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 residing in the lymph node, and monocytes which can travel to a lymph node after phagocytosing a bloodborne pathogen which is why all of these cells are referred to as antigen presenting cells.
Now, only T cells with a receptor that can bind to the specific shape of the antigen will get activated - 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 onto an MHC molecule and display it to T cells - and when the right T cell comes along it binds.
Other group the lymphoid progenitor cells become lymphoid cells which are the B cells. B and T cells make up the adaptive immune system, while NK cells are part of the innate immune system. B cells and NK cells complete their development where they started in the bone marrow, whereas some lymphoid progenitor cells migrate to the thymus where they develop into T cells.
All of the lymphocytes are able to travel in and out of tissue and the bloodstream. NK cells are large lymphocytes with granules and they target cells infected with intracellular organisms, like viruses, as well as cells that pose a threat like cancer cells.
NK cells kill their target cells by releasing cytotoxic granules in their cytoplasm directly into the target cell. These granules contain some molecules that cause target cells to undergo apoptosis which is a programmed cell death and some that punch holes in the target cell’s membrane by binding directly to the phospholipids and creating pores.
B-cells, like T-cells, also have a receptor on their surface that allows them to only bind to an antigen that has a very specific shape. The main difference is that B cells don’t need antigen to be presented to them on an MHC molecule, they can simply bind an antigen directly. When a B cell binds to an antigen that’s on the surface of a pathogen, it is capable of phagocytosis and antigen presentation so technically, they’re also antigen presenting cells as well.
Like other antigen presenting cells, the B-cell will load the antigen onto an MHC molecule called MHC II, and display it to T- cells. When a T-cell gets activated it helps the B-cell mature into a plasma cell, and a plasma cell can secrete lots and lots of antibodies. Typically, it takes a few weeks for antibody levels to peak. The antibodies, or immunoglobulins, have the exact same antigen specificity as the B cell they come from.
Antibodies, are just the B-cell receptor in a secreted form, so they can circulate in serum, which is the non-cellular part of blood- attaching to pathogens and tagging them for destruction. Because antibodies aren’t bound to cells and float freely in the blood, this is considered humoral immunity a throwback to the term“humors” which refers to body fluids.
The final type of lymphoid cell is the T-cell and its in charge of cell mediated immunity. T-cells are antigen specific, but they can’t secrete their antigen receptor. A naive T-cell can be activated or primed to allow it to turn into a mature T-cell by any of the antigen presenting cells, but most often it’s done by a dendritic cell. Now, there are two main types of T-cells, CD4 T-cells and CD8 T- cells
“CD” stands for cluster of differentiation.
There are hundreds of CD markers in the immune system, and these CD markers are useful in telling them apart. For example, all T-cells are CD3+, because CD3 is part of the T-cell receptor. So, CD4+ T-cells, are actually CD3+ CD4+, and these cells are called helper cells because they’re like generals on the battlefield, they secrete cytokines that help coordinate the efforts of macrophages, B-cells, and NKcells.
Helper T-cells can only see their antigen if it is presented on an MHC II molecule. CD8+ T-cells are CD3+,CD8+, and they’re called cytotoxic T-cells T-cells because they kill target cells, really similarly to how NK cells doit with one major difference. CD8+ T- cells only kill cells that presenta specific antigen on an MHC I molecule which is structurally similar to the MHC II molecule,where as NK cells aren’t nearly as specific in who they kill.
So now let’s go through a complete immune response with a bacterial pathogen in the lungs. To start, the bacteria will have to get breathed in, slip by your nose hairs, past the cilia in the airways, and then will have to penetrate past the epithelium layer of the lungs. Once it’s in the lung tissue, the bacteria will start to divide and might encounter a resident macrophage in the lung tissue which will ingest the bacteria and start releasing cytokines. Those cytokines start the inflammatory process by making blood vessels leaky and attracting nearby eosinophils, basophils, and mast cells, which release their own cytokines and granules amplifying the inflammation.
Neutrophils from the blood as well as fresh new ones from the bone marrow dive into the tissue and join the battle. If the pathogen was a virus, NK cells would help destroy the infected cells at this point. This is all part of the innate immune response. Around this point in the infection, immature dendritic cells digest the pathogens and move from the lung tissue over to a nearby lymphnode where they present the processed antigen on an MHC II protein to a naive T-cell. The dendritic cell, which is part of the innate immune system, bridges the innate and adaptive immune responses when it presents the antigen to the T-cell part of the adaptive immune system.
Sometimes, if the infection is spreading,bacteria might find its own way to a lymph node without the help of the dendritic cell. In this case, B-cells part of the adaptive immune system might directly phagocytose the bacteria and present it to a naive CD4+ T-cell. Either way, if the antigen is the right “fit” for the T-cell it will begin to differentiate and undergo clonal expansion. Differentiated CD4+ T-cells will release cytokines that will induce B-cells to differentiate into plasma cells which secrete antibodies that will go into the lymph and then the bloodstream. The antibodies will tag pathogens making it easier for phagocytes to eat them. Once again, at this point, if the pathogen was a virus, the CD8+ T- cells would kill any infected cells that express the viral antigen on an MHC I.

Over time, as the invading pathogen dies off, most of the B and T-cells die of neglect, but a few turn into memory B-cells and memory T-cells, which linger for years in case their needed in the future. So, to recap the immune system has innate and adaptive response. The innate immune response is immediate, but non-specific, and lacks memory, where as the adaptive immune response is highly specific and remembers everything, but it takes several days to get started and almost two weeks to peak.
