The one about Innate and Adaptive Immunity
I originally intended this blog to be about immune system and immunizations. But there is just so much detail in how our immune system functions that by the time I was done with adaptive immunity, this was already a 20 minute read. So, I will have to do a post on immunizations later but knowing the details of this blog is essential in understanding why and how immunizations work. In this blog, I hope to explain the several lines of defense our immune system employs to help combat a pathogen.
Our immune system has three lines of defense, all of which must be overcome if a pathogen is to establish an infection and then exploit its human host for the remainder of that person’s life, like in case of HIV and hepatitis. The first defense is our skin and enzymes in saliva and other mucosal areas. The skin creates a barrier to entry for the pathogen. The enzymes inactivate pathogens. If a pathogen does manage to get in the tissues, our second line of defense kicks in. This involves white blood cells eating up the pathogens. These two lines of defense are collectively called the innate immunity. Mechanisms and key players of innate immunity are common amongst our plant, microbial, and animal relatives. Innate immunity is quick, omnipresent and not specific to any pathogen. It works by recognizing self vs foreign molecules. All human cells display a human or self receptors. A pathogen or allergen that doesn’t have this receptor will get tagged by white blood cells to be eaten up. The innate immune system is enough for majority of the pathogens our body is exposed to.
If the infection manages to overwhelm our innate immune system, our third line of defense kicks in. This is called the adaptive immunity and is unique to vertebrates. Certain cells of innate immunity will present a part of the pathogen(a protein) to cells of adaptive immunity to ask for help. Unlike innate immunity, adaptive immunity is much slower and very specific to the pathogen. Adaptive immunity can take up to two weeks to build up an army of antibodies that will target that specific pathogen. If the adaptive immune system succeeds then memory cells of the immune system will remember how to fight the infection the second time around. A secondary infection caused by a pathogen will be much less severe and will subside soon. This “immunity” to a secondary infection is what immunizations/vaccinations hope to achieve by inducing a mild, harmless primary infection.
GERM THEORY
For centuries it was believed that infectious diseases were due to miasmas (poisons in the air). It wasn’t until 1878, when French chemist Louis Pasteur, in a series of spectacular experiments had shown that fermentation, putrefaction and infection were all due to contamination by living microbes. He proved that microbes were the cause and not the effect of these processes. His researches led to immediate practical triumphs: he saved the French silk industry by introducing heat sterilization or ‘pasteurization’ to prevent souring; and demonstrated the effectiveness of vaccinations against anthrax in animals and rabies in humans. Learning of his studies, English surgeon Joseph Lister deduced that wound sepsis was due to bacterial contamination. In 1867 he began soaking his instruments and dressings in carbolic acid, a disinfectant.
PATHOGENS
A pathogen is any organism with a potential to cause disease. This could be a bacteria, a fungus, a parasite, or a virus. Unlike virus, the other pathogens usually cause infections outside a cell. These pathogens can be eaten up by white blood cells. But virus needing a host nuclear machinery to survive, causes infections inside a cell. In this case, the entire infected human cells need to die. Our immune system deals with these two kinds of infections differently as in one you are killing the actual pathogen while in the other you are killing the human cell.
DISCOVERY OF VIRUS
In 1895, Dutch botanist Martinus Beijerinck was researching tobacco mosaic disease, which stunted the growth of tobacco plants and mottled their leaves. He found that when he crushed up the leaves of a diseased plant and passed the sap through the finest porcelain filter, the filtrate infected healthy plants. Whatever the infective agent, it could not be grown on a culture medium or killed using chemical and heat treatments. Nor was it a toxin, as it seemed to multiply: he could infect a healthy plant, and from that infect another plant and so on. Calling the agent a ‘virus’ (Latin for poison), he showed it could grow and reproduce only within living cells. That same year Friedrich Loeffler and Paul Frosch found the virus responsible for foot-and-mouth disease in animals; in 1901 yellow fever was recognized as first human viral disease; and in 1909 Peyton Rous identified in chickens the first tumour virus. Specific viruses were also found to prey on bacteria. These bacteriophages were discovered by Frederick Twort and Felix D’Herelle in 1915. Study of bacteriophages provided fundamental insights into molecular biology, yielding the secrets of how genes are switched on and off and providing a vehicle for inserting foreign genes into bacteria.
BRIEF OVERVIEW OF IMMUNE CELLS
The cells of the immune system are the white blood cells or Leukocytes. Immune system also includes megakaryocytes which make platelets and plethora of soluble proteins that help tag pathogens for destruction and call for help. All immune cells including platelets and erythrocytes(red blood cells) are formed from the same stem cell called hematopoietic stem cell. The stem cell gives birth to two lineages — lymphocytes and rest of the blood cells. Lymphocytes are the main cellular component of lymph — fluid that flows through lymphatic system. Lymphatic system is part of our circulatory system and is responsible for circulating lymphocytes throughout our body going via 500–600 lymph nodes spread throughout our body. Lymphocytes like B cells and T cells are involved in the adaptive immunity and all the other cells are part of the initial innate response. If a lymphocyte becomes activated by a pathogen it remains in the lymph node to mature and start preparing for the attack. Lymphocytes also include Natural Killer cells (NK cells) that are part of innate immunity and specifically tag virus infected cells for destruction.
All other white blood cells like neutrophils, eosinophils, basophils, and monocytes are part of the innate response as well. These white blood cells also have reactive substance inside called granulocytes. Neutrophils and monocytes are also phagocytes (Greek for eating cells). Monocytes which are usually mobile in blood later mature into macrophages that reside in tissues. Monocytes also give birth to dendritic cells that present the pathogen to B cells and T cells and trigger adaptive immune response. The diagram of family tree of blood cells above will help you visualize this. Because blood cells are short-lived, they are constantly being formed in the bone marrow.
NORMAL FLORA
A human body contains trillions of microorganisms. These symbiotically living organism are called the normal flora of our body. These can be found in skin, mouth, gut and vagina. For the most part, they are harmless and actually do a lot of work for us like digest our food and make vitamins. They also help by preventing other dangerous species from colonizing in our body. For example, E.Coli, a major component of our gut flora, secretes antimicrobials to fight off other dangerous species.
Sometimes our normal flora can be reduced by antibiotic or steroid use. When this happens certain pathogens in our body which are otherwise good, turn against us. These are called opportunistic pathogens because they only attack when the opportunity of a weaker immune system is presented. Candida Albicans, a yeast species that normally resides in our mouth and vagina is a opportunistic pathogen. If people don’t rinse their mouth after using a steroid inhaler, they are at a higher risk of getting candidiasis or oral thrush because steroids are immunosuppressants. Similarly, women who overuse antibiotics, can get recurrent yeast infections caused by our normal flora.
INNATE IMMUNITY
The word ‘innate’ means that the collective defenses involved in this type of immunity are all entirely determined by genes a person inherits from parents. In the innate immune response, pathogens are recognized by a fixed repertoire of cell receptors and immune molecules that have evolved by natural selection over hundreds of millions of years. Genes encoding these innate immune molecules are inherited from one generation to next in a stable form. Every now and then new variants arise from mutations. A few of these mutations will provide advantage and get positively selected for. Because the pathogens themselves have similar innate immunity as us, their immune molecules evolve as well in response to our evolving immunity. This evolutionary cat and mouse game of innate immunity never ends.
This immune response is always present, always ready to go, and always have the same strength. It does not get better with multiple encounters with same pathogen. Innate immunity takes anywhere from a few hours to 4 days to become fully functional and eliminate the invading pathogen. The main basis of innate immunity is distinguishing self vs non-self cells. Human cells display certain receptors on their surface that helps immune cells identify them as self and not eat them. Any cell that doesn’t display human specific receptors on them will be tagged by the innate immune system to be eaten. Some bacteria like Staph aureus have evolved to add these human like receptors on their surfaces to hide from the our immune system. Innate immunity includes our first two lines of defense.
FIRST LINE OF DEFENSE
The skin and mucosal surfaces form the first line of defense against pathogens. Our skin forms an impenetrable barrier of keratinized cells. Perspiration, sloughing off of skin, and the normal skin flora also help prevent infection. Our normal flora help by competing for nutrients and resources with the more dangerous pathogens. But this barrier can still be breached by cuts, burns, abrasions etc. The underlining of the skin called the epithelium is continuous with the respiratory, gastrointestinal, and urogenital linings. These surfaces known as mucosal surfaces are more vulnerable to microbial invasion. Our respiratory and intestinal are usually bathed in the mucus which helps wash away any unwanted matter. Even our urine helps wash away unwanted microorganisms. The entire epithelium also produces antimicrobial proteins called defensins which help kill bacteria, fungi, and enveloped viruses. When this first line of defense made of skin and mucosal barriers is breached, the second line of defenses is brought into play.
SECOND LINE OF DEFENSE
Any pathogen that succeeds in penetrating an epithelium surface is immediately faced by the effector cells and complement proteins of innate immune response. This second line of defense consists of two parts. First step is recognition which is done by the complement proteins and second step is eating the pathogen which is done by effector cells. When I say “eat the pathogen” I mean it in a literal way. White blood cells that eat pathogens are called phagocytes.
A pathogen is recognized as a foreign object using cell receptors and proteins. There are these small soluble proteins floating in blood, lymph, and the area between cells called complement proteins. There are 30 different kinds of complement proteins in our body. The most common one called C3 is responsible for recognizing and binding to the pathogen. Once a C3 protein recognizes something as a foreign object, it gets activated and cleaved in two unequal pieces. The big piece(C3b) attaches to the pathogen and due to a positive feedback mechanism, many more proteins follow till the entire pathogen is coated in C3b proteins in a process known as opsonization. The small piece of the C3 complement protein(C3a) goes off to recruit effector cells to eat the protein-coated pathogen.
This protein coating makes it easier for effector cells like macrophages to eat the pathogen. The reason being that literally any change in a cell can only be caused by two methods — a direct instruction from nucleus or an effect caused by binding of a receptor on the cell. There are many many different kinds of receptors with all kinds of effects. The way a cell eats a pathogen is literally by gobbling it up(illustration below). In order to gobble, a change needs to happen in the shape of the cell. When the receptor on our effector cell attaches to the C3b receptor, it gets the signal to change its shape till it has completely enclosed the pathogen.
Effector cells that eat up their pathogen are called phagocytes. There are several different phagocytic white blood cells that help with our innate immunity like neutrophils, monocytes and their mature versions — macrophages. The phagocyte that usually helps first when the skin is breached is macrophage. A complement protein will bring the coated pathogen to a macrophage so it can eat it. Macrophages are immobile white blood cells that resides in tissues. Once a pathogen is eaten, it gets digested in compartments filled with enzymes inside these phagocytes. This system of skin, mucous, white blood cells and immune proteins take care of most of the pathogens.
The pathogens that remain gain strength and begin to divide and set up infection. The complement proteins and macrophages in these damages tissues send out soluble protein called cytokines for help. Cytokines recruit an army of neutrophils and other cells to the site of infection. This is done by dilating blood capillaries which leads to inflammation a common sign of infection. Inflammation enables molecules of immune system to be brought rapidly and in large numbers to infected tissue. Expansion of the local fluid volume also caused edema or swelling. Fever is also caused by cytokines and helps fight off infection as pathogens replicate slower at higher tempereatures. But the primary job of cytokines is to recruit neutrophils. Being the most abundant white blood cell, a healthy human has at any given time up to 50 billion neutrophils circulating the blood awaiting for a call from macrophage to enter an infected tissue. These are short-lived white blood cells that eat up a pathogen and either commit suicide or get eaten up by a macrophage right away. Pus is nothing but dead neutrophils.
Bacterial infections are frequently overcome by phagocytic powers but if the pathogen is a virus then the entire cell must be killed. Because viruses are not considered alive, it is not possible to kill them. So, we need specialized cells like NK cells and cytotoxic T cells that are trained to kill entire human cells. The difference between the two cells is that NK cells is part of the innate immunity and all T cells are part of adaptive immune response. So, NK cells control virus replication and the spread of infection while cytotoxic T cells are developing. These white blood cells instruct the entire infected cell to commit suicide which is known as apoptosis. During apoptosis, compartments inside cells filled with enzymes break open digesting the entire cellular contents. A virus infected cell needs to signal other cells about its status. This can be done by cytokines like when macrophages produced cytokines to recruit neutrophils. Since viuses cause intracellular infections by getting inside a cell, we need different kinds of cytokines that can function inside. These virus targeting cytokines are called interferons. Virtually all human cells are equipped to make interferons. Interferons activate cellular genes that inhibit viral replication and also increase receptors for NK cells on infected cells. Patients who lack NK cells suffer from recurrent viral infections, particularly from herpes simplex.
For majority of infections, this is all that you need. But every once in a while a pathogen will overwhelm our innate immune system. When this happens, a group of cells called dendritic cells carry a piece of that pathogen to one of the lymph nodes to show to the lymphocytes and ask for help from the adaptive immunity. The pathogen then faces the combined forces of innate and adaptive immunity. Because of the way this is setup, innate immunity is required to trigger a response from adaptive immunity. In people who lack innate immunity, an uncontrolled infection occurs as adaptive immunity cannot be deployed. This is important in making vaccinations as an effective vaccine will have to trigger the innate immune system first in order to get the adaptive immune system to form long lasting memory of the pathogen.
Innate immunity can also have negative consequences. One dangerous result of innate immunity is septic shock. One of the cytokines released by macrophages is called Tumour Necrosis Factor -α or TNF-α. These cytokines activate platelets and clotting of local blood vessels to prevent pathogens from leaking into the blood circulation. For local infections, this is a helpful thing. But if a pathogen breaches inside our blood circulation, TNF-α can unfortunately cause a widespread clotting leading to organ failure due to lack of blood flow and septic shock. Septic shock kills more than 100,000 people in U.S.A each year.
ADAPTIVE IMMUNITY
Vertebrates have evolved additional defenses of adaptive immunity, which are brought into play when innate immunity fails to stop an infection. The first step in an adaptive immune response is for the pathogen to be carried by dendritic cells from the infected site to the nearest lymph node. When innate immune system starts to get overwhelmed, dendritic cells gobble one pathogen and using enzymes break it down into its protein constituents. It also makes cell receptors called Major Histocompatability Complex(MHC) which carry the protein to the cell surface. These pieces of proteins are called antigens and these dendrite cells just became antigen presenting cells(APC). Now, these dendrites will flow to the closest lymph node and show their antigens to T cells and B cells.
T cells and B cells are lymphocytes that flow in your lymphatic system and routing via lymph nodes. A dendritic cell will present the antigen to all incoming T cells and B cells in the lymph node. Unlike cells of innate immunity that can attach to any foreign pathogen, T and B cells can only bind to one specific pathogen with their cell receptors. There are millions of different T and B cells in flowing through lymph nodes — each with an affinity for a specific pathogen. Antigen presenting dendritic cells are looking for the T and B cells whose receptors match perfectly with its MHC and antigen complex. Once there is a match, the selected lymphocytes remain in the lymph node to go through clonal expansion where they multiply exponentially to form an army. In general B cells make antibodies to coat pathogens so they can be gobbled up. And T cells tag virus infected human cells to commit suicide.
IMPORTANT RECEPTORS
Now, there are several very important receptors that we should be familiar with. First one I have already mentioned earlier called the Major Histocompatibility complex or MHC. MHC molecules bind antigens and are displayed on surfaces of infected cells. Microorganisms that infect humans tissues are of two broad kinds: extracellular pathogens, such as many bacteria, that live and replicate in spaces between human cells, and intracellular pathogens, such as viruses, that live and replicate inside human cells. Because of this topological difference, proteins or antigen from these pathogens is derived differently. So, there are two kinds of MHC — MHC class 1 for intracellular pathogens and MHC class II for extracellular pathogens. Because all human cells are susceptible to viral infections, MHC class I receptors are expressed by almost all cells in body (except RBC because they have no nucleus and virus needs that).
The next set of receptors are displayed on surfaces of T cells. There are three kinds of T cells: cytotoxic, helper, and regulatory T cells. Cytotoxic T cells kill infected cells and are thus recruited for viral infections. This means cytotoxic T cells attach to antigens on MHC 1 which displays proteins from intracellular pathogen like virus. They attach to MHC receptor via CD8 receptor that’s displayed on a their cell surface. Helper T cells activate B cells to turn into plasma cells. Plasma cells produce antibodies which are used against pathogens themselves. For this reason, helper T cells bind to antigen on MHC II receptors which display proteins from extracellular pathogens. They bind to MHC via CD4 receptors. Regulatory T cells manage everything. All T cells have two kinds of cell surface receptors. All T cells in circulation express either CD4 or CD8 cells but not both.
The sole purpose of B cell is to make antibodies. There are several different kinds of antibodies: IgA, IgD, IgM, IgE, IgG. Antibodies are just soluble forms of B cell receptors. These B cells receptors when attached to the cell surface are called immunoglobulins. Once a B cell receptor recognizes the antigen presented by dendritic cells, it takes that antigen and displays it in its surface via a MHC receptor. The B cell then shows its MHC antigen complex to a helper T cell that has already been activated by the dendritic cell. If the B cell MHC binds to helper T cell’s CD 4 receptor then the B cell will be activated to produce millions of antibodies. These antibodies are replica of the B cell receptor that has an affinity for that specific pathogen. The antibodies then coat the pathogen just like our complement proteins in innate response did. The antibody-pathogen complex then gets eaten up by a macrophage.
SELF VS NON SELF
This double check system of activating B cell by an activated helper T cell is to ensure our immune cells don’t attack anything self. Innate immunity is based on self vs non self so it’s always accurate. But our adaptive immunity starts replicating once it finds a match for a protein sequence from the pathogen. If this protein sequence happens to be part of a human cell then our body just started building an army of antibodies to target our own self. This is the mechanism behind autoimmune conditions. So, making sure T cells and B cells only bind to a pathogen protein is extremely important. To ensure this, T cells go through training and selection process known as clonal selection before being released in circulation. Immature T cells are subject to two rounds of selection process. Positive clonal selection ensures T cells are able to bind to all MCH receptors on human cells. One’s that bind weakly are tagged for self destruction. One’s that survive are subject to negative clonal selection where T cells that bind strongly to self MHC proteins are tagged for self destruction. This selection process is so stringent that only 20% of all T cells make it circulation and rest get tagged to commit suicide. Similarly, clone of B cells with immunoglobulin receptors that bind strongly to the self constituents like bone marrow tissue are negatively selected and get tagged for self destruction.
UNWANTED EFFECTS OF ADAPTIVE IMMUNITY CAUSE AUTOIMMUNE DISEASE, TRANSPLANT REJECTION AND ALLERGY
Despite the stringent processes ensuring accuracy of our adaptive system, it can still fail. Failures in this system is what causes autoimmune diseases, transplant rejections, and allergic symptoms. For example, insulin secretive cells of pancreas are the target of autoimmune response in Type I Diabetes. Other autoimmune diseases are rheumatoid arthritis, multiple sclerosis, myasthenia gravis, and Grave’s disease. CD4 T cells are attacked during HIV and CD4 count is a marker of progression of the disease. When searching for a right donor for organ transplants, it is important to find donors whose MHC receptors are as similar as possible to the patient. Allergic responses are triggered by IgE antibodies.
MEMORY CELLS
Once an infection has been successfully terminated, regulatory mechanisms come into play to stop the immune response, reduce inflammation and allow damaged tissues to be repaired. Effector T cells, whose cytokines often contribute to inflammation, are signaled to die off, but plasma cells are allows to persist, and pathogen-specific antibodies can be maintained in the circulation for years. These are memory cells and help deliver a stronger and faster response if the same pathogen was to infect us again.
SUMMARY
Our body is full of pathogens are live symbiotically in us and even help up digest our food, make vitamins, and provide protection against more dangerous pathogens. In order to cause a chronic infection, a pathogen has to survive our three lines of defense. The first two lines of defense are collectively known as the innate immune. Our first line includes mechanical barrier of our skin, and chemical barriers in our mucous and saliva. If a pathogen penetrates this and finds its way in our tissues, our second line of defense kicks in. This includes a lot of different players from white blood cells like macrophages, neutrophils, and dendritic cells to soluble proteins of complement system that coat the entire pathogen so it can be eaten up. Sometimes extra help is recruited by cytokines released by these white blood cells. These cytokines cause blood capillaries to dilate around the site of infection to allow more immune cells to enter. This leads to inflammation which is a sign of our innate immunity at work. Sometimes cytokines are released to cause clotting in infected area to prevent pathogen from spreading. But in systemic infections a widespread clotting can occur leading to septic shock. Our innate immune system is usually enough for majority of infections. We also share this immune mechanism with plants, microbes, and other animals.
If our pathogen is replicating faster than our innate immune system can handle, then the dendritic cells will trigger our adaptive immunity which is a higher level of immunity specific to vertebrates. Adaptive immunity includes the highly specific lymphocytes called T cells and B cells. There are millions of different T cells and B cells circulating our body each with a receptor that will recognize one specific pathogen. Once there is a match between a specific T cell or B cell and the pathogen presented by dendritic cell, those specific lymphocytes will stop circulating and remain in the lymph node to build an army of clones.
There are three types of T cells that get activated depending on the type of infection. Intracellular infections by viruses that require entire human cell to be killed trigger cytotoxic T cells. These cytotoxic cells then tag virus infected cells to commit suicide. That is what cytotoxic mean — toxic to cells. Extracellular infections that need specificity for the pathogen itself trigger helper T cells. These helper T cells in return activate B cells to produce antibodies specific to that pathogen. These antibodies then coat the surfaces of the pathogens to be eaten up. Regulatory T cells regulate the positive and negative selection of immune cells.
Once an infection is overcome by our adaptive immune system, antibodies persist in circulation for years providing immunity from a secondary infection. This is the mechanism that vaccinations employ. But since adaptive immunity is only deployed if triggered by our innate immune system, an effective vaccination will first have to trigger our innate immune system.
Failure in differentiating between self (human) and non self (pathogen) protein sequences lead to autoimmune diseases, transplant rejections, and allergy responses.
Hope you found this post informative as well as interesting :)
