The immune system, defined in the simplest terms, is the system in our bodies that defends us against infectious disease. However, our immune systems are far more complex. Not only does it defend us against pathogens, it is also responsible for protecting us against cancer, initiating allergy symptoms, and determining the state of our general health. The Immune system itself is like a miniature world in our bodies, and it is populated with various immune cells that are supported by the cells making up the tissues and organs of the body. Each type of immune cell has its own specialized function. Some are good at fighting infectious bodies “hand to hand” like soldiers, while others are specialized at scouting, intelligence and recruiting other cell types during battle. During an immune response, the cells of the surrounding tissues also play their roles and, much like civilians in war, they fight, warn others, or die as a result of the battles. I will do my best to introduce you to this exciting world in simple terms. Sections: Self and Non-self Generation of Immune Cells Where are Immune Cells Located? Induction of an Immune Response Innate Immune Responses Adaptive Immune Responses Innate and Adaptive Interplay Self and Non-self To put it quite simply, the Immune System is designed to protect you. Immunologist refer to the body often as “self”. This includes all the products of the body ranging from your tissues to the smallest secreted molecules. Life forms and molecules that interact with your body are considered “non-self”. The non-self life forms are parasites, bacteria and viruses as well as friendly intestinal bacteria. Common non-self molecules that we often encounter are food, pollen and chemical substances from our environments (like drugs, cleaning products and hygienic products)1. The Generation of Immune Cells Cells of the immune system are born from hematopoietic stem cells found deep in the bone marrow. Hematopoietic stem cells are immortal, capable of generating daughter cells, called progenitors that will later give rise to different type of immune cells. There are two main types of progenitors created, the myeloid progenitors and the lymphoid progenitors2. Cells of Myeloid Progenitors Monocytes/macrophages, Dendritic cells Neutrophils Eosinophils Basophils Mast cells Cells of the Lymphoid Progenitors NK cells T cells B cells Dendritic cells3 Where Are the Immune Cells Located? For immunologists, the mammalian body is divided into three main regions: the primary lymphoid areas, the secondary lymphoid areas and the periphery. Primary Lymphoid Areas The primary lymphoid areas include the bone marrow and the thymus. The bone marrow, as we mentioned, is the site of immune cell generation2. The thymus, on the other hand, is the location of T cell development4. Lymphoid progenitor populations travel there from the bone marrow and produce a population of immature thymocytes. It is these thymocytes that give rise to the varied T cell populations. Secondary Lymphoid Areas The secondary lymphoid areas include the adenoids, tonsils, spleen, lymph nodes and lymphoid follicles found in the gastrointestinal system and the mucosa (areas adjacent to a mucus membrane). These areas house lymphocytes and support the development of an adaptive immune responses5-7. Periphery The periphery includes all regions that are not included in the primary and secondary lymphoid areas. This includes areas like the skin, brain, joints, muscles and gastrointestinal/mucosal areas surrounding lymphoid follicles. The Induction of an Immune Response In order for an immune response to be initiated, there must be some kind of danger. This is a fairly simple idea, but it leads to the question: How is danger defined by the immune system? This question is actually one of the most exciting topics of immunology today. Simply put, danger is sensed by the immune system through two main avenues: the recognition of a pathogen-associated molecular pattern (PAMP)8 or through the release of cell molecules associated with trauma which are called danger-associated molecular patterns (DAMPs) or alarmins9. Examples of PAMPs would be cell wall lipoproteins of bacteria and an example of DAMPs would be ATP (adenosine triphosphate), a nucleotide used as an energy source in cells10. PAMPs and DAMPs are recognized by the cells of the immune system and non-immune cells, through receptors located at the cell surface or internally8,9. PAMPs are also recognized by several non-cellular systems as well11,12. This recognition initiates the very first processes of an immune response called the innate immune response. Innate Immune Responses Immune cells, non-immune cells and non-cellular systems all participate in initiating an innate immune response. Why is it called “innate”? It’s innate because it depends on intrinsic systems that are built into your body to recognize danger and there is no learning or adaptation involved. Receptors of the Innate Immune Response In order to detect PAMPs or DAMPs, cells need tools to recognize them. These tools are protein receptors that can be found on the cell surface as well as internally. In general, they are called pattern recognition receptors or PRRs. These receptors come in families consisting of multiple members. Receptors that recognize PAMPs include the Toll-like receptors (TLRs), the C-type lectin receptors (CLRs), the NOD-like receptors (NLRs), RIG-I-like receptors (RLRs)8 and invariant T cell receptors13,14. DAMP receptors are not so clear-cut. TLRs have been implicated15 as well as the receptor for advanced glycation endproducts (RAGE)15. Also the purinergic receptors that recognize ATP would also fall into this category10. Toll-like Receptors These receptors are found on most cells of the body. They recognize a variety patterns associated with a number of pathogens including virus-associated nucleic acids; bacterial-associated cell wall components, protein, ribosomal RNA and DNA; and protozoan-associated proteins8. The majority is found extracellularly, but a number are also found intracellularly. When stimulated they activate the transcription factor NFκB, which is essential for activating a cell’s immune functions and set off a signal cascade via MAP kinase (a phosphorylating enzyme)8. C-type Lectin Receptors These receptors are specialized in recognizing carbohydrate structures, such as the sugar mannose, which is a common component of fungal cell walls16. Thus, these receptors are found on the cell surface. Though much of the literature involves their expression on immune cells, reports of CLR variants on non-immune cells can also be found17. On the phagocytic cells, it is known that they can participate in endocytosis, the engulfment of particles or pathogens and respiratory burst16. Some also appear to initiate signal cascades similar to TLRs leading to NFκB and MAP kinase activation, but it also appears that they can work in concert with TLRs, enhancing or inhibiting their function16. NOD-like Receptors These receptors are found in the cytoplasm of cells. Traces of their expression is found in most organs of the body18 and it is probably safe to say that most immune cells express at least some members of the NLR family. These receptors are designed to detect intracellular bacteria and, possibly, endogenous stress molecules and allow the cell to produce one of the most potent inflammatory mediators, Interleukin (IL)-1β19. RIG-I-like Receptors Like NLRs, RLRs are also found in the cytoplasm of a cell. Instead of detecting bacterial products, these receptors help detect viral infection20. They do this by binding to RNA produced during viral replication. Working together with nucleic-acid detecting TLRs, they lead to NFκB, MAP kinase activation and activation of Interferon regulatory factor (IRF) transcription factors20. The IRF transcription factors are necessary to produce cytokines specialized for the control of viral infections. Cytokines are small, secreted proteins used as messengers between cells, which alert surrounding immune cells about danger. Non-immune Cells in Innate Immunity Areas of the body that come in contact with the outside world (skin, gastrointestinal and mucosal areas) are covered with an epithelial layer. Epithelial layers are composed mainly of cells called epithelial cells. These cells form an anatomical barrier and they have their own immune functions. When exposed to DAMPs or PAMPs, epithelial cells produce inflammatory cytokines 21. The cells of the epithelial layer are often the main cells involved in the first detection of pathogens and/or danger. The majority of cells in the body also have this capacity. Other cell types like muscle cells, adipocytes and fibroblasts are all outfitted with receptors to detect PAMPs and DAMPs8,22. Just like citizens of a city, they will alert the authorities if there are any problems.
Immune Cells of the Innate Response Under epithelial layers are resident macrophages, neutrophils, dendritic cells, NK cells, mast cells and a number of T cell-related cells. Macrophages The name macrophage is derived from Greek, meaning “large eaters”. Their main function is to phagocytize (engulf) pathogens and particles. It does this by wrapping its plasma membrane around particles until they are enveloped and pinched off to form an endosome inside the cell. Once inside the cell, the endosome merges with a lysosome that contains enzymes and acids that can digest the contents. Macrophages also have the ability to generate a “respiratory burst”, which is a release of oxygen radicals that damage surrounding pathogens and cells. They also can alert and attract other immune cells through inflammatory cytokine release23. Neutrophils Neutrophils are the main foot soldiers of the innate immune response and are certainly the most abundant. They also have a wide arsenal of tools to deal with invaders. Like macrophages, neutrophils can phagocytize particles, release a respiratory burst and produce inflammatory cytokines. Unlike macrophages, neutrophils have the internal caches of anti-microbial substances called granules24. Dendritic Cells Dendritic cells are also phagocytic cells, but they have the special ability of initiating an adaptive immune response (will be discussed later). Unlike neutrophils and macrophages, Dendritic cells or DCs are not simple foot soldiers. Instead, they function more as spies and provide intelligence about invaders to T cells through a phenomenon called “antigen presentation” and through cytokine production25. NK Cells The NK stands for Natural Killer and the name implies their function. These cells, however, do not kill pathogens directly. Instead, these cells have the ability to recognize when other cells are harboring internal pathogens using special receptors and then kill them. Situations where this might occur is during viral and mycobacterial infections. These pathogens easily reside in host cells, finding ways to block lysosome fusion and their own destruction26. Mast Cells Mast cells are the cells that are responsible for the classic signs of inflammation, which include redness, swelling and heat. Though well known for their association with allergy, they also can detect PAMPs and DAMPs through receptors and become immunologically active. Mast cells exert their functions mainly through cytokine and granule release. Unlike neutrophils, which release antimicrobial substances, mast cells release histamine and heparin. Histamine is well known for its vasodilator function and ability to allow fluid to leak between cells, causing redness and swelling. It also causes inflammatory itching by triggering neurons (unmyelinated C-fibers) responsible for the itch feeling. Heparin prevents blood coagulation27. T cell-like Cells Most T cells are part of the adaptive immune response as they have adaptive T cell receptors (receptors that learn to recognize pathogens). NK T cells and γδ T cells, however, use invariant T cell receptors (receptors that do not rearrange) or semi-invariant T cell receptors and participate in the innate immune response. NK T cells are similar to the NK cells mentioned above. Not so much in function, but more in how they look. These cells share many of the same surface protein markers. NK T cells, however, do not kill compromised cells. Instead, they are quick cytokine producers. In doing so, they quickly notify all surrounding cells that there is problem when they recognize PAMPs presented to them via dendritic cells28. The γδ T cells are important for innate immune reactions and the adaptive immune response as they have invariant and variant T cell receptors. Their precise function remains unclear, but they can secrete cytokines and, like the NK T cells above, participate in alerting and strengthening local immune responses29. Non-cellular Systems of the Innate Immune Response Besides cells, there are also defenses in your body that are ready to react to pathogens as soon as they are encountered, much like booby traps. These systems rely on small proteins that are found within the bodily fluids. Complement System The liver synthesizes the proteins of the complement system and they work in concert to aid in phagocytosis, bacteria lysing and immune cell attraction. One can visualize it as a self-assembling machine that starts to assemble as soon as the first proteins are bound and in place. The complement “machine” is known to be initiated by three different pathways: the classical pathway, the alternative pathway and the lectin pathway. The classical pathway is triggered when antibodies are bound to a pathogen. The alternative pathway is triggered when the victim is unable to block the cascade (normal cells can, while pathogens cannot). The lectin pathway uses free lectin proteins (lectins are proteins that bind sugars) to bind sugars associated with bacterial cell walls)11. Acute Phase Proteins These proteins are also produced by the liver and especially during inflammation when pro-inflammatory cytokines are produced. Many are designed to coat pathogens and have chemotactic properties (have the ability to attract cells). Some inhibit microbial growth by sequestering iron from the environment. The lectins from the lectin pathway of complement activation are considered acute phase proteins30. Anti-microbial Peptides Often called “defensins”, these peptides function as natural antibiotics and our produced by cells that guard the external surfaces and internal surfaces such as the skin and the gastrointestinal system. In the skin, the main sources are keratinocytes, mast cells, neutrophils, sebocytes and eccine epithelial cells. In the intestines, one of the main producers are the Paneth cells of intestinal crypts31. Adaptive Immune Responses The adaptive immune response is what gives individuals long-term immunity to a pathogen after vaccination. Instead of relying on germ-line encoded receptors for the recognition of pathogens like the innate immune system, it depends on the development of receptors that can recognize any unique molecular characteristic of pathogens32. The molecules that can be recognized are called antigens. The classical definition of an antigen is any molecule that can provoke the development of antibodies. A better, and less-confusing, definition is a molecule that can be recognized by the adaptive immune system. The molecules are often protein peptides (small pieces of protein). But, they can also be sugars, lipids and other small molecules under the right circumstances. The main players of the adaptive immune response are the T cells (both T helper cells and cytotoxic T cells) and the B cells. The Bridge Between Innate and the Adaptive Responses: Dendritic Cells During the innate immune response, the first steps are taken to initiate an adaptive immune response. The main cells responsible for this step are the DCs that we described earlier25. As we mentioned before, DCs are a phagocytic cell type. This means that they have the ability to engulf pathogens/particles in endosomes and later fuse these vesicles to lysosomes for destruction. The process, however, does not stop here. Instead of just disposing of the pathogen/particle waste, the DC, instead, uses these parts to educate T helper cells about the pathogens. It does this by traveling from the location where it picked up its parcel to the local lymph node, where it finds T helper cells. Once there, it presents the pathogen-associated peptides on its surface using molecules called MHC class II molecules and provides information to T cells about how it should respond using surface molecules called co-stimulatory molecules and cytokines. Educating T helper cells is the first step towards initiating an adaptive immune response. T helper Cells and Their Education T helper cells or Th cells are crucial cells in the adaptive immune response and they are characterized by a surface protein called, CD4. They hold the key to initiating the functions of cytotoxic T cells33 and B cells34. Furthermore, they can also increase the efficacy of macrophages23. Th cells interact with the MHC class II/peptide complexes presented by antigen presenting cells through its receptor, called the T cell receptor (TCR). If a T cell has never before seen antigen, it is called a naïve T cell. In this situation, the T cell will need instruction from a professional antigen presenting cells, usually a DC, about how to perform its function. DCs do this through cell surface proteins call co-stimulatory molecules and through cytokine expression. This process is consists of three main signals. The first signal is the antigen recognition; the second signal is co-stimulation and the third cytokine exposure. This whole process is referred to as “priming” of the naïve T cell. Once primed, the T cells begin to divide; a process that is referred to as expansion or proliferation35. The most important set of co-stimulatory molecules is CD80 or CD86 on the DC and CD28 on the T cells. This second signal is necessary to tell the Th cell that there is a problem. If signal one is given without this second signal, the T cell will assume that the antigen is actually harmless and become non-responsive in a process called “anergy”36. Only a DC that has encountered a PAMP or another danger signal will express CD80 or CD86 on its surface reassuring the Th cell that there is, indeed, a problem. Signal three is the secretion of cytokines of the DC. There are several cytokines important for Th cell eduction. They most important ones are IL-4, IL-12, IL-6, TGFβ and IL-10. Th cells will differentiate into different types of Th cells depending on which cytokines prevail. The main types of Th cells are T helper 1 (Th1) cells, T helper 2 (Th2) cells, T helper 17 (Th17) cells, and induced regulatory T cells (iTreg)35. Th Cell Subtypes Each Th cell subtype has its own unique set of skills. One could almost see differentiation as an occupation. Just like an athlete will choose to develop her body and a scientist will choose to develop her mind. In humans, these choices are reflected at the level of gene transcription and protein expression. The athlete will stimulate muscle growth and the scientist develops the cerebral cortex of the brain. It’s the same for Th cell differentiation. The four main subtypes of Th cells are listed. There are, however, rare forms that have been observed that are not listed and Th cells, much like humans, can fall into gray areas between the stereotypes. T helper 1 Cells The Th1 path is chosen when T cells are exposed to IL-12 during priming. Th1 cells are characterized by the production of the cytokine, interferon-γ (IFNγ) and the expression of the master transcription factor, T-bet. Th1 cells are experts at gearing the immune response towards to the control of internal pathogens like viruses and mycobacteria, which reside internally in macrophages. They perform this function by initiating cytotoxic T cell responses, helping macrophages to become more effective, by helping B cells to produce certain types of antibodies. These functions are executed, in part, through IFNγ exposure, however, some require cell-cell contact and will be explained in more detail later37. T helper 2 Cells Th2 cells are created during exposure to high amounts of IL-4. This leads to the expression of the Th2-associated master transcription factor, GATA3. Th2 cells are also characterized by the production of IL-4 (indeed, the same cytokine needed to create them). These cells are designed to skew the immune system towards a humoral immune response (antibody response) that can deal with parasite infection. Unfortunately, Th2 responses are also the ones associated with allergy development as well. Th2 cells do their work by effectively helping B cells and encouraging specific forms of antibodies. This is done through a combination of IL-4 exposure and cell-cell interactions37. T helper 17 Cells The Th17 subtype is the most recently described of the Th subtypes. It is most effective at controlling extracellular bacterial and fungi responses, like those found during intestinal food poisoning or during a yeast infection. Its creation is dictated by the cytokines IL-6 and TGFβ and this leads to the expression of the master transcription factor, RORγt. Th17 cells produce the cytokine IL-17. IL-17 production is one of the main facilitators of their function and it encourages surrounding cells to increase neutrophil migration. Neutrophils are excellent phagocytic cells with many bacterial killing tools38. Induced Regulatory T cells To those just learning about the immune system, the existence of the following Th subtype may be confusing. iTreg are designed to counter the functions of other immune cells. Why? The reason is that immune responses are highly damaging to surrounding tissues and, without them, immune responses would spiral out of control. That said; these cells are induced by DCs when they are exposed to high amounts of IL-10 or TGFβ. This causes the expression of the master transcription factor, Foxp3. In turn, iTreg produce IL-10 or TGFβ. IL-10 and TGFβ are what is called “anti-inflammatory” cytokines. They have the ability to limit the functions of immune cells. IL-10, for instance, lowers Th1 and Th17 responses and reduces macrophage efficacy. TGFβ encourages apoptosis (induced death of cells), prevents cell division and lowers phagocytosis39. Cytotoxic T cell Responses Th cells are not the only kind of T cell. Cytotoxic T cells (CTLs), characterized by the surface marker CD8, are not to be missed and are essential for the elimination of viral infections. The function of a CTL is found in its name. “Cyto” refers to cell and “toxic” means just how it sounds. These cells are “cell toxic” and kill other cells. In many ways, they are similar to the NK cells and NK T cells of the innate immune system. However, they do not use invariant receptors to recognize problems in other cells, but instead use an adaptive system. CTLs, like Th cells, have a TCR. This means that they can detect unique peptides presented to them by other cells. In the case of Th cells, these are MHC class II molecules presented via DCs. In the case of CTLs, they are MHC class I molecules. During an infection, as we earlier mentioned, DCs will travel to the lymph node and present samples of the intruder to the T cells. This is also happens for CTLs. However, despite the presence of all the priming signals, priming will be suboptimal. CTLs need an additional signal, jokingly called “the license to kill”. This signal is given by a Th1 cell through the production of a cytokine called IL-2, which stimulates CTL expansion; and through an interaction between the Th1 cell and the DC via CD40 on the DC and CD40 ligand on the Th1 cell, which makes the DC more effective at priming CTLs33. Once a CTL is primed and active, it has the ability to kill. As you can see, CTL activity is highly controlled to ensure that they react only to pathogen-associated peptides. The reason is that MHC class I can be expressed by every cell type in the body. MHC class I on a cell is like a sign advertising the health of the cell. The cell is constantly displaying samples of the proteins it’s making. If an active CTL recognizes one of these samples as being of viral origin, it kills that cell; eliminating a viral host. Adaptive Humoral Immune Responses The word “humor” means fluid in Latin and, therefore, humoral immune responses relate to non-cellular systems found in the bodily fluids. We’ve already discussed non-cellular components of the innate immunity, however, in immunology most people are not referring to these non-cellular systems when they use the term “humoral immune response”. Instead, they are referring to the immune response mediated by antibodies and this is part of the adaptive immune response. The cell behind antibody responses is the B cell. Naïve B cells of the immune system produce rudimentary antibodies (see below) until other cells activate them. B cells, unlike the T cells, are not required to interact with DCs; instead B cells reside in lymphoid tissues and fish for antigens that they recognize using their B cell receptors or BCR. The BCR looks like a surface bound antibody and once it binds a molecule, the B cell engulfs it and much like the phagocytes, digests it. Just like the DC, the B cell will then present pieces of the antigen to Th cells using MHC class II molecules. Primed and activated Th cells, which recognize the presented peptides, are then able to “help” the B cell through a CD40-CD40 ligand interaction. The Th cell also provides cytokine signals to tell the B cell which kinds of antibodies it should make34. This process is reminiscent of the priming process of Th cells. Signal one is the MHC class II/peptide and TCR interaction between the B cell and the T cell. Signal two is the costimulatory help provided by the T cell in the form of CD40-CD40 ligand interactions. And, signal three is the cytokine message provided by the T cell. Helped B cells will then further differentiates into plasma cells, which can produce massive quantities of antibodies. Antibodies Antibodies, by themselves, cause very little harm. However, their strength lies in their ability to tag a molecule as harmful and block molecular functions. Antibodies enhance the functions of the innate immune system. They can bind to pathogens and particles to initiate the complement system and induce phagocytosis. They can also block/neutralize molecular interactions. Examples of this function would be an antibody that blocks the toxic effects of diphtheria toxin or antibodies the block viral binding sites to cells. Antibodies also interact directly with cells and can change their function by binding to specific antibody receptors found on the surfaces of immune cells40. An Antibody is a small protein structure produced by B cells. It is also called an immunoglobulin (Ig). It looks like a “Y” and it is formed from four separate proteins. Each tip of the “Y” recognizes and sticks to the antigen, meaning that each antibody can bind two similar antigens. A single arm is called a Fab (Fragment, antigen binding) fragment. The base of the “Y” is called the Fc (Fragment constant) region and, while the Fab fragments dictate the specificity of the antigen binding, the Fc region dictates the type of antibody or isotype. The antibody isotype is dictated by the prevalent cytokines in the environment as well as additional danger signals that the B cell experienced while being helped by the Th cell41. Rudimentary Antibodies: IgM and IgD The first types of antibodies that a B cell can produce are IgM and IgD. The “M” and “D” refers to different classes of the Fc region. IgM is found as a pentamer, with five individual IgM antibodies bound by their Fc regions in the center forming a star. They are effective at complement activation. IgD is found as a monomer and its function is undefined. However, it has the ability to bind mast cells via an Fcδ receptor (δ for D) and induce anti-microbial peptide secretion. IgG IgG antibodies are found as monomers and they are very potent at stimulating immune responses. They are capable of neutralization, inducing phagocytosis in macrophages and neutrophils via Fcγ receptors (γ for G), activation of complement, and also the activation of NK cells (also via Fcγ receptors). IgE IgE antibodies are monomers. They are known to cause mast cell degranulation via binding of Fcε receptors (ε for E). They are induced during parasite infection and, unfortunately, also during allergy. IgA IgA is found as a dimer of two antibodies attached via their Fc regions. It is involved with mucosal defense: found in gastrointestinal system, the respiratory systems. They are particularly effective at neutralization of microbes and toxins. How the Adaptive Response Strengthens the Innate Response Once the adaptive immune system has formed a response, the body has a long-term record of the invading pathogen in the form of long-lived plasma cells, memory T cells (not covered here) and antibodies. This is why vaccination is so important. It allows your body to create an adaptive immune response against an invader without having to truly become infected42. When a body encounters a pathogen for the second time, it’s a completely different situation than the first encounter. During a second infection, T cells drawn to the inflammation site will have knowledge to help macrophages, recruit more neutrophils, and kill infected cells. Antibodies will be now present to assist complement activation, the phagocytosis of particles, and even kill microbes. The response will be quicker and more effective. Though separating the two types of responses: innate and adaptive, helps with learning; it can also become an obstacle to seeing the immune response as a complex, dynamic system. It is important when looking at an immunological problem to consider the host’s previous history as it has so much influence on the immune response. Source
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