BioLegend Basic Immunology
Immunology is the study of the mechanisms that organisms use to defend against pathogens and other unwanted matter, including cancer, toxins, and other materials. The immune system is a complex network of cells and tissue that work together to preserve the overall health of the organism. This page provides some basics on immunologic concepts.

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Cytokines With all these immune cells monitoring your body, there has to be a line of communication. Cytokines (derived from the Greek cyto meaning cell and kinos meaning movement) were simultaneously discovered by Barry Bloom and John David. They placed macrophages in a capillary tube. Upon addition of the media of stimulated lymphocytes, the macrophages failed to migrate out of the tube (this was later attributed to Macrophage Migration Inhibitory Factor). Cytokines can be classified on a number of things like structure and function. Cytokines are soluble factors that can help activate or suppress cells, induce cell movement (chemokines), regulate hematopoiesis, and more. Cells will express receptors for cytokines under certain conditions. These receptors can either be constitutively expressed or upregulated. Cytokines can affect the cell that secreted it (autocrine action), a nearby cell (paracrine action), or a distant cell (endocrine action). Cytokine-receptor interaction causes a number of downstream actions, leading to an immunological response. In regards to chemokines, cells often follow a gradient. This leads them to the source of the release to investigate the area. In some cases, cells follow chemokines as a regular part of their development. Autocrine, Paracrine, Action, Cytokine, Circulation, Endocrine Action
Antigen Presentation An antigen is defined as anything that can be bound by an antibody or a T cell receptor. Antigens can be derived from either endogenous (self) or exogenous (foreign pathogens) sources and are often presented by the Major Histocompatability Complex (MHC). MHC I is expressed on every nucleated cell and typically displays an endogenous antigen. This complex often serves as a flag to ensure a cell is OK.  In some cases, viral infection can decrease MHC I expression, alerting Natural Killer cells. In some cases when viruses take over the host cell's ?machinery?, viral proteins and antigens can be made and displayed on MHC I. This also alerts the body of the infected cell. MHC I can also express exogenous antigen through a special mechanism called cross-presentation. While MHC I is expressed by a majority of cells, only a select few get to express MHC II.  As such, these cells are called ?Professional Antigen Presenting Cells?.  They consist of B cells, Macrophages, and Dendritic cells. MHC II is typically involved with exogenous antigen, acquired externally through processes like phagocytosis or endocytosis. Antigen presentation requires not just the acquisition of the material to be presented, but also its digestion and breakdown. This is because the MHC molecules require peptides to be of a certain length to be bound in their groove. Virus, T Cell, T Cell Receptor, Antigen, MHC Complex, Antigen Presenting Cell
Cardinal Signs of Inflammation. Inflammation Inflammation (derived from the Latin inflammo, meaning ?I set alight, I ignite?) is a complex biological response to harmful stimuli like pathogens or injury. Inflammation was diagnosed as early as 2,000 years ago by the Romans when they noted patients with swelling, redness, heat, pain, and immobility (loss of function). Fluids can leak from the blood vessels and collect in tissues (edema). Leukocytes will also begin to exit from blood vessels to investigate the local tissue in a process known as extravasation.
The Extravasation Process. Rolling Neutrophil, CXCR1, CXCR2, E-Selectin, LFA-1, KCAM-1, Blood Vessel, Tissue, Endothellium, Pro-inflamatory Cytokines, IFN-gamma, CXCL8, TNF-alpha, IL-1, Chemokine Gradient, Epithelium. Extravasation occurs when an injury or infection causes damage and the release of chemotactic factors (like chemokines) and vasodilating factors that allow capillary permeability. Cells will begin to roll along the endothelial cells until they latch on via integrins and adhesion molecules. In general, these attachments are loose and the cells can be swept away by the circulating blood. Upon inflammation, additional signals are present, which tighten the bond between the leukocyte and endothelial cell. The leukocyte can then squeeze through the endothelium, find the target, and release proinflammatory molecules. This process will attract additional cells to hopefully clear the pathogen or address the injury.  Th1 and Th17 cells, in particular, are known to promote inflammatory responses. It should be noted that these responses must be controlled once the threat has passed or the inflammation can become chronic and potentially problematic.
Hematopoiesis/Stem Cells All great things have to start somewhere. All of the red and white blood cells in circulation are derived from hematopoietic stem cells (HSCs), which originate from the bone marrow. These cells have two distinctive features: the ability to self-renew (at least some of the daughter cells remain HSCs) and the ability to differentiate into a new cell type. Early on, HSCs can become a particular progenitor. Lymphoid progenitors can become T, NK, and B cells. Myeloid progenitors can become many of the other cell types, including red blood cells, granulocytes, monocytes, mast cells, dendritic cells,  and platelet generating cells. The main goal of hematopoiesis is to balance out the number of cells that are lost due to apoptosis or cell death. The average human produces 3.7 x 1011 new cells daily. Granulocytes, Monocytes, Macrophages, Myeloid Dendritic Cells, Myeloid Progenitor, HSC, Lymphoid Progenitor, Lymphoid Dendritic Cells, NK cells, B and T cells, Megakaryocyte Erythroid Progenitor, Megakaryoblast, Thrombocytes, Erythrocytes, Proerythroblast, Granulocyte Monocyte Progenitor, Myeloblast.
Innate Immunity The immune system can essentially be divided into two branches: the innate and the adaptive. An innate response is typically your first line of defense. However, an innate response won't generate a long-lasting immunity like an adaptive response would. An innate immune response is also very general, whereas an adaptive response may target a specific antigen on a pathogen. This section will focus on looking at the different components of the innate immune system. Anatomical Barriers Your first line of innate defense can be called anatomical barriers. One of the more obvious barriers is your skin. It constantly sweats and sheds its outer epithelial layers (desquamation). In addition, your skin is impermeable to most infections agents and will secrete anti-microbial peptides. The low pH of your stomach acid and the digestive enzymes of your body will also eliminate many potential pathogens. Cilia in your lungs and airways will move mucus (which may have trapped antigens) outward and out of your body. Even the flushing of your tears and saliva help to prevent infection of the eyes and mouth, respectively. Adaptive Response, Intensity, Innate Response, Time, Initial Infection.
Inflammation If pathogens can breach the anatomical barriers, a process known as inflammation can be initiated to combat the intruder. Inflammation recruits phagocytes and induces the release of proinflammatory cytokines. It is important that this process is controlled and stopped once the threat is removed as chronic inflammation can do excessive damage. Pattern Recognition Receptors A car has certain components that are absolutely required for it to run properly. While you can change the tints or the hubcaps, you cannot remove the engine or wheels and have it function. Similarly, microbes have vital components that are evolutionarily conserved and are not found in the host body. As such, the body has learned to recognize these patterns as foreign via receptors (i.e., Toll-like, C-type lectin, and NOD-like receptors) on innate immune cells. Once the receptor's ligand is detected, phagocytosis, complement activation, and inflammation can ensue. Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. TLR4 recognizes it and can initiate a signal cascade so that the cell can mount an immune response. LPS,LBP,CD14,TLR4,TAK1,TRAF6,RIP,IRAK1,IRAK4,MyD88,TRAP,TRAM,TRIF,TBK1,IRF3,AP-1,NF,kappaB,IkBa,Akt,Pl3k, MEK1/2,MKK4/7,MKK3/6,ERK1/2,JNK,p38
Innate Immune Cells Neutrophils are first responders for inflammation and are present in high numbers in the blood. They release granules containing antimicrobial peptides upon contact with the pathogen. They also help to eliminate pathogens through phagocytosis and the release of reactive oxygen and nitrogen species (ROS, RNS). Eosinophils and Basophils, which like neutrophils are granulocytes, can release histamine upon contact with parasites. They also play a role in the innate response in allergies. NK cells help to destroy cells infected with viruses. Virus infection often changes marker expression on the host cell. The NK cell sees this and targets it for destruction. They also produce inflammatory cytokines like TNF-alpha and IFN-gamma. gamma delta T cells straddle the line between adaptive and innate immunity. They possess adaptive traits like a T cell receptor generated by recombination (utilizing gamma and delta chains as opposed to the more common alpha and beta chains) and the ability to develop a memory phenotype. But, they also have innate characteristics like the ability to recognize pathogen associated molecular patterns and perform phagocytosis. Macrophages and Dendritic cells are two powerhouse phagocytes. Both cell types express heavy amounts of pattern recognition receptors like TLRs and proinflammatory cytokines. They can also present antigens through MHC I and II (Dendritic cells are typically better at this) and bridge the gap between innate and adaptive immunity. Macrophages are also proficient at using ROS and RNS.
Adaptive Immunity Unlike innate immunity, adaptive immunity can help generate a long-term or memory response against a particular antigen/epitope. The hypermutations and recombinations in the antigen receptors allows for the recognition of a  wide repertoire of targets. Adaptive immunity also ensures a quicker response should the same pathogen re-infect the host. Attenuated vaccines utilize this concept to prime and prepare your body to give a stronger, more potent immune response should you be infected with the same pathogen later on. T and B cells The main card-carrying members of adaptive immunity are the T and B cells. B cells are primarily associated with a humoral or antibody-generating response. T cells respond through cell-mediated mechanisms, whether by directly lysing the target, activating other cell types, or becoming a helper class to enact its function. Before they encounter an antigen, these cells are considered to be na?ve.  Upon exposure to antigen, the cells can become effector cells to eliminate the invader. Some of the effectors will further differentiate into effector memory cells, which remember the offending antigen for future responses. Vaccines let your body sample the pathogen so that it knows how to respond to the pathogen later on.
Endogenous and exogenous antigen can be presented through MHC I and II to T cells. Endogenous antigen is produced by virally infected host cells. These peptides are usually displayed on MHC I and activate CD8+ T cells (cytotoxic T cells). Exogenous antigens are obtained when professional antigen presenting cells phagocytose and then display the foreign antigen (i.e., bacteria, fungi, or parasites) with MHC II. This helps to activate CD4+ T cells (helper T cells). B cells produce antibodies (IgA, IgD, IgE, IgG, IgM) and can recognize the natural, unprocessed form of antigen via its B cell receptor (BCR). The B cell can display the antigen on its MHC and become activated by a T cell specific for that same antigen. Upon maturation, the B cell becomes a plasma cell and releases copious amounts of antibody. A select few among the plasma cells will live on as memory B cells. Monomer, IgD, IgE, IgG, Dimer IgA, Pentamer IgM, CD4+ T cells can be polarized into a variety of T helper classes depending on the cytokine environment.
T Cell Central Tolerance Your immune system is undoubtedly useful for clearing potential pathogens and keeping you healthy. However, a delicate balance must be maintained. While foreign antigen must be eliminated, your body must avoid targeting itself for destruction (autoimmunity). As such, your body maintains several checkpoints during the development of your immune cells, particularly in B and T cells. These checkpoints in B and T cell development are known as central tolerance. T cells can create an abundant amount of inflammatory cytokines and promote the polarization of other potential autoimmune cells. As such, it undergoes scrutiny during its development in the thymus (for mammals).  In the cortex of the thymus, MHCs are displayed by epithelial cells. The developing T cell has to be able to recognize self MHC or it will be targeted for cell death (positive selection). Within the cortex and medulla regions, the T cells then undergo negative selection. Any cells that bind too strongly to self MHC loaded with self peptide are also eliminated. Autoimmunity, Tolerance, Positive Selection, Self MHC Restriction, Death by neglect, Lack of MHC recognition, Negative Selection, Deletion of high affinity self MHC/peptide binding cells.
Complement System In the 1890s, experiments in immunology by Jules Bordet and Paul Ehrlich theorized that the bacteriolytic ability of antiserum was due to specific anti-bacterial antibodies and another substance in the serum which completes or complements the action of the antibody.  This latter component became known as the complement system. Complement serves many purposes, as its individual parts and assembled complexes can: Lyse cells, bacteria, and viruses. Opsonize antigens. Trigger immune functions and inflammation. Clear immune complexes from circulation. A majority of complement proteins are synthesized from the liver in an inactive, or zymogen, state. Upon cleavage, the larger fragment typically forms a part of a complex, while the smaller fragment can diffuse away, drawing attention to the site by inducing inflammation. The components  were numbered (i.e., C3, C4) based on their order of discovery and not on their order of function, which can lead to some confusion. The classical pathway relies on antibody recognition of the pathogen. The alternative pathway starts when C3b (generated by spontaneous hydrolysis) binds to the target. Finally, the lectin pathway (not shown) begins when  mannose residues on the pathogen's surface are recognized.
While these pathways start differently, they all converge at one point: the formation of the Membrane Attack Complex (MAC). This complex essentially creates a large hole in the target cell, allowing ions and molecules to diffuse across the membrane. The cell cannot retain osmotic stability and will be killed upon the incoming flood of water and loss of electrolytes. Like all immune mechanisms in your body, the complement system also has its own system of checks and balances. A majority of complement proteins become inactive if they are not stabilized by the proper components.  Damage to the host is also minimized due to differential marker expression. For example, C3b, which is formed from spontaneous cleavage of C3 protein, can bind to host cells in the Alternative Pathway. Unlike pathogens, mammalian host cells express high levels of sialic acid, which prevent C3b from binding for long periods of time. The body also has regulatory proteins that can sequester and inactivate members of the complement process. When functioning optimally, the complement system helps to keep your body secure and healthy. The membrane attack complex. C9, C5b, C6, C7, C8, Intracellular, Extracellular
Phagocytosis Phagocytosis comes from the Greek phagein, meaning to eat or devour. True to its name, this process is the engulfing of foreign particles, cell debris, or dying cells. Neutrophils, monocytes, macrophages, dendritic cells, and mast cells are all capable of phagocytosis. Over time, many features on microbes became evolutionarily conserved and could not be lost without destroying the microbe itself. Phagocytes and innate cells can target these patterns via special receptors (i.e., Nod-like, Toll-like, and C-type lectin receptors). The figure and steps below are an example of receptor-mediated phagocytosis, where the receptor recognizes antibody-bound antigens: 1. Antibodies recognize the antigen and bind its surface. 2. This attracts phagocytes to ingest the object, as they possess receptors for the Fc portion of the antibodies. This process is known as opsonization. 3. Once contact is made, the object is ingested and held within a phagosome. 4. Next, a lysosome will fuse with the phagosome, creating a phagolysosome. The lysosome unloads a variety of hydrolytic enzymes upon fusion. In addition, the phagolysosome will decrease in pH and deploy reactive oxygen and nitrogen species to destroy the target. 5. Once this is completed, the waste is released, potentially allowing other phagocytes to restart the process on the remaining debris. It is interesting to note that this process also plays a key role in safely managing cells that have undergone apoptosis. The phagocytosis process. Phagosome, Lysosome, Phagolysosome.
B Cell Central Tolerance B cells will follow guidelines similar to T cells for their development. As the main producers of antibodies, B cells have the ability to guide opsonization and the complement system. If they were to produce auto-antibodies, there would be serious potential for developing autoimmune complications. In mammals, B cells are educated and mature within the bone marrow. Immature B cells will express IgM on its surface. If the IgM makes contact with and binds self antigen expressed on cell surfaces, the cell is lost (clonal deletion) to apoptosis. However, these cells do get the opportunity to correct their mistake. They can rearrange this receptor in the hopes it will no longer recognize self antigen. If the immature B cell recognizes soluble self-antigen, but does not die, IgM expression is lost from the cell. As such, they can migrate out of the bone marrow expressing only IgD and are unable to react to antigen. This is called anergy. The role of positive selection in B cell development is still being investigated. Strong recognition of self on cell surface, Successful receptor editing, Weak recognition of soluble self, IgM downregulation, Anergy, B Cell Central Tolerance, Failed receptor editing, Clonal deletion.
Apoptosis vs. Necrosis The body has rapid turnover, with roughly 50-70 billion cells dying a day in the average adult. This rapid turnover is often guided by a highly regulated process called apoptosis. This programmed cell death can be triggered by several factors (cytokines, hormones, etc.). There are a number of proteins that help prevent the onset of apoptosis (i.e., Bcl-2). On the other hand, factors like TNF-?, Granzyme B, and Fas receptor binding initiates a cascade of signals that leads to apoptosis. Caspases, in particular, are vital to the apoptosis process following their cleavage into an active form. Overall, the cell will begin to shrink and break down into packaged buds called blebs. Potentially inflammatory parts of the cell are neatly packaged and contained as the cell finally breaks apart into apoptotic bodies. These bodies are then disposed of by nearby phagocytic cells. It is important to note that when these bodies are properly cleared, it prevents a potential immune response  against self. Apoptosis (left) allows for the careful disposal of hazardous material in packaged form. Necrosis dumps all of the cell contents into the environment. In contrast to apoptosis, necrosis is the premature death of cells, typically caused by infection or some form of trauma. The cell loses the ability to regulate osmotic control, causing the organelles to swell and the cell to burst. The contents of the cell are not packaged as in apoptosis, and instead, are readily exposed to the immune system. Needless to say, necrosis is a dangerous process that can often prove fatal.
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