Immune System Design BIO 42 by Owen Borville August 21, 2025
Immune system design contains both innate and adaptive response elements. Innate immunity is the result of genetic factors or psychology and it is not caused by infection or vaccination but it works to reduce the workload for the adaptive immune response. Both the innate and adaptive response involve secreted proteins, receptor-mediated signaling, and intricate cell-to-cell communication. The innate immune system is a response to infection and it focuses on any pathogenic threat to identify the pathogen and clear the infection innately or by adaptive immune response.
Physical and chemical barriers work to block infections before any immune response is needed. The skin works as a physical barrier to infectious pathogens by drying them out or by the skin's acidity. There are also beneficial microorganisms living on the skin that fight harmful infections. Tears and mucus secretions trap and rinse away pathogens. Cilia in the nasal passages and respiratory tract push the mucus with the pathogens out of the body. The stomach has a low pH that stops the growth of pathogens. Blood proteins bind and disrupt bacterial cell membranes. Urination flushes pathogens from the urinary tract.
However, despite these barriers, pathogens can still enter the body through skin abrasions or punctures, or by collecting on mucosal surfaces in large numbers that overcome the mucus or cilia. When pathogens do enter the body, the innate immune system responds with inflammation, pathogen engulfment, and secretion of immune factors and proteins.
Infections by pathogens can be intracellular or extracellular. All viruses infect and replicate intracellularly. Bacteria and other parasites may replicate intracellularly or extracellularly. The innate immune system responds to the pathogen by identifying the extracellular pathogen or host cells that have been infected. When a pathogen enters the body, cells in the blood and lymph detect specific PAMPs (pathogen-associated-molecular-patterns) on the pathogen's surface. PAMPs are carbohydrate, polypeptide, and nucleic acid "signatures" that are expressed by viruses, bacteria, and parasites but differ from molecules on host cells. The immune system has specific cells with receptors that recognize these PAMPs:
A macrophage is a large phagocytic cell that engulfs foreign particles and pathogens. Macrophages recognize PAMPs via complimentary PRRs (pattern recognition receptors). PRRs are molecules on macrophages and dendritic cells which are in contact with the external environment. A monocyte is a type of white blood cell that circulates in the blood and lymph and differentiates into macrophages after it moves into infected tissue. Dendritic cells bind molecular signatures of pathogens and promote pathogen engulfment and destruction. Toll-like receptors (TLRs) are a type of PRR that recognizes molecules that are shared by pathogens but distinguishable from host molecules. TLRs are present in invertebrates, vertebrates, and mammals.
A mast cell dilates blood vessels and induces inflammation through the release of histamines and heparin, recruits macrophages and neutrophils, and heals wounds and defends against pathogens but can cause allergic reactions. Mast cells are located in connective tissues and mucous membranes.
Macrophages are large phagocytic cells that consume foreign pathogens and cancer cells. Macrophages also stimulate the response of other immune cells. Macrophages migrate from blood vessels into tissues.
Natural killer cells kill tumor cells and virus-infected cells as they circulate in blood and migrate into tissues.
Dendritic cells present antigens on its surface, thereby triggering adaptive immunity. Dendritic cells are found in epithelial tissue, skin, lung, and digestive tract tissues. Dendritic cells migrate to lymph nodes upon activation.
Monocyte cells differentiate into macrophages and dendritic cells in response to inflammation. Monocyte cells are stored in spleen, and move through blood vessels to infected tissues.
Neutrophil cells are phagocytic cells and first responders at the site of infection or trauma and represents more than half of all leukocytes. Neutrophil releases toxins that kill or slow bacteria and fungi and recruit other immune cells to the cite of infection. Neutrophil migrates from blood vessels into tissues.
Basophil is responsible for defense against parasites and releases histamines that cause inflammation and may be responsible for allergic reactions. Basophil circulates in blood and migrates to tissues.
Eosinophil releases toxins that kill bacteria and parasites but also causes tissue damage. Eosinophil circulates in blood and migrates to tissues.
PRRs and PAMPs are bound and that causes the release of cytokines, which signals that a pathogen is present and needs to be destroyed along with any infected cells. A cytokine is a chemical messenger that regulates cell differentiation (form and function), proliferation (production), and gene expression to affect immune responses.
A subclass of cytokines is interleukin, which mediates interactions between leukocytes or white blood cells. Interleukins are involved in connecting the innate and adaptive immune responses. Cytokines are released from cells, including infected cells to alert other uninfected cells to release more cytokines to act as messengers of information to regulate biological processes and immune responses.
Another type of cytokine is the interferon, which are released by infected cells as a warning to nearby uninfected cells. One of the functions of an interferon is to inhibit viral replication. Other functions of the interferon include tumor surveillance. Interferons work by signaling neighboring uninfected cells to destroy RNA and reduce protein synthesis, and signaling neighboring infected cells to undergo apoptosis (programmed cell death), and activating immune cells.
In response to interferons, uninfected cells alter their gene expression, which increases the cells' resistance to infection. One effect of interferon-induced gene expression is a sharply reduced cellular protein synthesis. Virally infected cells produce more viruses by synthesizing large quantities of viral proteins. Thus, by reducing protein synthesis, a cell becomes resistant to viral infection.
The first cytokines to be produced are pro-inflammatory because they encourage inflammation, the localized redness, swelling, heat, and pain that result from the movement of leukocytes and fluid through increasingly permeable capillaries to a site of infection. The population of leukocytes that arrive at an infection site depends on the nature of the infecting pathogen. Both macrophages and dendritic cells engulf pathogens and cellular debris through phagocytosis. A neutrophil is also a phagocytic leukocyte that engulfs and digests pathogens. Neutrophils are the most abundant leukocytes of the immune system. Neutrophils have a nucleus with two to five lobes, and they contain organelles, called lysosomes, that digest engulfed pathogens. An eosinophil is a leukocyte that works with other eosinophils to surround a parasite and it is involved in the allergic response and in protection against helminthes (parasitic worms).
Neutrophils and eosinophils are particularly important leukocytes that engulf large pathogens, such as bacteria and fungi. A mast cell is a leukocyte that produces inflammatory molecules, such as histamine, in response to large pathogens. A basophil is a leukocyte that, like a neutrophil, releases chemicals to stimulate the inflammatory response. Basophils are also involved in allergy and hypersensitivity responses and induce specific types of inflammatory responses. Eosinophils and basophils produce additional inflammatory mediators to recruit more leukocytes.
Cytokines also send feedback to cells of the nervous system to bring about the overall symptoms of feeling sick, such as lethargy, muscle pain, and nausea. These symptoms encourage the victim to rest and prevent spreading the infection to others. Cytokines also increase the core body temperature, causing a fever, which causes the liver to withhold iron from the blood, which in turn prevents some pathogens from replicating (known as nutritional immunity).
Lymphocytes are leukocytes that are histologically identifiable by their large, darkly staining nuclei. Lymphocytes are small cells with very little cytoplasm. Infected cells are identified and destroyed by natural killer cells (NK cells), lymphocytes that can kill cells infected with viruses or tumor cells (abnormal cells that uncontrollably divide and invade other tissue).
T cells are lymphocytes of the adaptive immune system that mature in the thymus gland and B cells are lymphocytes of the adaptive immune system that mature in the bone marrow. NK cells identify intracellular infections, especially from viruses, by the altered expression of major histocompatibility complex (MHC) I molecules on the surface of infected cells. MHC I molecules are proteins on the surfaces of all nucleated cells, thus they are scarce on red blood cells and platelets which are non-nucleated. The function of MHC I molecules is to display fragments of proteins from the infected agents within the cell to T cells. Healthy cells will be ignored, while "non-self" or foreign proteins will be attacked by the immune system. MHC II molecules are found mainly on cells containing antigens (non-self proteins) and on lymphocytes. MHC II molecules also interact with helper T cells to trigger the appropriate immune response, which may include the inflammatory response.
An infected cell (or tumor cell) is usually incapable of synthesizing and displaying MHC I molecules appropriately. The metabolic resources of cells infected by some viruses produce proteins that interfere with MHC I processing and/or trafficking to the cell surface. The reduced MHC I on host cells varies from virus to virus and results from active inhibitors being produced by the viruses. This process can deplete host MHC I molecules on the cell surface, which NK cells detect as "unhealthy" or "abnormal" while searching for cellular MHC I molecules. Similarly, the dramatically altered gene expression of tumor cells leads to expression of extremely deformed or absent MHC I molecules that also signal "unhealthy" or "abnormal."
NK cells are always active and do not target MHC I molecules on healthy cells. After the NK detects an infected or tumor cell, its cytoplasm secretes granules comprised of perforin, a destructive protein that creates a pore in the target cell. Granzymes are released along with the perforin in the immunological synapse. A granzyme is a protease (enzyme that breaks down proteins and peptides) that digests cellular proteins and induces the target cell to undergo programmed cell death, or apoptosis. Phagocytic cells then digest the cell debris left behind.
A compliment system is an array of about 20 types of soluble proteins which functions to destroy extracellular pathogens. Cells of the liver and macrophages synthesize compliment proteins continuously. These proteins are abundant in the blood serum and are capable of responding immediately to infecting microorganisms. Compliment proteins bind to the surfaces of microorganisms and are attracted to pathogens that are already bound by antibodies. Binding of compliment proteins occurs in a specific and highly regulated sequence, with each successive protein being activated by cleavage or structural changes induced upon binding of the preceding proteins. Compliment proteins perform several functions. These proteins serve as a marker to indicate the presence of a pathogen to phagocytic cells and enhance engulfment. This process is called opsonization. Certain compliment proteins can combine to open pores in microbial cell membranes, causing these cells to leak and be destroyed.
The adaptive or acquired immune response takes days or weeks to become established, much longer than the innate response. However, adaptive immunity is more specific to pathogens and has memory. Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. This part of the immune system is activated when the innate immune response is insufficient to control an infection. Without information from the innate immune system, the adaptive response could not be mobilized.
There are two types of adaptive responses: cell-mediated immune response, which is carried out by T cells, and the humoral immune response, which is controlled by activated B cells and antibodies. Activated T cells and B cells that are specific to molecular structures on the pathogen proliferate and attack the invading pathogen. Their attack can kill pathogens directly or secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory to provide the host with long-term protection from reinfection with the same type of pathogen. On re-exposure, this memory will facilitate an efficient and quick response.
B cells are a type of a white blood cell that gives rise to antibodies and T cells are a type of white blood cell that plays an important role in the immune response. T cells are an important part of cell-mediated response, the specific immune response that utilizes T cells to neutralize cells that have been infected with viruses and certain bacteria. There are three types of T cells: cytotoxic, helper, and suppressor T cells. Cytotoxic T cells destroy virus-infected cells in the cell-mediated immune response, and helper T cells play a part in activating both the antibody and the cell-mediated immune responses. Suppressor T cells deactivate T cells and and B cells when needed, and thus prevent the immune response from becoming too intense.
An antigen is a foreign or "non-self" macromolecule that reacts with cells of the immune system. However, not all antigens will create a response. Many of these antigens are harmless and come from food proteins, pollen, or dust. Immune response to these harmless antigens is suppressed to prevent damage to the host.
The innate immune system contains cells that detect harmful antigens, and then inform the adaptive immune response about the harmful antigens. An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material and are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, and therefore functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs.
After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome. Within the phagolysosome, the components are broken down into fragments, which are then loaded onto MHC class I or II molecules and are transported to the cell surface for antigen presentation.
Lymphocytes in human circulating blood are 80-90 percent T cells and 10-20 percent B cells. T cells are involved in the cell-mediated immune response and B cells are involved in the humoral immune response. T cells surround a heterogeneous population of cells with extremely diverse functions. Some T cells respond to APCs of the innate immune system, and indirectly induce immune responses by releasing cytokines. Other T cells stimulate B cells to prepare their own response. Other T cells detect APC signals and directly kill the infected cells. Other T cells are involved in suppressing inappropriate immune reactions to harmless or self antigens.
T and B (lymphocyte) cells exhibit a common theme of recognition/binding of specific antigens via a complimentary receptor, followed by activation and self-amplification/maturation to specifically bind to the particular antigen of the infecting pathogen. T and B lymphocytes are also similar in that each cell only expresses one type of antigen receptor. Any individual may possess a population of T and B cells that together express a near limitless variety of antigen receptors that are capable of recognizing virtually any infecting pathogen. T and B cells are activated when they recognize small components of antigens, called epitopes, presented by APCs. Recognition occurs at a specific epitope and not the entire antigen, and therefore epitopes are known as antigenic determinants. If the information from APCs are not available, the T and B cells will be unable to provide an immune response (inactive or naive).
Naive T cells can express one of two different molecules, CD4+ or CD8+ on their surface. These molecules regulate how a T cell will interact with and respond to an APC. Naive CD4+ cells bind to APCs via their antigen-embedded MHC II molecules and are stimulated to become helper T (Th) lymphocytes, cells that go on to stimulate B cells (or cytotoxic T cells) directly or secrete cytokines to inform more and various target cells about the pathogenic threat. In contrast, CD8+ cells engage antigen-embedded MHC I molecules on APCs and are stimulated to become cytotoxic T lymphocytes (CTLs), which directly kill infected cells by apoptosis and emit cytokines to amplify the immune response. The two populations of T cells have different mechanisms of immune protection, but both bind MHC molecules via their antigen receptors called T cell receptors (TCRs). The CD4 or CD8 surface molecules differentiate whether the TCR will engage an MHC II or an MHC I molecule. Because they assist in binding specificity, the CD4 and CD8 molecules are described as coreceptors.
There are many possible antigens that an individual could be exposed to in a lifetime. Each TCR (T cell receptor) consists of two polypeptide chains that span the T cell membrane and the chains are linked by a disulfide bridge. The binding between an antigen-displaying MHC molecule and a complimentary TCR match indicates that the adaptive immune system needs to activate and produce that specific T cell because its structure is appropriate to recognize and destroy the invading pathogen.
Helper T Lymphocytes (Th) function indirectly to identify potential pathogens for other cells of the immune system. These cells are important for extracellular infections, such as those caused by certain bacteria, helminths, and protozoa. Some helper T cells secrete cytokines to enhance the activities of macrophages and other T cells. Th cells also activate the action of cytotoxic T cells and macrophages. Th2 cells stimulate naive B cells to destroy foreign invaders through antibody secretion. Therefore Th1 responses are toward intracellular invaders while Th2 responses are toward extracellular invaders.
When stimulated by the Th2 pathway, naive B cells differentiate into antibody-secreting plasma cells. A plasma cell is an immune cell that secrets antibodies and these cells arise from B cells that were stimulated by antigens. Naive B cells are coated with thousands of B cell receptors, which are membrane-bound forms of immunoglobulin or antibody. The B cell receptor has connected chains with a constant and variable region for antigen binding and signaling. The activation of B cells corresponding to one specific BCR (B cell receptor) variant and the dramatic proliferation of that variant is known as clonal selection, which changes the proportions of BCR variants expressed by the immune system.
While T cells bind antigens that have been digested and embedded in MHC molecules by APCs, B cells function as APCs that bind intact antigens that have not been processed.
CTLs (Cytotoxic T Lymphocytes) are a subclass of T cells that function to clear infections directly by attacking and destroying infected cells. CTLs protect against viral infections inside the cell.
Plasma cells and CTLs are called effector cells because they represent differentiated versions of their naive counterparts and are involved in the immune defense of killing pathogens and infected host cells.
The mucosal immunity is distinct from the innate and adaptive immune system because mucosal immunity is formed by mucosa-associated lymphoid tissue, which functions independently of the systemic immune system, and has its own innate and adaptive components. The mucosa-associated lymphoid tissue (MALT) is a collection of lymphatic tissue that combines with epithelial tissue lining the mucosa throughout the body. This tissue functions as the immune barrier and response in areas of the body with direct contact to the external environment. Both the systemic and mucosal immune systems use similar cell types. MALT is important because mucosal surfaces, such as the nasal passages, are the first tissues onto which inhaled or ingested pathogens are deposited. Mucosal tissue is also found in the mouth, pharynx, esophagus, gastrointestinal, respiratory, and urogenital tracts.
Immune tolerance is the acquired ability to prevent an unnecessary or harmful immune response to a detected foreign substance not known to cause a disease. This immune tolerance is important for maintaining mucosal homeostasis among the large number of foreign substances that come in contact with the body. Specialized APCs make immune tolerance possible along with regulatory T cells, specialized lymphocytes that suppress local inflammation and inhibit the secretion of stimulatory immune factors. Other regulatory T cells prevent the autoimmune response, which is an inappropriate immune response to host cells and self-antigens.
Immunological memory is a component of the adaptive immune system that allows for an efficient and dramatic response upon reinvasion of the same pathogen.
A memory cell is an antigen-specific B or T lymphocyte that does not differentiate into effector cells during the primary immune response, but that can immediately become effector cells upon re-exposure to the same pathogen. Memory cells continue to exist in circulation in order to work as needed.
A subset of T and B cells of the mucosal immune system differentiates into memory cells just as in the systemic immune system.
The regulation, maturation, and intercommunication of immune factors occur at specific sites. The blood circulates immune cells, proteins, and other factors throughout the body, specifically leukocytes, which encompass monocytes, and lymphocytes. The majority of cells in the blood are erythrocytes (red blood cells). Lymph is a watery fluid that bathes tissues and organs with protective white blood cells and does not contain erythrocytes. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by the process of extravasation, or passing through to surrounding tissue.
The cells of the immune system originate from hematopoietic stem cells in the bone marrow. Cytokines stimulate these stem cells to differentiate into immune cells. B cell maturation occurs in the bone marrow, whereas naive T cells transit from the bone marrow to the thymus for maturation.
Mature T and B cells circulate throughout the body and lymph nodes house large amounts of T and B cells, dendritic cells, and macrophages. Lymph gathers antigens and are filtered through the lymph nodes by APCs.
The spleen houses B and T cells, macrophages, dendritic cells, and NK cells. In the spleen APCs with foreign particles can communicate with lymphocytes. Antibodies are created and secreted by plasma cells in the spleen, and the spleen filters foreign substances and pathogens from the blood.
Antibodies, (antibody, singular) or immunoglobulin (lg), is a protein that is produced by plasma cells after stimulation by an antigen. Antibodies are the functional basis of humoral immunity. Antibodies occur in the blood, in gastric and mucus secretions, and in breast milk. Antibodies in these bodily fluids can bind pathogens and mark them for destruction by phagocytes before they can infect cells.
The antibody molecule is comprised of four polypeptides: two identical heavy chains of large peptide units that are partially bound to each other in a Y formation, and which are flanked by two identical light chains or small peptide units.
Bonds between the cysteine amino acids in the antibody molecule attach the polypeptides to each other. The areas where the antigen is recognized on the antibody are variable domains and the antibody base is comprised of constant domains.
Antibody diversity is produced by the mutation and recombination of approximately 300 different gene segments encoding the light and heavy chain variable domains in precursor cells that are destined to become B cells.
Antibodies can be divided into five classes: IgM, IgG, IgA, IgD, IgE, and are based on their physiochemical, structural, and immunological properties. IgGs are the majority of antibodies and have heavy chains of one variable domain and three identical constant domains. IgA and IgD also have three constant domains per heavy chain, and IgM and IgE each have four constant domains per heavy chain. The variable domain determines the binding specificity and the constant domain of the heavy chain determines the immunological mechanism of action of the corresponding antibody class.
After an adaptive defense is produced against a pathogen, typically plasma cells first secrete IgM into the blood.
IgA is found in mucous, saliva, tears, and breast milk and protects against pathogens. IgD is part of the B cell receptor and activates basophils and mast cells. IgE protects against parasitic worms and is responsible for allergic reactions. IgG is secreted by plasma cells in the blood and is able to cross the placenta into the fetus. IgM may be attached to the surface of a B cell or secreted into the blood and is responsible for early stages of immunity.
Passive immunity is a phenomenon and function of antibodies where they circulate freely and act independent of plasma cells. Antibodies can be transferred from one individual to another to temporarily protect against infectious disease, such as through donated blood from one person to another or during breastfeeding between mother and child.
Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the pathogen that enhance their infectivity and prevent pathogens from entering and infecting host cells. The neutralized pathogen can be filtered out of the body through the spleen and through waste material. Antibodies may block infection by preventing the antigen from binding to its target, tagging a pathogen for destruction by phagocytic cells such as macrophages or neutrophils, or activating the compliment cascade. Phagocytic enhancement by antibodies is called opsonization. Compliment fixation allows IgM and IgG in serum to bind to antigens and allows other compliment proteins to bind.
Antibodies do not always bind with the same strength, specificity, and stability. Antibodies exhibit different affinities or attraction strength depending on the molecular complementarity between antigen and antibody molecules. Avidity refers to the strength of all interactions combined when binding by antibody classes are secreted as joined, multivalent structures. The avidity depends on the number of identical binding sites on the antigen being detected along with other physical and chemical factors. Cross reactivity occurs when an antibody binds not to the antigen that elicited its synthesis and secretion, but to a different antigen. Cross reactivity can be beneficial if an individual develops immunity to several related pathogens despite having only been exposed to or vaccinated to one of them.
Antibodies of the mucosal immune system include IgA and IgM. Activated B cells differentiate into mucosal plasma cells that create and secrete dimeric IgA and IgM. Secreted IgA is abundant in tears, saliva, breast milk, and in secretions of the gastrointestinal and respiratory tracts.
The variety, specificity, and reliability of antibodies makes them ideally suited for certain medical tests and investigations, such as radioimmunoassays (RIA), which use the antigen-antibody interaction to detect the presence and or concentration of certain antigens.
Immunodeficiency is the failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including medical treatments, radiation), malnutrition, or extreme stress. Radiation exposure can damage the immune system in particular lymphocytes, increasing risk of infections and cancer. Some genetic disorders result in immunodeficiencies, such as not producing enough neutrophils or phagocytes.
Hypersensitivities are maladaptive immune responses toward harmless foreign substances or self antigens that occur after tissue sensitization. The types of hypersensitivities include immediate, delayed, and autoimmunity. More that one type of hypersensitivity can affect an individual.
Allergies are the immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a harmless antigen. Upon initial exposure to an potential allergen, an allergic individual creates antibodies of the IgE class via the typical process of APCs presenting processed antigen to Th cells that stimulate B cells to produce IgE and attached to mast cells. Additional exposure to the antigen causes the binding of the antigen to IgE primed mast cells and causes the release of chemical mediators that elicit an allergic reaction. Allergic reactions can cause sneezing, itchy, watery eyes, intense itching, airway contraction, and low blood pressure.
Delayed hypersensitivity is a cell-mediated immune response that takes about one to two days after secondary exposure for a maximum reaction to be observed.
Autoimmunity is when the immune system incorrectly identifies the body's own healthy tissues as foreign, leading to an immune response to them. Autoimmunity is a type of hypersensitivity to self antigens that usually involve the humoral immune response. Antibodies that inappropriately mark self components as foreign are termed autoantibodies. Autoimmunity can develop over time and its causes could be from molecular mimicry, genetics, or environmental causes. Autoimmunity can cause diseases like type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. Symptoms include fatigue, joint pain, skin issues, and inflammation.
Immune system design contains both innate and adaptive response elements. Innate immunity is the result of genetic factors or psychology and it is not caused by infection or vaccination but it works to reduce the workload for the adaptive immune response. Both the innate and adaptive response involve secreted proteins, receptor-mediated signaling, and intricate cell-to-cell communication. The innate immune system is a response to infection and it focuses on any pathogenic threat to identify the pathogen and clear the infection innately or by adaptive immune response.
Physical and chemical barriers work to block infections before any immune response is needed. The skin works as a physical barrier to infectious pathogens by drying them out or by the skin's acidity. There are also beneficial microorganisms living on the skin that fight harmful infections. Tears and mucus secretions trap and rinse away pathogens. Cilia in the nasal passages and respiratory tract push the mucus with the pathogens out of the body. The stomach has a low pH that stops the growth of pathogens. Blood proteins bind and disrupt bacterial cell membranes. Urination flushes pathogens from the urinary tract.
However, despite these barriers, pathogens can still enter the body through skin abrasions or punctures, or by collecting on mucosal surfaces in large numbers that overcome the mucus or cilia. When pathogens do enter the body, the innate immune system responds with inflammation, pathogen engulfment, and secretion of immune factors and proteins.
Infections by pathogens can be intracellular or extracellular. All viruses infect and replicate intracellularly. Bacteria and other parasites may replicate intracellularly or extracellularly. The innate immune system responds to the pathogen by identifying the extracellular pathogen or host cells that have been infected. When a pathogen enters the body, cells in the blood and lymph detect specific PAMPs (pathogen-associated-molecular-patterns) on the pathogen's surface. PAMPs are carbohydrate, polypeptide, and nucleic acid "signatures" that are expressed by viruses, bacteria, and parasites but differ from molecules on host cells. The immune system has specific cells with receptors that recognize these PAMPs:
A macrophage is a large phagocytic cell that engulfs foreign particles and pathogens. Macrophages recognize PAMPs via complimentary PRRs (pattern recognition receptors). PRRs are molecules on macrophages and dendritic cells which are in contact with the external environment. A monocyte is a type of white blood cell that circulates in the blood and lymph and differentiates into macrophages after it moves into infected tissue. Dendritic cells bind molecular signatures of pathogens and promote pathogen engulfment and destruction. Toll-like receptors (TLRs) are a type of PRR that recognizes molecules that are shared by pathogens but distinguishable from host molecules. TLRs are present in invertebrates, vertebrates, and mammals.
A mast cell dilates blood vessels and induces inflammation through the release of histamines and heparin, recruits macrophages and neutrophils, and heals wounds and defends against pathogens but can cause allergic reactions. Mast cells are located in connective tissues and mucous membranes.
Macrophages are large phagocytic cells that consume foreign pathogens and cancer cells. Macrophages also stimulate the response of other immune cells. Macrophages migrate from blood vessels into tissues.
Natural killer cells kill tumor cells and virus-infected cells as they circulate in blood and migrate into tissues.
Dendritic cells present antigens on its surface, thereby triggering adaptive immunity. Dendritic cells are found in epithelial tissue, skin, lung, and digestive tract tissues. Dendritic cells migrate to lymph nodes upon activation.
Monocyte cells differentiate into macrophages and dendritic cells in response to inflammation. Monocyte cells are stored in spleen, and move through blood vessels to infected tissues.
Neutrophil cells are phagocytic cells and first responders at the site of infection or trauma and represents more than half of all leukocytes. Neutrophil releases toxins that kill or slow bacteria and fungi and recruit other immune cells to the cite of infection. Neutrophil migrates from blood vessels into tissues.
Basophil is responsible for defense against parasites and releases histamines that cause inflammation and may be responsible for allergic reactions. Basophil circulates in blood and migrates to tissues.
Eosinophil releases toxins that kill bacteria and parasites but also causes tissue damage. Eosinophil circulates in blood and migrates to tissues.
PRRs and PAMPs are bound and that causes the release of cytokines, which signals that a pathogen is present and needs to be destroyed along with any infected cells. A cytokine is a chemical messenger that regulates cell differentiation (form and function), proliferation (production), and gene expression to affect immune responses.
A subclass of cytokines is interleukin, which mediates interactions between leukocytes or white blood cells. Interleukins are involved in connecting the innate and adaptive immune responses. Cytokines are released from cells, including infected cells to alert other uninfected cells to release more cytokines to act as messengers of information to regulate biological processes and immune responses.
Another type of cytokine is the interferon, which are released by infected cells as a warning to nearby uninfected cells. One of the functions of an interferon is to inhibit viral replication. Other functions of the interferon include tumor surveillance. Interferons work by signaling neighboring uninfected cells to destroy RNA and reduce protein synthesis, and signaling neighboring infected cells to undergo apoptosis (programmed cell death), and activating immune cells.
In response to interferons, uninfected cells alter their gene expression, which increases the cells' resistance to infection. One effect of interferon-induced gene expression is a sharply reduced cellular protein synthesis. Virally infected cells produce more viruses by synthesizing large quantities of viral proteins. Thus, by reducing protein synthesis, a cell becomes resistant to viral infection.
The first cytokines to be produced are pro-inflammatory because they encourage inflammation, the localized redness, swelling, heat, and pain that result from the movement of leukocytes and fluid through increasingly permeable capillaries to a site of infection. The population of leukocytes that arrive at an infection site depends on the nature of the infecting pathogen. Both macrophages and dendritic cells engulf pathogens and cellular debris through phagocytosis. A neutrophil is also a phagocytic leukocyte that engulfs and digests pathogens. Neutrophils are the most abundant leukocytes of the immune system. Neutrophils have a nucleus with two to five lobes, and they contain organelles, called lysosomes, that digest engulfed pathogens. An eosinophil is a leukocyte that works with other eosinophils to surround a parasite and it is involved in the allergic response and in protection against helminthes (parasitic worms).
Neutrophils and eosinophils are particularly important leukocytes that engulf large pathogens, such as bacteria and fungi. A mast cell is a leukocyte that produces inflammatory molecules, such as histamine, in response to large pathogens. A basophil is a leukocyte that, like a neutrophil, releases chemicals to stimulate the inflammatory response. Basophils are also involved in allergy and hypersensitivity responses and induce specific types of inflammatory responses. Eosinophils and basophils produce additional inflammatory mediators to recruit more leukocytes.
Cytokines also send feedback to cells of the nervous system to bring about the overall symptoms of feeling sick, such as lethargy, muscle pain, and nausea. These symptoms encourage the victim to rest and prevent spreading the infection to others. Cytokines also increase the core body temperature, causing a fever, which causes the liver to withhold iron from the blood, which in turn prevents some pathogens from replicating (known as nutritional immunity).
Lymphocytes are leukocytes that are histologically identifiable by their large, darkly staining nuclei. Lymphocytes are small cells with very little cytoplasm. Infected cells are identified and destroyed by natural killer cells (NK cells), lymphocytes that can kill cells infected with viruses or tumor cells (abnormal cells that uncontrollably divide and invade other tissue).
T cells are lymphocytes of the adaptive immune system that mature in the thymus gland and B cells are lymphocytes of the adaptive immune system that mature in the bone marrow. NK cells identify intracellular infections, especially from viruses, by the altered expression of major histocompatibility complex (MHC) I molecules on the surface of infected cells. MHC I molecules are proteins on the surfaces of all nucleated cells, thus they are scarce on red blood cells and platelets which are non-nucleated. The function of MHC I molecules is to display fragments of proteins from the infected agents within the cell to T cells. Healthy cells will be ignored, while "non-self" or foreign proteins will be attacked by the immune system. MHC II molecules are found mainly on cells containing antigens (non-self proteins) and on lymphocytes. MHC II molecules also interact with helper T cells to trigger the appropriate immune response, which may include the inflammatory response.
An infected cell (or tumor cell) is usually incapable of synthesizing and displaying MHC I molecules appropriately. The metabolic resources of cells infected by some viruses produce proteins that interfere with MHC I processing and/or trafficking to the cell surface. The reduced MHC I on host cells varies from virus to virus and results from active inhibitors being produced by the viruses. This process can deplete host MHC I molecules on the cell surface, which NK cells detect as "unhealthy" or "abnormal" while searching for cellular MHC I molecules. Similarly, the dramatically altered gene expression of tumor cells leads to expression of extremely deformed or absent MHC I molecules that also signal "unhealthy" or "abnormal."
NK cells are always active and do not target MHC I molecules on healthy cells. After the NK detects an infected or tumor cell, its cytoplasm secretes granules comprised of perforin, a destructive protein that creates a pore in the target cell. Granzymes are released along with the perforin in the immunological synapse. A granzyme is a protease (enzyme that breaks down proteins and peptides) that digests cellular proteins and induces the target cell to undergo programmed cell death, or apoptosis. Phagocytic cells then digest the cell debris left behind.
A compliment system is an array of about 20 types of soluble proteins which functions to destroy extracellular pathogens. Cells of the liver and macrophages synthesize compliment proteins continuously. These proteins are abundant in the blood serum and are capable of responding immediately to infecting microorganisms. Compliment proteins bind to the surfaces of microorganisms and are attracted to pathogens that are already bound by antibodies. Binding of compliment proteins occurs in a specific and highly regulated sequence, with each successive protein being activated by cleavage or structural changes induced upon binding of the preceding proteins. Compliment proteins perform several functions. These proteins serve as a marker to indicate the presence of a pathogen to phagocytic cells and enhance engulfment. This process is called opsonization. Certain compliment proteins can combine to open pores in microbial cell membranes, causing these cells to leak and be destroyed.
The adaptive or acquired immune response takes days or weeks to become established, much longer than the innate response. However, adaptive immunity is more specific to pathogens and has memory. Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. This part of the immune system is activated when the innate immune response is insufficient to control an infection. Without information from the innate immune system, the adaptive response could not be mobilized.
There are two types of adaptive responses: cell-mediated immune response, which is carried out by T cells, and the humoral immune response, which is controlled by activated B cells and antibodies. Activated T cells and B cells that are specific to molecular structures on the pathogen proliferate and attack the invading pathogen. Their attack can kill pathogens directly or secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory to provide the host with long-term protection from reinfection with the same type of pathogen. On re-exposure, this memory will facilitate an efficient and quick response.
B cells are a type of a white blood cell that gives rise to antibodies and T cells are a type of white blood cell that plays an important role in the immune response. T cells are an important part of cell-mediated response, the specific immune response that utilizes T cells to neutralize cells that have been infected with viruses and certain bacteria. There are three types of T cells: cytotoxic, helper, and suppressor T cells. Cytotoxic T cells destroy virus-infected cells in the cell-mediated immune response, and helper T cells play a part in activating both the antibody and the cell-mediated immune responses. Suppressor T cells deactivate T cells and and B cells when needed, and thus prevent the immune response from becoming too intense.
An antigen is a foreign or "non-self" macromolecule that reacts with cells of the immune system. However, not all antigens will create a response. Many of these antigens are harmless and come from food proteins, pollen, or dust. Immune response to these harmless antigens is suppressed to prevent damage to the host.
The innate immune system contains cells that detect harmful antigens, and then inform the adaptive immune response about the harmful antigens. An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material and are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, and therefore functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs.
After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome. Within the phagolysosome, the components are broken down into fragments, which are then loaded onto MHC class I or II molecules and are transported to the cell surface for antigen presentation.
Lymphocytes in human circulating blood are 80-90 percent T cells and 10-20 percent B cells. T cells are involved in the cell-mediated immune response and B cells are involved in the humoral immune response. T cells surround a heterogeneous population of cells with extremely diverse functions. Some T cells respond to APCs of the innate immune system, and indirectly induce immune responses by releasing cytokines. Other T cells stimulate B cells to prepare their own response. Other T cells detect APC signals and directly kill the infected cells. Other T cells are involved in suppressing inappropriate immune reactions to harmless or self antigens.
T and B (lymphocyte) cells exhibit a common theme of recognition/binding of specific antigens via a complimentary receptor, followed by activation and self-amplification/maturation to specifically bind to the particular antigen of the infecting pathogen. T and B lymphocytes are also similar in that each cell only expresses one type of antigen receptor. Any individual may possess a population of T and B cells that together express a near limitless variety of antigen receptors that are capable of recognizing virtually any infecting pathogen. T and B cells are activated when they recognize small components of antigens, called epitopes, presented by APCs. Recognition occurs at a specific epitope and not the entire antigen, and therefore epitopes are known as antigenic determinants. If the information from APCs are not available, the T and B cells will be unable to provide an immune response (inactive or naive).
Naive T cells can express one of two different molecules, CD4+ or CD8+ on their surface. These molecules regulate how a T cell will interact with and respond to an APC. Naive CD4+ cells bind to APCs via their antigen-embedded MHC II molecules and are stimulated to become helper T (Th) lymphocytes, cells that go on to stimulate B cells (or cytotoxic T cells) directly or secrete cytokines to inform more and various target cells about the pathogenic threat. In contrast, CD8+ cells engage antigen-embedded MHC I molecules on APCs and are stimulated to become cytotoxic T lymphocytes (CTLs), which directly kill infected cells by apoptosis and emit cytokines to amplify the immune response. The two populations of T cells have different mechanisms of immune protection, but both bind MHC molecules via their antigen receptors called T cell receptors (TCRs). The CD4 or CD8 surface molecules differentiate whether the TCR will engage an MHC II or an MHC I molecule. Because they assist in binding specificity, the CD4 and CD8 molecules are described as coreceptors.
There are many possible antigens that an individual could be exposed to in a lifetime. Each TCR (T cell receptor) consists of two polypeptide chains that span the T cell membrane and the chains are linked by a disulfide bridge. The binding between an antigen-displaying MHC molecule and a complimentary TCR match indicates that the adaptive immune system needs to activate and produce that specific T cell because its structure is appropriate to recognize and destroy the invading pathogen.
Helper T Lymphocytes (Th) function indirectly to identify potential pathogens for other cells of the immune system. These cells are important for extracellular infections, such as those caused by certain bacteria, helminths, and protozoa. Some helper T cells secrete cytokines to enhance the activities of macrophages and other T cells. Th cells also activate the action of cytotoxic T cells and macrophages. Th2 cells stimulate naive B cells to destroy foreign invaders through antibody secretion. Therefore Th1 responses are toward intracellular invaders while Th2 responses are toward extracellular invaders.
When stimulated by the Th2 pathway, naive B cells differentiate into antibody-secreting plasma cells. A plasma cell is an immune cell that secrets antibodies and these cells arise from B cells that were stimulated by antigens. Naive B cells are coated with thousands of B cell receptors, which are membrane-bound forms of immunoglobulin or antibody. The B cell receptor has connected chains with a constant and variable region for antigen binding and signaling. The activation of B cells corresponding to one specific BCR (B cell receptor) variant and the dramatic proliferation of that variant is known as clonal selection, which changes the proportions of BCR variants expressed by the immune system.
While T cells bind antigens that have been digested and embedded in MHC molecules by APCs, B cells function as APCs that bind intact antigens that have not been processed.
CTLs (Cytotoxic T Lymphocytes) are a subclass of T cells that function to clear infections directly by attacking and destroying infected cells. CTLs protect against viral infections inside the cell.
Plasma cells and CTLs are called effector cells because they represent differentiated versions of their naive counterparts and are involved in the immune defense of killing pathogens and infected host cells.
The mucosal immunity is distinct from the innate and adaptive immune system because mucosal immunity is formed by mucosa-associated lymphoid tissue, which functions independently of the systemic immune system, and has its own innate and adaptive components. The mucosa-associated lymphoid tissue (MALT) is a collection of lymphatic tissue that combines with epithelial tissue lining the mucosa throughout the body. This tissue functions as the immune barrier and response in areas of the body with direct contact to the external environment. Both the systemic and mucosal immune systems use similar cell types. MALT is important because mucosal surfaces, such as the nasal passages, are the first tissues onto which inhaled or ingested pathogens are deposited. Mucosal tissue is also found in the mouth, pharynx, esophagus, gastrointestinal, respiratory, and urogenital tracts.
Immune tolerance is the acquired ability to prevent an unnecessary or harmful immune response to a detected foreign substance not known to cause a disease. This immune tolerance is important for maintaining mucosal homeostasis among the large number of foreign substances that come in contact with the body. Specialized APCs make immune tolerance possible along with regulatory T cells, specialized lymphocytes that suppress local inflammation and inhibit the secretion of stimulatory immune factors. Other regulatory T cells prevent the autoimmune response, which is an inappropriate immune response to host cells and self-antigens.
Immunological memory is a component of the adaptive immune system that allows for an efficient and dramatic response upon reinvasion of the same pathogen.
A memory cell is an antigen-specific B or T lymphocyte that does not differentiate into effector cells during the primary immune response, but that can immediately become effector cells upon re-exposure to the same pathogen. Memory cells continue to exist in circulation in order to work as needed.
A subset of T and B cells of the mucosal immune system differentiates into memory cells just as in the systemic immune system.
The regulation, maturation, and intercommunication of immune factors occur at specific sites. The blood circulates immune cells, proteins, and other factors throughout the body, specifically leukocytes, which encompass monocytes, and lymphocytes. The majority of cells in the blood are erythrocytes (red blood cells). Lymph is a watery fluid that bathes tissues and organs with protective white blood cells and does not contain erythrocytes. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by the process of extravasation, or passing through to surrounding tissue.
The cells of the immune system originate from hematopoietic stem cells in the bone marrow. Cytokines stimulate these stem cells to differentiate into immune cells. B cell maturation occurs in the bone marrow, whereas naive T cells transit from the bone marrow to the thymus for maturation.
Mature T and B cells circulate throughout the body and lymph nodes house large amounts of T and B cells, dendritic cells, and macrophages. Lymph gathers antigens and are filtered through the lymph nodes by APCs.
The spleen houses B and T cells, macrophages, dendritic cells, and NK cells. In the spleen APCs with foreign particles can communicate with lymphocytes. Antibodies are created and secreted by plasma cells in the spleen, and the spleen filters foreign substances and pathogens from the blood.
Antibodies, (antibody, singular) or immunoglobulin (lg), is a protein that is produced by plasma cells after stimulation by an antigen. Antibodies are the functional basis of humoral immunity. Antibodies occur in the blood, in gastric and mucus secretions, and in breast milk. Antibodies in these bodily fluids can bind pathogens and mark them for destruction by phagocytes before they can infect cells.
The antibody molecule is comprised of four polypeptides: two identical heavy chains of large peptide units that are partially bound to each other in a Y formation, and which are flanked by two identical light chains or small peptide units.
Bonds between the cysteine amino acids in the antibody molecule attach the polypeptides to each other. The areas where the antigen is recognized on the antibody are variable domains and the antibody base is comprised of constant domains.
Antibody diversity is produced by the mutation and recombination of approximately 300 different gene segments encoding the light and heavy chain variable domains in precursor cells that are destined to become B cells.
Antibodies can be divided into five classes: IgM, IgG, IgA, IgD, IgE, and are based on their physiochemical, structural, and immunological properties. IgGs are the majority of antibodies and have heavy chains of one variable domain and three identical constant domains. IgA and IgD also have three constant domains per heavy chain, and IgM and IgE each have four constant domains per heavy chain. The variable domain determines the binding specificity and the constant domain of the heavy chain determines the immunological mechanism of action of the corresponding antibody class.
After an adaptive defense is produced against a pathogen, typically plasma cells first secrete IgM into the blood.
IgA is found in mucous, saliva, tears, and breast milk and protects against pathogens. IgD is part of the B cell receptor and activates basophils and mast cells. IgE protects against parasitic worms and is responsible for allergic reactions. IgG is secreted by plasma cells in the blood and is able to cross the placenta into the fetus. IgM may be attached to the surface of a B cell or secreted into the blood and is responsible for early stages of immunity.
Passive immunity is a phenomenon and function of antibodies where they circulate freely and act independent of plasma cells. Antibodies can be transferred from one individual to another to temporarily protect against infectious disease, such as through donated blood from one person to another or during breastfeeding between mother and child.
Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the pathogen that enhance their infectivity and prevent pathogens from entering and infecting host cells. The neutralized pathogen can be filtered out of the body through the spleen and through waste material. Antibodies may block infection by preventing the antigen from binding to its target, tagging a pathogen for destruction by phagocytic cells such as macrophages or neutrophils, or activating the compliment cascade. Phagocytic enhancement by antibodies is called opsonization. Compliment fixation allows IgM and IgG in serum to bind to antigens and allows other compliment proteins to bind.
Antibodies do not always bind with the same strength, specificity, and stability. Antibodies exhibit different affinities or attraction strength depending on the molecular complementarity between antigen and antibody molecules. Avidity refers to the strength of all interactions combined when binding by antibody classes are secreted as joined, multivalent structures. The avidity depends on the number of identical binding sites on the antigen being detected along with other physical and chemical factors. Cross reactivity occurs when an antibody binds not to the antigen that elicited its synthesis and secretion, but to a different antigen. Cross reactivity can be beneficial if an individual develops immunity to several related pathogens despite having only been exposed to or vaccinated to one of them.
Antibodies of the mucosal immune system include IgA and IgM. Activated B cells differentiate into mucosal plasma cells that create and secrete dimeric IgA and IgM. Secreted IgA is abundant in tears, saliva, breast milk, and in secretions of the gastrointestinal and respiratory tracts.
The variety, specificity, and reliability of antibodies makes them ideally suited for certain medical tests and investigations, such as radioimmunoassays (RIA), which use the antigen-antibody interaction to detect the presence and or concentration of certain antigens.
Immunodeficiency is the failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including medical treatments, radiation), malnutrition, or extreme stress. Radiation exposure can damage the immune system in particular lymphocytes, increasing risk of infections and cancer. Some genetic disorders result in immunodeficiencies, such as not producing enough neutrophils or phagocytes.
Hypersensitivities are maladaptive immune responses toward harmless foreign substances or self antigens that occur after tissue sensitization. The types of hypersensitivities include immediate, delayed, and autoimmunity. More that one type of hypersensitivity can affect an individual.
Allergies are the immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a harmless antigen. Upon initial exposure to an potential allergen, an allergic individual creates antibodies of the IgE class via the typical process of APCs presenting processed antigen to Th cells that stimulate B cells to produce IgE and attached to mast cells. Additional exposure to the antigen causes the binding of the antigen to IgE primed mast cells and causes the release of chemical mediators that elicit an allergic reaction. Allergic reactions can cause sneezing, itchy, watery eyes, intense itching, airway contraction, and low blood pressure.
Delayed hypersensitivity is a cell-mediated immune response that takes about one to two days after secondary exposure for a maximum reaction to be observed.
Autoimmunity is when the immune system incorrectly identifies the body's own healthy tissues as foreign, leading to an immune response to them. Autoimmunity is a type of hypersensitivity to self antigens that usually involve the humoral immune response. Antibodies that inappropriately mark self components as foreign are termed autoantibodies. Autoimmunity can develop over time and its causes could be from molecular mimicry, genetics, or environmental causes. Autoimmunity can cause diseases like type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. Symptoms include fatigue, joint pain, skin issues, and inflammation.