The innate immunity is present before any prior exposure to pathogens and is effective from the time of birth. These are largely unspecific and are quick to recognize and respond to a broad range of microbes regardless of their precise identity.
Innate Immunity [Rapid response]
- Mucous membrane
|- Phagocytic cells
- Antimicrobial proteins
- Inflammatory Response
- Natural Killer Cell
|- Humoral Response
- Cell-mediated response
Intact skin is a barrier that is normally impenetrable by virus or bacteria, but even tiny abrasions might allow their passage. Likewise, the mucous membranes lining the digestive, respiratory tract bars entry of potentially harmful microbes. Certain cells of these mucous membranes also produce mucus, a viscous fluid that traps microbes and other particles. In the trachea for example ciliated epithelial cells sweep mucus and entrapped microbes upwards, preventing microbes from entering the lungs.
Beyond the physical role of inhibiting microbe entry, secretions also provide an environment that is hostile to microbes. Take for example secretions from sebaceous glands and sweat glands that give the skin a pH ranging from 3 to 5 which is acidic enough to inhibit microbe colonization. Secretions from the skin and mucous membranes also contain antimicrobial proteins like lysozyme which digests the cell walls of most bacteria.
Microbes that penetrate the body’s external defense such as those that enter via a break in the skin would face the body’s internal innate defense. These defenses rely mainly upon phagocytosis, the ingestion of invading microorganisms by certain types of blood cells. Generically referred to as phagocytes, these cells produce certain antimicrobial proteins that help initiate inflammation which can limit the spread of microbes in the body. Non-phagocytic white blood cells, called natural killer cells also play a key role in innate defense. These various non-specific mechanisms help to limit the spread of microbes before the body can mount acquitted specific immune response.
Phagocytes attach to their prey via surface receptors that bind to structures found on many micro-organisms. Among the structures bound by these receptors are certain polysaccharides on the surface of bacteria. After attaching to one or more microbes, a phagocyte engulfs the microbes, forming a vacuole that fuses with a lysosome. First, nitric oxide and other forms of oxygen contained in the lysosomes may poison the engulfed microbes. Second, lysozymes and other enzymes degrade microbial components. Some microorganisms have adaptations that enable them to evade destruction by phagocytic cells, by for example hiding their surface polysaccharides, thus preventing binding of phagocytes. Other bacteria like the one that causes tuberculosis are resistant to destruction within the lysosomes.
There are four different types of white blood cells which are phagocytic and they differ in abundance, average life span and phagocytic ability.
By far, the most abundant are neutrophils, which constitute about 60% to 70% of all white blood cells. Neutrophils are attracted to and then enter infected tissue, engulfing and destroying the microbes there. However, neutrophils tend to self-destruct in the process of phagocytosis, and their average life span is only a few days. Macrophages are more effective and they develop from monocytes which constitutes about 5% of the circulating white blood cells. New monocytes circulate the blood for a few hours before being transformed into macrophages. The other two forms of phagocytes are less abundant and play a more limited role in innate defense. Eosinophils have low phagocytic activity but are crucial to defense against multicellular parasitic invaders, such as blood fluke. Rather than engulfing the parasite, they position themselves against the parasite’s body and then discharge destructive enzymes that damage the invader. The last form of phagocyte is dendritic cells that ingest microbes.
Numerous proteins function in innate defense by attacking microbes directly attacking the microbes or by impeding their reproduction. Apart from lysozyme, there are about 30 other serum proteins that make up the complement system. In the absence of an infection, these proteins are inactive. Substances on the surface of many microbes, however, can trigger a cascade of steps that activate the complement, leading to lysis of invading cells.
Two types of interferon provide innate defense against viral infections. These proteins are secreted by virus-infected body cells and induce neighboring uninfected cells to produce other substances that inhibit viral production, thus limiting the cell-to-cell spread of virus in the body, helping to control viral infections such as colds and influenza. This innate defense mechanism is not virus specific and interferon produced in response to one virus might also confer short term resistance to unrelated viruses.
Damage to tissue by physical injuries or the entry of pathogens leads to release of numerous chemical signals that trigger a localized inflammatory response. One of the most active chemical is histamine which is stored in mast cells found in connective tissues. When injured, mast cells release histamine that triggers dilation and increased permeability of nearby capillaries. These result in increased local blood supply, causing redness and heat typical of inflammation. The blood-engorged capillaries leak fluid into neighboring tissues, causing swelling. These vascular changes help deliver antimicrobial protein and clotting elements to the injured location. Blood clotting begins repair process and helps block the spread of microbes to other parts of the body. Increased blood flow and vessel permeability would also allow more neutrophils and monocyte macrophages to move from the blood into injured tissue. A minor injury causes a local inflammation, but the body may also mount a systemic (widespread) response to severe tissue damage or infection. In a severe infection such as meningitis or appendicitis the number of white blood cells would rapidly increase. Another systemic response is fever which may occur when certain toxins produced by pathogens and substances released by actuated macrophages set the body’s thermostat at a higher slightly higher temperature. A very high fever is dangerous, but a moderate fever can facilitate phagocytosis and, by speeding up body reactions, hasten the repair of tissues. Certain bacterial infection can induce an overwhelming systemic inflammatory response, leading to a condition called septic shock which is characterized by high fevers and low blood pressure.
Natural Killer Cells
Natural killer cells patrol the body and attack virus-infected body cells and cancer cells. Surface receptors on natural killer cells recognize general features on the surface of its targets. Once it is attached to a virus infected cell or cancer cell, the natural killer cell releases chemicals that lead to the death of the stricken cell by apoptosis, or programmed cell death.
Invertebrate Immune Mechanism
Invertebrates also have highly effective innate defense, for example, sea stars possess amoeboid cells that ingest foreign matter via phagocytosis and secrete molecules that enhance the animal’s defensive response. The insects’ equivalent to blood, hemolymph, contains circulating cells called hemocytes. Some of them ingest bacteria and foreign substances while others would form a cellular capsule around large parasites.
Pathogens would inevitably come into contact with lymphocytes while under the assault by one’s innate defense. Lymphocytes are the key cells of acquired immunity – the body’s second major form of defense. Direct contact with microbes and signals from active innate defenses will cause lymphocytes to join the battle. Any foreign molecule that is specifically recognized by lymphocytes and elicits response from them is called an antigen. Most antigens are large molecules, either polysaccharide. Some antigens, such as toxins secreted by bacteria, are dissolved in extracellular fluid, but many protrude from the surface of pathogens or transplanted cells. A lymphocyte actually recognizes and binds to just a small, accessible portion of an antigen, called an epitope (antigenic determinant). A single antigen usually has several epitopes, each capable of inducing a response from lymphocytes that recognize that epitope. Antibodies which are secreted by certain lymphocytes in response to antigens, likewise bind to specific epitopes.
Antigen recognition by Lymphocytes
The body is populated by two main types of lymphocytes – T cells and B cells. Both types are circulated through the blood and lymph and are concentrated in the spleen, lymph nodes and other lymphoid tissues. B cells and T cells recognize antigens by means of antigen-specific receptors embedded in their plasma membranes, a single B or T cell bears about 100,000 of these antigen receptors, and all the receptors on a single cell are identical – that is, they all recognize the same epitope. Each lymphocyte displays specificity for a particular epitope on an antigen and defends against that antigen or a small set of closely related antigens. A great diversity of T cells and B cells are present, however, only a tiny fraction of the lymphocytes would ever be used.
B cell Receptors for Antigens
Each B cell receptor for an antigen is a Y-shaped molecule consisting of four pol-peptide chains: two identical heavy chains and two identical light chains linked by disulfide bridges. A region in the tail portion of the molecules, the trans-membrane region anchors the receptor in the cell’s plasma membrane and a short region at the end of the tail extends into the cytoplasm. At the tips of the Y are the light and heavy chain variables which vary extensively from one B cell to another. The remainder of the molecule is the constant regions whose amino acids vary little from cell to cell. The unique contour of each binding site is formed from part of a light-chain V region. The interaction between an antigen binding site and its corresponding antigen is stabilized by multiple non-covalent bonds between chemical groups on the respective molecules. The antigens bound by the B cell receptors in this way include molecules that are on the surface of, or are released from, all types of infectious agents, thus meaning that it can recognize an intact antigen in its native state.
T cell receptors for antigens and role of the MHC
Each T cell receptor for an antigen consists of two different polypeptide chains, a cell and a chain, linked by a disulfide bridge. Near the base of the molecule is a trans-membrane region that anchors the molecule in the cell’s plasma membrane. At the outer tip of the molecule, the cell and a chain variable regions form a single antigen binding site. The remainder of the molecule is made up of constant regions.
T cell receptors recognize and bind with antigens just as specifically as a B cell receptors. However, while the receptors on B cells recognize intact antigens, the receptors on T cells recognize small fragments of antigens that are bound to normal cell surface proteins called major histocompatibility complex (MHC) molecules. As a newly synthesizes MHC molecule is transported towards the plasma membrane, it bind with a fragment of protein antigen within the cell and brings it to the cell surface via a process called antigen presentation. A nearby T cell can detect the antigen fragment thus displayed on the cell surface. There are two ways in which foreign antigens can end up inside cells of the body. Depending on their source, these peptide antigens are handled by a different class of MHC molecule and recognized by a particular subgroup of T cells.
- Class 1 MHC molecules, found on almost all nucleated cells of the body bind peptides derived from foreign antigens that have been synthesized within the cell. Any body cell that becomes infected or cancerous can display such peptide antigens by virtue of its Class 1 MHC molecules. Class 1 molecules displaying bound peptide antigens are recognized by a subgroup of T cells, called cytotoxic T cells.
- Class 2 MHC molecules are made by just a few cell types, mainly dendritic cells, macrophages and B cells. In these cells, class 2 MHC molecules bind peptides derived from foreign materials that have been internalized and fragmented through phagocytosis or endocytosis. Dendritic cells, macrophages and B cells are known as antigen presenting cells because of their key role in displaying such internalized antigens to another subgroup of T cells called T helper cells.
Each vertebrate species possesses numerous different alleles for each class 1 and 2 MHC gene. Because of the large number of different MHC alleles in the human population, most of us are heterozygous for every one of our MHC genes and produce a broad array of MHC molecules. Collectively these molecules are capable of binding to and presenting a large number of peptide antigens. Thus MHC produces a biochemical fingerprint unique to virtually every individual. That marks body cells as ‘self’.
Humoral and Cell Mediated Immunity
There are two separate branches of acquired immunity, humoral immune response which involves the activation and clonal selection of B cells, resulting in production of secreted antibodies that circulate in the blood and lymph. The cell mediated immune response involves the activation and clonal selection of cytotoxic T cells, which directly destroy certain target cells. Central to the network of the humoral and cell mediated immune response are the helper T cells which responds to peptide antigens displayed on antigen presenting cells and in turn stimulates the activation of nearby B cells and cytotoxic T cells.
Helper T cells: A response to antigens
When a helper T cell encounters and recognizes a class 2 MHC molecule-antigen complex on an antigen presenting cell, the helper T cell proliferates and differentiate into a clone of activated helper T cells and memory helper T cells. Activated helper T cells secrete several different cytokine that would stimulate other lymphocytes, thereby promoting humoral and cell mediated response. The helper T cell itself is also subject to regulation by cytokines.
Cytotoxic T cells: A response to infected cells and cancer cells
Cytotoxic T cells, the effectors of cell-mediated immunity eliminate body cells infected by viruses or other intracellular pathogens as well as cancer cells and transplanted cells. Fragments of non-self-proteins synthesized in such target cells associate with class 1 MHC molecules and are displayed on the cell surface. When a cytotoxic cell is selected by binding to class 1 MHC molecule-antigen complexes on an infected body cell, the cytotoxic T cell is activated and differentiates into an active killer. Cytokines secreted from nearby helper T cells promote this activation. The activated cytotoxic T cell then secretes proteins that act on the bound infected cell, leading to its destruction. The death of the infected cell not only deprives the pathogen of a place to reproduce but also exposes it to circulating antibodies, which marks it for disposal. After destroying an infected cell, the cytotoxic T cell may move on and kill other cells infected with the same pathogen. In the same way, cytotoxic T cells defend against malignant tumors. Because tumor cells carry distinctive molecules not found on normal body cells, they are identified as foreign by the immune system. Class 1 MHC molecules of a tumor cell display fragments of tumor antigens to cytotoxic T cells.
B Cells: A response to extracellular Pathogens
Antigens that elicit a humoral immune response are typically proteins and polysaccharides present on the surface of bacteria or incompatible transplanted tissue or transfused blood cells. The activation of B cells is aided by cytokines secreted from helper T cells activated by the same antigen. Stimulated by both an antigen and cytokines, the cell proliferates and differentiates into a clone of antibody-secreting plasma cells and a clone of memory B cells. When an antigen first binds to receptors on the surface of memory B cells, the cell takes in a few of the foreign molecules by receptor mediated endocytosis. In process similar to antigen presentation by macrophages and dendritic cells, the B cell then presents antigen fragments to the helper T cells. However, a macrophage or dendritic cell can present peptide fragments from a wide variety of antigens, whereas a B cell internalizes and presents only the antigen to which is specifically binds.
Antigens that induce antibody production only with assistance from helper T cells are known as T-dependent antigens. Some antigens however, can evoke a B cell response without involvement of helper T cells. Such t-independent antigens include polysaccharide of many bacterial capsules and proteins that make up the bacteria flagella. However, this response is generally weaker than the response to T-dependent antigens and through this process; no memory B cells are generated.
Active and Passive Immunization
Immunity conferred by natural exposure to an infectious agent is called active immunity because it depends on the actions of a person’s own lymphocytes and the resulting memory cells specific for the invading pathogen. Active immunity also can develop following immunization, or vaccination. Modern vaccines include inactivated bacterial toxins, killed microbes or parts of microbes, viable but weakened microbes that generally do not cause illness. All these agents would induce an immediate immune response and long lasting immunological memory.
Immunity can also be conferred by transferring antibodies from an individual who is immune to a particular infectious agent to someone who is not. This is known as passive immunity because it does not result from the action of the recipient’s own B and T cells. Instead, the transferred antibodies are poised to immediately help destroy any microbes for which they are specific. Passive immunity provides immediate protection, but it only persists for as long as the transferred antibodies last.
Allergies are exaggerated response to certain antigens called allergens. One hypothesis to explain the origin of allergies is that they are evolutionary remnants of the immune system’s response to parasitic worms. The humoral mechanism that combats worms is similar to the allergic response that causes such disorders.
The most common allergies involve antibodies of the IgE class. Hay fever; for instance, occur when plasma cells secrete IgE antibodies specific for antigens on the surface of pollen grains. Some of the antibodies attach by their tails to mast cells present in the connective tissues. Later when pollen grains enter the body, it induces the mast cell to release histamine and other inflammatory agents from their granules, a process called degranulation. Such vascular changes lead to typical allergy symptoms: sneezing, runny nose, teary eyes or difficulties in breathing. Antihistamines diminish allergy symptoms by blocking receptors for histamine.
An acute allergic response can sometimes lead to anaphylactic shock, a whole body, life threatening reaction that can occur within seconds of exposure to an allergen. Anaphylactic shock develops when widespread mast cell degranulation triggers abrupt dilation of peripheral blood vessels, causing a precarious drop in blood pressure.