Glossary of Terms Frequently Used in the Database
microorganism or microbe is an organism that is microscopic (too small to be visible to the human eye). The study of microorganisms is called microbiology. Microorganisms can be bacteria, fungi, archaea or protists, but not viruses and prions because they are generally classified as non-living (though database includes them also) . Micro-organisms are often described as single-celled, or unicellular organisms; however, some unicellular protists are visible to the human eye, and some multicellular species are microscopic.
Microorganisms live almost everywhere on earth where there is liquid water, including hot springs on the ocean floor and deep inside rocks within the earth's crust. Microorganisms are critical to nutrient recycling in ecosystems as they act as decomposers. As some microorganisms can also fix nitrogen, they are an important part of the nitrogen cycle. However, pathogenic microbes can invade other organisms and therefore cause disease.
An antigen is a molecule that stimulates an immune response, especially the production of antibodies by plasma B cells. Antigens are usually proteins or polysaccharides, but can be any type of molecule, including small molecules (haptens) coupled to a carrier-protein.
Types of antigens
Immunogen - Any substance that provokes the immune response when introduced into the body. An immunogen is always a macromolecule (protein, polysaccharide). Its ability to stimulate the immune reaction depends on its commonness to the host, molecular size, chemical composition and heterogeneity (e.g. similar to amino acids in a protein).
Tolerogen - An antigen that invokes a specific immune non-responsiveness due to its molecular form. If its molecular form is changed, a tolerogen can become an immunogen.
Allergen - An allergen is a substance that causes the allergic reaction. It can be ingested, inhaled, injected or brought into contact with skin.
Cells present their antigens to the immune system via a histocompatibility molecule. Depending on the antigen presented and the type of the histocompatibility molecule, several types of immune cells can become activated.
Origin of antigens
Antigens can be classified in order of their origins.
Exogenous antigens are antigens that have entered the body from the outside, for example by inhalation, ingestion, or injection. By endocytosis or phagocytosis, these antigens are taken into the antigen-presenting cells (APCs) and processed into fragments. APCs then present the fragments to T helper cells (CD4+) by the use of class II histocompatibility molecules on their surface. Some T cells are specific for the peptide:MHC complex. They become activated and start to secrete cytokines. Cytokines are substances that can activate cytotoxic T lymphocytes (CTL), antibody-secreting B cells, macrophages and other cells.
Endogenous antigens are antigens that have been generated within the cell, as a result of normal cell metabolism, or because of viral or intracellular bacterial infection. The fragments are then presented on the cell surface in the complex with class I histocompatibility molecules. If activated cytotoxic CD8+ T cells recognize them, the T cells begin to secrete different toxins that cause the lysis or apoptosis of the infected cell. In order to keep the cytotoxic cells from killing cells just for presenting self-proteins, self-reactive T cells are deleted from the repertoire as a result of central tolerance (also known as negative selection which occurs in the thymus). Only those CTL that do not react to self-peptides that are presented in the thymus in the context of MHC class I molecules are allowed to enter the bloodstream.
There is an exception to the exogenous/endogenous antigen paradigm, called cross-presentation.
An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease. These antigens should under normal conditions not be the target of the immune system, but due to mainly genetic and environmental factors the normal immunological tolerance for such an antigen has been lost in these patients.
Tumor antigens are those antigens that are presented by the MHC I molecules on the surface of tumor cells. These antigens can sometimes be presented only by tumor cells and never by the normal ones. In this case, they are called tumor-specific antigens (TSAs) and typically result from a tumor specific mutation. More common are antigens that are presented by tumor cells and normal cells, and they are called tumor-associated antigens (TAAs). Cytotoxic T lymphocytes that recognized these antigens may be able to destroy the tumor cells before they proliferate or metastasize.
Tumor antigens can also be on the surface of the tumor in the form of, for example, a mutated receptor, in which case they will be recognized by B cells.
An epitope is the part of a macromolecule that is recognized by the immune system, specifically by antibodies, B cells, or cytotoxic T cells. Although usually epitopes are usually thought to be derived from nonself proteins, sequences derived from the host that can be recognized are also classified as epitopes.
Most epitopes recognized by antibodies or B cells can be thought of as three-dimensional surface features of an antigen molecule; these features fit precisely and thus bind to antibodies. The part of an antibody that recognizes the epitope is called a paratope. Exceptions are linear epitopes, which are determined by the amino acid sequence (the primary structure) rather than by the tertiary structure of a protein.
T cell epitopes are presented on the surface of an antigen-presenting cell, where they are bound to MHC molecules. T cell epitopes presented by MHC class I molecules are typically peptides between 8 and 11 amino acid in lengths, while MHC class II molecules present longer peptides, and non-classical MHC molecules also present non-peptidic epitopes such as glycolipids.
Epitopes can be mapped using protein microarrays, and with the ELISPOT or ELISA techniques.
Genetic sequences coding for epitopes that are recognised by common antibodies can be fused to genes, thus aiding further molecular characterization of the gene product. Common epitopes used for this purpose are c-myc, HA, FLAG, V5.
Interestingly, epitopes are sometimes cross-reactive. This property is exploited by the immune system in regulation by Anti-idiotypic antibodies (originally proposed by Nobel laureate Niels Kaj Jerne). If an antibody binds to an antigen's epitope, the paratope could become the epitope for another antibody that will then bind to it. If this second antibody is of IgM class, its binding can upregulate the immune response; if the second antibody is of IgG class, its binding can downregulate the immune response.
Intensive research is currently taking place to design reliable tools that will predict epitopes on proteins.
B cells are lymphocytes that play a large role in the humoral immune response as opposed to the cell-mediated immune response that is governed by T cells. The abbreviation "B" comes from bursa of Fabricius that is an organ in birds in which avian B cells mature. The principal function of B cells is to make antibodies against soluble antigens. B cells are an essential component of the adaptive immune system.
The human body makes millions of different types of B cells each day that circulate in the blood and lymph performing the role of immune surveillence. They do not produce antibodies until they become fully activated. Each B cell has a unique receptor protein (referred to as the B cell receptor (BCR)) on its surface that will bind to one particular antigen. The BCR is a membrane-bound immunoglobulin, and it is this molecule that allows the distinction of B cells from other types of lymphocyte, as well as being the main protein involved in B cell activation. Once a B cell encounters its cognate antigen and receives an additional signal from a helper T cell, it can further differentiate into one of the two types of B cells listed below. The B cell has two choices at this stage; it can either become one of these cell types directly or it can go through an intermediate differentiation step (the germinal center reaction) where the B cell will hypermutate the variable region of its immunoglobulin gene and possibly undergo class switching.
T cells belong to group of white blood cells known as lymphocytes and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and NK cells by the presence of a special receptor on their cell surface that is called the T cell receptor (TCR). The abbreviation "T", in T cell, stands for thymus since it is the principal organ for their development.
Several different subsets of T cells have been described, each with a distinct function.
Cytotoxic T cells (Tc cells) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells, since they express the CD8 glycoprotein at their surface.
Helper T cells, (Th cells) are the "middlemen" of the adaptive immune system. Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or "help" the immune response. These cells (also called CD4+ T cells) are a target of HIV infection; the virus infects the cell by using the CD4 protein to gain entry. The loss of Th cells as a result of HIV infection leads to the symptoms of AIDS.
Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+.
Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell mediated immunity towards the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of regulatory T cells have been described, including the naturally occurring Treg cells and the adaptive Treg cells. Naturally occurring Treg cells (also known as CD4+CD25+FoxP3+ Treg cells) arise in the thymus, whereas the adaptive Treg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.
Natural Killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigen presented by MHC molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both Th and Tc cells (i.e. cytokine production and release of cytolytic/cell killing molecules).
Adjuvants are agents which modify the effect of other agents while having few if any direct effects when given by themselves. In this sense, they are very roughly analogous with chemical catalysts.
In immunology an adjuvant is an agent which, while not having any specific antigenic effect in itself, may stimulate the immune system, increasing the response to a vaccine. Aluminum salts are used in some human vaccines,although a recent study revealed aluminum adjuvants can cause neuron death.
During the last two decades a variety of technologies have been investigated to improve the widely used, but unfavorable adjuvants based on aluminum salts. These salts develop their effect by inducing a local inflammation, which is also the basis for the extended side-effect pattern of this adjuvant.
Vaccines may be living, weakened strains of viruses or bacteria that intentionally give rise to unapparent-to-trivial infections. Vaccines may also be killed or inactivated organisms or purified products derived from them.
There are four types of traditional vaccines:
Inactivated - these are previously virulent micro-organisms that have been killed with chemicals or heat. Examples are vaccines against flu, cholera, bubonic plague, and hepatitis A. Most such vaccines may have incomplete or short-lived immune responses and are likely to require booster shots.
Live, attenuated - these are live micro-organisms that have been cultivated under conditions that disable their virulent properties. They typically provoke more durable immunological responses and are the preferred type for healthy adults. Examples include yellow fever, measles, rubella, and mumps.
Toxoids - these are inactivated toxic compounds from micro-organisms in cases where these (rather than the micro-organism itself) cause illness. Examples of toxoid-based vaccines include tetanus and diphtheria.
Subunit - rather than introducing a whole inactivated or attenuated micro-organism to an immune system, a fragment of it can create an immune response. Characteristic examples include the subunit vaccine against HBV that is composed of only the surface proteins of the virus (produced in yeast) and the virus like particle (VLP) vaccine against Human Papillomavirus (HPV) that is composed of the viral major capsid protein.
The live tuberculosis vaccine is not the contagious TB strain, but a related strain called "BCG"; it is used in the United States very infrequently.
A number of innovative vaccines are also in development and in use:
Conjugate - certain bacteria have polysaccharide outer coats that are poorly immunogenic. By linking these outer coats to proteins (e.g. toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.
Recombinant Vector - by combining the physiology of one micro-organism and the DNA of the other, immunity can be created against diseases that have complex infection processes
DNA vaccination - in recent years a new type of vaccine, created from an infectious agent's DNA called DNA vaccination, has been developed. It works by insertion (and expression, triggering immune system recognition) into human or animal cells, of viral or bacterial DNA. Some cells of the immune system that recognize the proteins expressed will mount an attack against these proteins and cells expressing them. Because these cells live for a very long time, if the pathogen that normally expresses these proteins is encountered at a later time, they will be attacked instantly by the immune system. One advantage of DNA vaccines is that they are very easy to produce and store. As of 2006, DNA vaccination is still experimental, but shows some promising results.
Note that while most vaccines are created using inactivated or attenuated compounds from micro-organisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates or antigens.
The immune system recognizes vaccine agents as foreign, destroys them, and 'remembers' them. When the virulent version of an agent comes along, the immune system is thus prepared to respond, by (1) neutralizing the target agent before it can enter cells, and (2) by recognizing and destroying infected cells before that agent can multiply to vast numbers.
Vaccines have contributed to the eradication of smallpox, one of the most contagious and deadly diseases known to man. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were just a hundred years ago. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only between humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of four countries. The difficulty of reaching all children, however, has caused the eradication date to be missed twice by 2006.