Immune system

The immune system is the collection of organs and tissues involved in the adaptive defense of a body against foreign biological material. It may be broken down into the adaptive immune system, composed of four lymphoid organs (thymus, lymph nodes, spleen and submucosal lymphoid nodules) and the group motile cells that are involved in the body's defense against foreign bodies. The term may also be used to refer to the totality of a body's defense systems, encompassing both the adaptive immune system and other passive defenses, such as the skin.

In multicellular organisms, the immune system is an organ system that acts as a defense against foreign pathogens (such as viruses, bacteria, parasites), some poisons, as well as cancer. Components of the immune system also function in the return of extracellular fluid to the blood.

Bacteria and monocellular organisms have an "immune system" (under the broader of the two definitions above) designed to combat bacteriophages (viruses that infect bacteria). They do this by simultaneously expressing restriction enzymes that cut DNA at certain sequences, and enzymes that protect their own DNA from this enzyme by methylating the same sequence. Therefore, the bacterium's DNA will not be damaged by the first enzyme because of the presence of the second enzyme. However, when a bacteriophage attempts to infect this bacterium, the viral DNA has not been protected, and gets degraded by the first enzyme. While study of the bacterial immune system provides useful insights into immunology, the remainder of this article will focus on higher organisms' immune systems, particularly the human immune system.

Recognizing self and non-self

The immune system defends the body by recognizing agents that represent self and those that represent non-self, and launching attacks against harmful members of the latter group. Distinguishing between self and non-self and between harmful non-self and harmless non-self is a difficult problem, and a variety of human disorders arise from failures of discriminatory systems (see Immune System#Disorders of the human immune system).

Some self/non-self discrimination is effected by hard-wired mechanisms that recognize features displayed only by pathogens. The MBL pathway of the complement system, for instance, recognizes mannose sugars, which appear only in the polysaccharide coats of bacterium. The most interesting mechanisms of discrimination, however, are not hard-wired --- rather, they involve the immune system learning to recognize non-self.

For instance, the plasma membrane of every nucleated cell contains molecules of a large glycoprotein called the major histocompatibility complex (MHC). These proteins have configurations and amino acid sequences that are unique to every individual. T cells, a group that encompasses cytotoxic T lymphocytes (CTLs), the cells that kill virally-infected cells, contain surface-mounted receptors that they use to determine if a given cell is virally infected by reading the peptides displayed on its MHC molecules. During their development, T cells are tested for self-reactivity. If a given cell contains receptors that bind strongly to an existing molecule in the body, it is destroyed by forced apoptosis, leaving behind T cells that can be safely released into the body. (This is a much-truncated picture of T cell development; see the article on T cells for more).

Structure of the immune system

Most multicellular organisms possess an immune system consisting of innate immunity which generally consists of a set of genetically-encoded responses to pathogens and does not change during the lifetime of the organism. Adaptive immunity, in which the response to pathogens changes during the lifetime of an individual, appeared somewhat abruptly in evolutionary time with the appearance of cartilaginous (jawed) fish. Organisms that possess an adaptive immunity also possess an innate immunity and many of the mechanisms between the systems are common, so it not always possible to draw a hard and fast boundary between the individual components involved in each, despite the clear difference in operation. Higher vertebrates and all mammals have both an innate and an adaptive immune system.

Innate immune system

The adaptive immune system may take days or weeks after an initial infection to have an effect. However, most organisms are under constant assault from pathogens, which must be kept in check by the faster-acting innate immune system. Innate immunity fights pathogens using defenses that are quickly mobilized and triggered by receptors that recognize a broad spectrum of pathogens. Plants and many lower animals do not possess an adaptive immune system and instead rely on innate immunity.

The study of the innate immune system has recently flourished. Earlier studies of innate immunity utilized model organisms that lack adaptive immunity such as the plant Arabidopsis thaliana, the fly Drosophila melanogaster, and the worm Caenorhabditis elegans. Recent advances have been made in the field of innate immunology with the discovery of the toll-like receptors, which are the receptors in mammals that are responsible for a large proportion of the innate immune recognition of pathogens. There is strong evidence that these toll-like receptors are responsible for sensing the "pathogen-associated molecular patterns" and/or providing the "danger signal" as speculated by Janeway and Matzinger, respectively.

Physical barrier

The first defense includes barriers to infection such as skin and mucus coating of the gut and airways, physically preventing the interaction between the host and pathogen. Pathogens which penetrate these barriers encounter constitutively expressed anti-microbial molecules that restrict the infection.

Phagocytic cells

The second-line defense includes phagocytic cells, which includes macrophages and neutrophil granulocytes (polymorphonuclear leukocytes, PMN) that can engulf (phagocytose) foreign substances. Macrophages are thought to mature continuously from circulating monocytes.

Phagocytosis involves chemotaxis, where phagocytic cells are attracted to microorganisms by means of chemotactic chemicals like microbial products, complements, damaged cells and white blood cell fragments; chemotaxis is followed by adhesion, where the phagocyte sticks to the microorganism. Adhesion is enhanced by opsonization, where proteins like opsonins are coated on the surface of the bacterium. This is followed by ingestion, in which the phagocyte extends projections, forming pseudopods that engulf the foreign organism. Finally the bacterium is digested by the enzymes in the lysosome.

Anti-microbial proteins

In addition, anti-microbial proteins may be activated if a pathogen pass through the barrier offered by skin. There are several class of antimicrobial proteins, such as acute phase proteins (C-reactive protein, for example, binds to the C-protein of S. pneumoniae - enhances phagocytosis and activates complement), lysozyme and the complement system.

Complement system

The complement system is a very complex group of serum proteins which is activated in a cascade fashion. Three different pathways, the classical, alternative, and mannose-binding lectin pathways, are involved in complement activation. The first recognizes antigen-antibody complexes, the second spontaneously activates on contact with pathogenic cell surfaces, the third recognizes mannose sugars, which tend to appear only on pathogenic cell surfaces. A cascade of protein activity follows complement activation; this cascade can result in a variety of effects including opsonization of the pathogen, destruction of the pathogen by formation and activation of the membrane attack complex, and inflammation.

Adaptive immune system

The adaptive immune system, also called the acquired immune system, ensures that most mammals that survive an initial infection by a pathogen are generally immune to further illness caused by that same pathogen. Vaccination exploits this mechanism to produce immunity by way of introducion of an attenuated pathogen. The adaptive immune system is based on immune cells called leukocytes (or white blood cells) that are produced by stem cells in the bone marrow. In many species, including mammals, the adaptive immune system can be divided into two major sections:

The humoral immune system, which acts against bacteria and viruses in the body liquids (such as blood). Its primary means of action are proteins called immunoglobulins, also called antibodies, which are produced by B cells
The cellular immune system, which (among other duties) destroys virus-infected cells. The functions of CMI are performed by T cells, also called T lymphocytes (T means they develop in the thymus). There are two major types of T cells:
- Cytotoxic T cells (T_C cells) recognize infected cells by using T-cell receptors to probe the surface of other cells. If they recognize an infected cell, they release granzymes to signal that cell to become apoptotic ("commit suicide"), thus killing that cell and any viruses it is in the process of creating.
- Helper T cells (T_H cells) activate infected macrophages (cells that ingest dangerous material), and also produce cytokines (interleukins) that induce the proliferation of B and T cells.
- In addition, there are Regulatory T cells (T_reg cells) which are important in regulating cell-mediated immunity.

The intersection between innate and adaptive immune systems

Splitting the innate and adaptive immunity has served to simplify discussions of immunology. However, the systems are quite intertwined in a number of important respects.

One of the most important examples are the mechanisms of antigen presentation. After they leave the thymus, T cells require activation to proliferate and differentiate into "killer" T cells (CTLs). Activation is provided by antigen presenting cells (APCs). A major category of APCs involved in T cell activation, the dendritic cells, are part of the innate immune system. Activation occurs when a DC simulatenously binds to a T "helper" cell's antigen receptor and to its CD28 receptor, which provides the "second signal" needed for DC activation. This signal is a means by which the DC conveys that the antigen is indeed dangerous, and the next encountered T "killer" cells need to be activated. This mechanism is based on antigen danger evaluation by T cells that are all belonging to the adaptive immune system. But the dendritic cells are often directly activated by engaging their toll like receptors, getting their "second signal" directly from the antigen. In this way they actually recognize in "first person" the danger and direct the T killer attack. In this way, the innate immune system plays a critical role in the activation of the adaptive immune system.

Adjuvants, or chemicals that stimulate an immune response, provide artificially this "second signal" in procedures when an antigen that would not normally raise an immune response is artificially introduced into a host. With the adjuvant, the response is much more robust. Historically, a commonly used formula Freund's Complete Adjuvant, an emulsion of oil and mycobacterium. It was later discovered that toll-like receptors, expressed on innate immune cells, are critical in the activation of adaptive immunity.

Disorders of the human immune system

Many disorders of the human immune system fall into two broad categories: those characterized by attenuated immune response and those characterized by overzealous immune response.

Immunodeficiency is characterized by an attenuated response. There are congenital (inborn) and acquired forms of immune deficiency. Chronic granulomatous disease, in which phagocytes have trouble destroying pathogens, is an example of the former. AIDS ("Acquired Immune Deficiency Syndrome"), an infectious disease, caused by the HIV virus that destroys CD4⁺ T cells, is an example of the latter. Immunosuppressive medication intentionally induces an immunodeficiency in order to prevent rejection of transplanted organs.

On the other end of the scale, an overactive immune system figures in a number of other disorders, particularly autoimmune disorders such as lupus erythematosus, type I diabetes (sometimes called "juvenile onset diabetes"), multiple sclerosis, psoriasis, and rheumatoid arthritis. In these the immune system fails to properly distinguish between self and non-self and attacks a part of the patient's own body. Other examples of overzealous immune responses in disease include hypersensitivities such as allergies and asthma.