Immune system

The immune system is the system of specialized cells and organs that protect an organism from outside biological influences. (Though in a broad sense, almost every organ has a protective function — for example, the tight seal of the skin or the acidic environment of the stomach.) When the immune system is functioning properly, it protects the body against bacteria and viral infections, destroying cancer cells and foreign substances. If the immune system weakens, its ability to defend the body also weakens, allowing pathogens, including viruses that cause common colds and flu, to grow and flourish in the body. The immune system also performs surveillance of tumor cells, and immune suppression has been reported to increase the risk of certain types of cancer.

The immune system is often divided into two sections:

Innate immunity: Comprised of hereditary (always there) components that provide an immediate "first-line" of defense to continuously ward off pathogens.
Adaptive (acquired) immunity: By manufacturing a class of proteins called antibodies, and by producing T-cells specifically designed to target particular pathogens, the body can develop a specific immunity to particular pathogens. This response takes days to develop, and so is not effective at preventing an initial invasion, but it will normally prevent any subsequent infection, and also aids in clearing up longer-lasting infections.

Note: One text divides between Nonspecific Defenses (skin, mucous membranes, phagoctyes, fever, interferon) and Specific Defenses (the cell-mediated immune system using cells, and the humoral system using proteins, both of which attack specific pathogens), and notes both the primary response and the seondary response for a secondary infection of the same pathogen.)

Structure

Most multicellular organisms possess an "innate immune system", generally comprising a set of germ-line encoded receptors to pathogens, that does not change during the lifetime of the organism. Adaptive immunity, in which the responses to pathogens change and develop during the lifetime of an individual, seems to have appeared somewhat abruptly in evolutionary time, with the appearance of chondrichthyes (cartilaginous or jawed fish).

Organisms that possess an adaptive immunity also possess an innate immunity, and with many of the mechanisms between the systems being common, it is 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 could take days or weeks after an initial infection to have an effect. However, most organisms are under constant assault from pathogens that must be kept in check by the faster-acting innate immune system. Innate immunity defends against pathogens by rapid responses coordinated through "innate" receptors that recognize a wide spectrum of conserved pathogenic components. Prior to jawed fish, lower animals, there is no evidence of adaptive immunity, animals therefore relied instead on their innate immunity. Plants on the other hand rely on secondary metabolites (aka phytochemicals) to defend themselves against fungal and viral pathogens as well as insect herbivory. Plant secondary metabolites are derived through vast arrays of plant biosynthetic pathways not needed directly for plant survival, hence why they are named secondary. Plant secondary metabolism should not be confused with innate or adaptive immunity as they evolved along an entirely different evolutionary lineages and rely on entirely different signal cues, pathways and responses when compared to each other.

The innate immune system, when activated, has a wide array of effector cells and mechanisms. There are several different types of phagocytic cells, which ingest and destroy invading pathogens. The most common phagocytes are neutrophils, macrophages, and dendritic cells. Another cell type, natural killer cells are especially adept at destroying cells infected with viruses. Another component of the innate immune system is known as the complement system. Complement proteins are normally inactive components of the blood. However, when activated by the recognition of a pathogen or antibody, the various proteins are activated to recruit inflammatory cells, coat pathogens to make them more easily phagocytosed, and to make destructive pores in the surfaces of pathogens.

Research

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 toll-like receptors (TLRs) and the intracellular nucleotide-binding site leucine-rich repeat proteins (NODs), which are receptors in mammal cells that are responsible for a large proportion of the innate immune recognition of pathogens.

In 1989, prior to the discovery of mammalian TLRs, Charles Janeway conceptualized and proposed that evolutionarily conserved features of infectious organisms were detected by the immune system through a set of specialized receptors, which he termed pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs), respectively. This was a remarkable insight at the time but was only fully appreciated after the discovery of TLRs by the Janeway lab in 1997. The TLRs now comprise the largest family of innate immune receptors (or PRRs). Janeway’s hypothesis has come to be known as the ‘stranger model’ and substantial debate in the field persists to this day as to whether or not the concept of PAMPs and PRRs, as described by Janeway, is truly suitable to describe the mechanisms of innate immunity. The competing ‘danger model’ was proposed in 1994 by Polly Matzinger and argues against the focus of the stranger model on microbial derived signals, suggesting instead that endogenous danger/alarm signals from distressed tissues serve as the principle purveyors of innate immune responses.

Both models are supported in the current literature, with discoveries that substances of both microbial and non-microbial sources are able to stimulate innate immune responses, which has led to increasing awareness that perhaps a blend of the two models would best serve to describe the currently known mechanisms governing innate immunity.

First-line defense: physical and chemical barrier

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

In addition to the usual defense, the stomach secretes gastric acid which, apart from aiding digestive enzymes in the stomach to work on food, prevents bacterial colonization by most pathogens.

Second-line defense: Phagocytic cells

The second-line defense includes phagocytic cells (macrophages and neutrophil granulocytes) 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 such as microbial products, complement, 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, involving reactive oxygen species and proteases.

Anti-microbial proteins

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

The complement system is a very complex group of serum proteins, which is activated in a cascade fashion. Three different pathways are involved in complement activation:

classical pathway: recognizes antigen-antibody complexes
alternative pathway: spontaneously activates on contact with pathogenic cell surfaces
mannose-binding lectin pathway: 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 the formation and activation of the membrane attack complex, and inflammation.

Interferons are also anti-microbial proteins. These molecules are proteins that are secreted by virus-infected cells. These proteins then diffuse rapidly to neighboring cells, inducing the cells to inhibit the spread of the viral infection. Essentially, these anti-microbial proteins act to prevent the cell-to-cell proliferation of viruses.

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. The adaptive immune system is based on dedicated immune cells termed leukocytes (white blood cells) that are produced by stem cells in the bone marrow, and mature in the thymus and/or lymph nodes. In many species, including mammals, the adaptive immune system can be divided into two major sections:

Humoral immune system

The humoral immune system acts against bacteria and viruses in the body liquids (e.g., blood) by means of proteins, called immunoglobulins (also known as antibodies), which are produced by B cells. Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction.

Humoral immunity refers to antibody production, and all the accessory processes that accompany it: Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation. It also refers to the effector functions of antibody, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.

B cells need two signals to initiate activation. Most antigens are T-dependent, meaning T cell help is required for maximal antibody production. With a T-dependent antigen, the first signal comes from antigen cross linking BCR and the second from the Th2 cell. T dependent antigens contain protein so that peptides can be presented on B cell Class II MHC to Th2 cells, which then provide co-stimulation to trigger B cell proliferation and differentiation into plasma cells. Isotype switching to IgG, IgA, and IgE and memory cell generation occur in response to T-dependent antigens.

Some antigens are T-independent, meaning they can deliver both the antigen and the second signal to the B cell. Mice without a thymus (nude or athymic mice) can respond to T-independent antigens. Many bacteria have repeating carbohydrate epitopes that stimulate B cells to respond with IgM synthesis in the absence of T cell help.

T-dependent responses require that B cells and their Th2 cells respond to epitopes on the same antigen. T and B cell epitopes are not necessarily identical. (Once virus-infected cells have been killed and unassembled virus proteins released, B cells specific for internal proteins can also be activated to make opsonizing antibodies to those proteins.) Attaching a carbohydrate to a protein can convert the carbohydrate into a T-dependent antigen; the carbohydrate-specific B cell internalizes the complex and presents peptides to Th2 cells, which in turn activate the B cell to make antibodies specific for the carbohydrate.

Cell-mediated immune system

The cell-mediated immune system destroys virus-infected cells (among other duties) with T cells (also called "T lymphocytes"; "T" means they develop in the thymus).

Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages and natural killer cells, the production of antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen. Historically, the immune system was separated into two branches; 1. Humoral immunity, for which the protective function of immunization could be found in the humor (cell-free bodily fluid or serum), 2. Cellular immunity, for which the protective function of immunization was associated with cells. Cellular immunity protects the body by:

activating antigen-specific cytotoxic T-lymphocytes that are able to lyse body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;
activating macrophages and natural killer cells, enabling them to destroy intracellular pathogens; and
stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.

Cell-mediated immunity is directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers, and intracellular bacteria. It also plays a major role in transplant rejection.

There are two major types of T cells:

- Cytotoxic T cells (CD₈ cells): These cells recognize infected cells by using T cell receptors to probe cell surfaces. If they recognize an infected cell, they release granzymes to trigger that cell to become apoptotic ("commit suicide"), thus killing that cell and any viruses that it is in the process of creating; they also release perforins, which perforate the infected cell's membrane, exposing its contents to the perhaps-hostile outside.
- Helper T cells (CD₄ cells): These cells activate 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.

Intersections between 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 cytotoxic ("killer") T cells (CTLs). Activation is provided by antigen-presenting cells (APCs), a major category of which are the dendritic cells. These cells are part of the innate immune system.

Activation occurs when a dendritic cell simultaneously binds itself 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 dendritic cell conveys that the antigen is indeed dangerous, and that the next encountered T "killer" cells need to be activated. This mechanism is based on antigen-danger evaluation by the T cells that belong 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 respect, the innate immune system therefore 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 is 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

The most important function of the human immune system occurs at the cellular level of the blood and tissues. The lymphatic and blood circulation systems are highways for specialized white blood cells to travel around the body. White blood cells include B cells, T cells, natural killer cells, and macrophages. Each has a different responsibility, but all function together with the primary objective of recognizing, attacking and destroying bacteria, viruses, cancer cells, and all substances seen as foreign. Without this coordinated effort, a person would not be able to survive more than a few days, before succumbing to overwhelming infection.

Infections set off an alarm that alerts the immune system to bring out its defensive weapons. Natural killer cells and macrophages rush to the scene to consume and digest infected cells. If the first line of defense fails to control the threat, antibodies, produced by the B cells, upon the order of T helper cells, are custom-designed to hone in on the invader.

Many disorders of the human immune system fall into two broad categories that are characterized by:

Attenuated immune response: There are 'congenital' (inborn) and 'acquired' forms of immunodeficiency, characterized by an attenuated response. Chronic granulomatous disease, in which phagocytes have trouble destroying pathogens, is an example of the former, while 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.

Overzealous immune response: 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.

Other factors that affect immune response

Many factors can also contribute to the general weakening of the immune system:

Malnutrition (unbalanced diet / poor eating habits that cause a lack of vitamins and minerals)
Alcohol abuse
Drug abuse either intravenous or other. (Appears related to associated factors i.e. poor diet, use of infected/dirty needles, poor exercise, stress/depression)
Medications (particularly the use of anti-cancer drugs, corticosteroids, and antibiotics);
Radiation
Exposure to certain environmental toxins, whether naturally occurring or from pollution. These include:
- Cigarette smoke
Stress/Depression - Research shows that psychological stress can greatly increase your susceptibility to colds and other viral diseases, namely through an increase in serum corticosteroid levels
Age - Ability of the immune system to respond is decreased at early and old age.
Decrease ability to heal due to disease or medications (i.e. Diabetes, corticosteroids, immune suppressant drugs), causing constant exposure to infectious agents without natural defense (intact skin)
Inadequate sleep at the Delta brain wave level. According to a sleep study, we need 4 hours of Delta sleep every night
Lack of exercise as well as excessive exercise resulting in physiological stress
Long-term weightlessness
Diseases either infectious or other causing more depression on the immune system like:
- Cancer, and hematological malignancy (such as leukemia, lymphoma and myeloma) in particular.
- Diabetes Mellitus
- Cystic fibrosis
- Lupus Erythematosus
- Nephrotic syndrome
- Viral infections i.e. viral respiratory infections then allowing for bacterial pneumonia to develop.
- HIV
- Ulcerative colitis
- Bulimia (due to malnutrition, stress, depression).
- Sickle-cell disease.
- Liver disease / cirrhosis
- Cushing's syndrome

Pharmacology

Despite high hopes, there are no medications that directly increase the activity of the immune system. Various forms of medication that activate the immune system may cause autoimmune disorders.

Suppression of the immune system is often used to control autoimmune disorders or inflammation when this causes excessive tissue damage, and to prevent transplant rejection after an organ transplant. Commonly used immunosuppressants include glucocorticoids, azathioprine, methotrexate, ciclosporin, cyclophosphamide and mercaptopurine. In organ transplants, ciclosporin, tacrolimus, mycophenolate mofetil and various others are used to prevent organ rejection through selective T cell inhibition.

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