Immune System

Immune System

The immune system is any system present in an organism to prevent predation by biological agents. All living organisms have these protective measures, although they vary radically in scope and mechanism.

In humans and domesticated animals, the immune system is involved in a large proportion of all known diseases, which has led to an increased understanding of this immensely complex system and the introduction of therapies that modify the immune response.

Types of systems

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, and the formation of white blood cells.

Bacteria and monocellular organisms have an "immune system" designed to combat bacteriophages (viruses that infect bacteria). They do this by simultaneously expressing enzymes that cut DNA at certain sequences, and enzymes that protect 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.

However, when we talk about immune systems we are usually referring to the immune systems of multicellular organisms, usually vertebrates.

Recognizing self and non-self

The Latin term immunis means exempt, referring to protection against foreign agents. The recognition of what is foreign is found in all life. In self-pollinating plants, a pollen grain landing on the stigma of a flower will send a pollen tubule down the style to the ovary for fertilization. A pollen grain from a genetically distinct plant will not germinate or the pollen tubule, once formed, will disintegrate in the style. In cross-pollinating species, self-marked pollen grains disintegrate, while nonself grains germinate and fertilize.

We may conceive of an arrangement where the cells of self are marked, so that they are not attacked by its own defense mechanism. But not all foreign cells may be destroyed since some must be assimilated for nourishment. Therefore, the immune system must have the capacity to detect self and some nonself. But since self needs to assimilate some nonself for its survival, it cannot mark itself. It is easier to mark potentially dangerous selves. But if only certain nonselves are marked, how does the body prepare to defend itself from selves not seen? The defense system must have the capacity to transform itself to deal with future dangers. It must also have the capacity to change, since the self itself evolves with time. An additional challenge to understanding is the mechanism by which sexually reproducing organisms prevent the growing embryo from being destroyed by the immune system of the 'mother'. It is believed that this is achieved by the specialized tissue such as the placentum in placental mammals. New theories attempt to solve some of these paradoxes. One such is the 'danger theory' proposed by Polly Matzinger which suggests that cellular apoptosis signals and directs the immune mechanism. Another is the 'Pathogen-Associated Molecular Pattern' theory proposed by Charles Janeway which suggested that conserved molecular patterns found on pathogens provide a context in which a particular antigen is recognized.

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.

The complement system is a very complex group of serum proteins which is activated in a cascade fashion. There are three pathways of activation: classical, alternative and lectin. The classical pathway is activated by the adaptive immune system, the antigen-antibody complex. The alternative pathway activates C1,C4,C2,C3,C5 and finally C6 to C9, which forms the membrane attack complex. The Lectin pathway activates C2, C3, C4, and some C1 homologue calcium-dependent lectin family proteins.

Complement binding results in cytolysis, chemotaxis, opsonization and inflammation.

Last but not least, interferon ± and ² are important for resistance to viral infection by modulating the immune response. They have no innate activity

Adaptive immune system

The adaptive immune system, also called the acquired immune system, explains the interesting fact that when most mammals survive an initial infection by a pathogen, they are generally immune to further illness caused by that same pathogen. This fact is exploited by modern medicine through the use of vaccines. 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. The immune system can be divided into two parts. Many species, including mammals, have the following type:

The humoral immune system, which acts against bacteria and viruses in the body liquids (such as blood). Its primary means of action are immunoglobulins, also called antibodies, which are produced by B cells (B means they develop in the bone marrow).
The cellular immune system, which takes care of other cells that are infected by viruses. This is done 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) interact with macrophages (which 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

Although the dichotomy of the innate and adaptive immune systems has served to simplify and facilitate the reductionist approach to immunology, a number of fairly recent discoveries have helped to explain old mysteries of the immune system as well as blur the division between innate and adaptive immune systems.

adjuvants - Although the text book explanation of the adaptive immune system would suggest that the adaptive immune system could raise antibodies and T-cells specific to any antigen, including artificial peptides, introduced to a mammal, the fact was that, in order to induce a robust immune response, the antigen had to be delivered with an adjuvant. The most commonly used adjuvant was 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.
antigen presentation - It was known that T-cell activation required other cells to process and present antigens. These cells were called antigen presenting cells (APC), and this function was thought to be performed by macrophages and/or B-cells in vivo. However, isolated macrophages and B-cells were not potent antigen presenting cells. The later discovery of dendritic cells (DC) (by Ralph Steinman) demonstrated that there existed a specialized cell type for this function. Dendritic cells are a type of myeloid cell derived (probably) from monocytes whose main function appears to be the activation of T-cells. Here you have an innate immune cell that is critical in the function of adaptive immunity.

Disorders of the human immune system

An ineffective immune system is a feature of immune deficiency; there are congenital (inborn) or acquired forms of immune deficiency, dependent on the cause. AIDS ("Acquired Immune Deficiency Syndrome") is an infectious disease, transmitted by HIV, which causes degeneration of the body's immune system.

On the other hand, an "overactive" immune system is a feature of a large number of different autoimmune disorders, such as lupus erythematosus, type I diabetes (sometimes called "juvenile onset diabetes"), multiple sclerosis, psoriasis, and rheumatoid arthritis. In these the self-recognition ability of the immune system fails and it attacks a part of the patient's own body.

People who are immunocompromised have a suppressed immune system. This may include people with acquired or inherited diseases which affect the immune system, and those who are taking medications to prevent rejection of transplanted organs.