It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response.[1] Many species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally most simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages.[67] Prokaryotes also possess acquired immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of RNA interference.[68][69]
Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity.[1] The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.[70]
Unlike animals, plants lack phagocytic cells, and most plant immune responses involve systemic chemical signals that are sent through a plant.[71] When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent.[71] RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.[72]
Tumor immunology
Another important role of the immune system is to identify and eliminate tumors. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources;[74] some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer,[75] while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (e.g. melanocytes) into tumors called melanomas.[76][77] A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.[74][78][79]
The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells.[77][80] Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal.[81] NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors.[82] Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.[78]
Clearly, some tumors evade the immune system and go on to become cancers.[83] Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells.[81] Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes.[84] In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.[83]
Paradoxically, macrophages can promote tumor growth [85] when tumor cells send out cytokines that attract macrophages which then generate cytokines and growth factors that nurture tumor development. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells.
Physiological regulation
Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive[86] and innate immune responses.[87] Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive.[88] Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.[89][90] It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals.[91] Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity.[92]
Sleep
The immune system is enhanced by sleep and rest,[93] and is impaired by stress.[94] Sleep deprivation is detrimental to immune function, and sleep can be considered a vital part of the immune system. Viewed in this light, decreases in the length and quality of sleep in the population have far-reaching public health implications.[95] Complex feedback loops exist between the sleep cycle and immune response: acute infection causes changes in the sleep cycle, including an increase in slow-wave sleep relative to REM sleep.[96] Cytokines, a class of peptides, appear to be one of the main mechanisms through which the immune system and sleep cycle interact, as cytokines are produced by the immune system in response to infection, and also play a role in the normal sleep cycle.[97]
Nutrition and diet
The functioning of the immune system, like most systems in the body, is dependent on proper nutrition. It has been long known that severe malnutrition leads to immunodeficiency. Overnutrition is also associated with diseases such as diabetes and obesity which are known to affect immune function. More moderate malnutrition, as well as certain specific trace mineral and nutrient deficiencies, can also compromise the immune response.[98]
Specific foods may also affect the immune system; for example, fresh fruits, vegetables, and foods rich in certain fatty acids may foster a healthy immune system.[99] Likewise, fetal undernourishment can cause a lifelong impairment of the immune system.[100] In traditional medicine, some herbs are believed to stimulate the immune system, such as echinacea, licorice, ginseng, astragalus, sage, garlic, elderberry, and hyssop, as well as honey.
Medicinal mushrooms like Shiitake,[101] Lingzhi mushrooms,[102][103], the Turkey tail mushroom,[104] Agaricus blazei,[105] and Maitake[106] have shown evidence of immune system up-regulation in vitro, in vivo, as well as in people. An isolated compound from Shiitake, known as Active Hexose Correlated Compound[107][108][109] has also shown evidence of being able to up-regulate certain aspects of the immune system. Research suggests the compounds in medicinal mushrooms most responsible for up-regulating the immune system, are a diverse collection of polysaccharides, particularly beta-glucans, and to a lesser extent, alpha-glucans. Specifically, beta-glucans stimulate the innate branch of the immune system. Research has shown beta-glucans have the potential to stimulate dendritic cells[110] macrophage,[111] NK cells,[112] T cells,[113] and immune system cytokines. The mechanisms in which beta-glucans stimulate the immune system is only partially understood. One mechanism in which beta-glucans are able to activate the immune system, is by interacting with the Macrophage-1 antigen (CD18) receptor on immune cells.[114] Other human receptors have been identified as being able to receive signals from beta-glucans such as Toll-like receptor 2,[115] Dectin-1, lactosylceramide, and scavenger receptors.[116]
Published research has suggested that certain herbs can stimulate aspects of the immune system,[117] although further research is often needed to discover their mode of action.
Manipulation in medicine
The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization). Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent transplant rejection after an organ transplant.[26][118]
Anti-inflammatory drugs are often used to control the effects of inflammation. The glucocorticoids are the most powerful of these drugs; however, these drugs can have many undesirable side effects (e.g., central obesity, hyperglycemia, osteoporosis) and their use must be tightly controlled.[119] Therefore, lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine. Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects.[118] Immunosuppressive drugs such as ciclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.[120]
Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids;[121] however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set.[122] A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells.[123] The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics.[124]
Manipulation by pathogens
The success of any pathogen is dependent on its ability to elude host immune responses. Therefore, pathogens have developed several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system.[125] Bacteria often overcome physical barriers by secreting enzymes that digest the barrier — for example, by using a type II secretion system.[126] Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.[127]
An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement.[128] Many pathogens secrete compounds that diminish or misdirect the host's immune response.[125] Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.[129] Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).[130]
The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus.[131] The parasite Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response.[132] Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the viron is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures.[133]
History of immunology
Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known mention of immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time.[134] In the 18th century, Pierre-Louis Moreau de Maupertuis made experiments with scorpion venom and observed that certain dogs and mice were immune to this venom.[135] This and other observations of acquired immunity was later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease.[136] Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease.[137] Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.[138]
Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of humoral immunity and cellular immunity.[139] Particularly important was the work of Paul Ehrlich, who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction; his contributions to the understanding of humoral immunity were recognized by the award of a Nobel Prize in 1908, which was jointly awarded to the founder of cellular immunology, Elie Metchnikoff.[140]
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