The immune system

The second delivery method, called in vivo, means that the virus is used to direcdy infect the patient s tissues. The most common vector for this delivery is the adenovirus (which is a DNA virus). A particular vector can be chosen based on specific receptors on the target tissue. Adenovirus has receptors in lung and liver cells, and it has been used in clinical trials for gene therapy of cystic fibrosis and ornithine transcarbamoylase deficiency. 

Over the years, researchers have unraveled some of the mysteries of the immune system and have used its properties as a therapeutic aid. The first vaccine, that against smallpox, was developed about 200 years ago. Since that time it has been used so effectively as a preventive measure that smallpox has been eradicated. The action of vaccines of this sort depends on exposure to the infectious agent in a weakened form. The immune system mounts an attack, and the immune system retains memory of the exposure. In subsequent encounters with the same pathogen, the immune system can mount a quick and effective defense. This ability to retain memory is another major characteristic of the immune system. It is hoped that current research can be carried to the point of developing vaccines that can treat AIDS in people who are already infected. Other strategies are directed at finding treatments for autoimmune diseases. StiU others are attempting to use the immune system to attack and destroy cancer cells. 

There are two important aspects to the immunity process those that operate on the cellular level and those that operate on the molecular level. In addition, we have to look at whether the immune system is acquired or whether it is always present. We shall discuss these two aspects in turn. 

A major component of the immune system is the class of cells called leukocytes, otherwise known as white blood cells. Like all blood cells, they arise from common precursor cells (stem cells) in the bone marrow. Unlike other blood cells, however, they can leave the blood vessels and circulate in the lymphatic system. Lymphoid tissues (such as lymph nodes, the spleen, and, above all, the thymus gland) play important roles in the workings of the immune system. 

The immune system protects humans and animals from microbial infections by such infectious agents as bacteria, yeasts and fungi, viruses and protozoa. These differ greatly not only in their size but in their structural and molecular properties, as well as in the ways in which they seek to infect our bodies. Some of these pathogens infect bodily fluids, some penetrate tissues and some even survive and multiply within individual host cells. These intracellular pathogens include viruses, some parasitic protozoa (such as Plasmodium, the causative agent of malaria, which infects erythrocytes) and 

Neutrophils and host defence The fight against infection 

Several studies indicate that the presence of errvirorrmental adjuvants such as diesel exhaust particles may play a role in the development of airway allergies. It has recently been suggested that also phthalate plasticizers may possess adjuvant effect, which is in 

As a result of the increase in the number of subjects srrffering from respiratory allergies, the illnesses have become an increasing econorttical brrrden for most industrialized societies. Thus in 1998, asthma accounted for an estimated 12.7 billion US dollars in the United States. The costs of prescription antihistarttines and nasal steroids for the treatment of allergic rhinitis exceeded 4 billion US dollars in 1999.  

The immune system consists of a non-specific, innate defense system and a specific, adapted defense system that is directed agairrst the pathogens. The macrophage is an example of a cell type that belongs to the irmate defense. This cell type sirrrply eats  

Cells that produce antibody that reacts with normal body components are killed early in fetal life so that the adult animal normally is unable to make antibodies against self, a condition called self-tolerance. 

Antibodies bound to an invading microorganism activate the complement system via the classical pathway. This consists of a cascade of proteolytic reactions leading to the formation of membrane attack complexes on the plasma membrane of the microorganism that cause its lysis. Polysaccharides on the surface of infecting microorganisms can also activate complement directly in the absence of antibody via the alternative pathway. 

Functions There are two vital functions of the immune system recognition of an invading 

Instant Notes in Biochemistry 2nd Edition, B.D. Hames N.M. Hooper, (c) 2000 BIOS Scientific Publishers Ltd, Oxford. 

In both cellular and humoral immunity, recognition of the foreign invader depends upon the recognition of foreign macromolecules (proteins, carbohydrates, nucleic acids) these foreign components are called antigens. 

A relatively sharp distinction must be drawn between what are termed the innate and the adaptive immunities (Ml). When an organism infects the body, the defense systems already in place may well be sufficient to prevent replication and spread of the infectious agent, thereby preventing the development of disease. These established mechanisms constitute the innate immune system. However, should innate immunity be insufficient to prevent the invasion by the infectious agent, the adaptive immune system then comes into action, although it takes time 

On the one hand, are the soluble factors such as lysozyme and complement, together with the phagocytic cells that contribute to the innate system, and on the other hand are the lymphocyte-based mechanisms that produce antibody and the T lymphocytes, which represent the main elements of the adaptive immune system. Not only do these lymphocytes provide improved resistance by repeated contact with a given infectious agent, but the memory with which they become endowed shows very considerable specificity to that infection. 

There are two classes of cells those that respond to a specific foreign agent or substance, and those that are not specific. The cells that are specific for a certain foreign agent are lymphocytes. Cells that are not specific for the foreign agent they attack include phagocytes, mast cells, eosinophils, and natural killer cells. 

Major elements Soluble factors Lysozyme, complement, acute Antibody 

Cells phase proteins, e.g., C reactive protein, interferon Phagocytes T lymphocytes 

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The viruses responsible for AIDS are human immunodeficiency virus 1 and 2 (HIV 1 and HIV 2) Both are retroviruses, meaning that their genetic material is RNA rather than DNA HI Vs require a host cell to reproduce and the hosts m humans are the T4 lymphocytes which are the cells primarily responsible for inducing the immune system to respond when provoked The HIV penetrates the cell wall of a T4 lymphocyte and deposits both its RNA and an enzyme called reverse transcriptase inside There the reverse transcriptase catalyzes the formation of a DNA strand that is complementary to the viral RNA The transcribed DNA then serves as the template from which the host lymphocyte produces copies of the virus which then leave the host to infect other T4 cells In the course of HIV reproduction the ability of the T4 lymphocyte to reproduce Itself IS compromised As the number of T4 cells decrease so does the body s ability to combat infections... 

Unfortunately, excess consumption of fatty foods has been correlated with serious human disease conditions. Effects on cardiovascular disease (95), cancer (96), and function of the immune system (97) have been shown. Numerous studies have been conducted to determine the effects of saturated, monounsaturated, and polyunsaturated fatty acids on semm cholesterol and more recently high density Hpoprotein (HDL) and low density Hpoprotein... 

T-Lymphocytes (4,5) and other cellular components of the immune system also have equally wide implications in regulation of the normal immune system. The T-lymphocytes play a central role in the body s response to harmful antigens and tumor—host interaction (4). Responses involve antigens derived from vimses, bacteria, parasites, and tumors. T-ceUs also participate in the immune surveillance response, where self-antigens are recognized, but usually sequestered within the cell and, when exposed, become markers of cellular damage. 

Secondary immunodeficiencies (9) are much more common than primary ones and frequently occur as a result of immaturity of the immune system in premature infants, immunosuppressive therapy, or surgery and trauma. Illnesses, particularly when prolonged and serious, have been associated with secondary immunodeficiencies, some of which may be reversible. Acquked immune deficiency syndrome (AIDS) (10—12) may be considered a secondary immunodeficiency disease caused by the human immunodeficiency vimses HIV-1 or HIV-2. Hitherto unknown, the disease began to spread in the United States during the latter part of the 1970s. The agent responsible for this infection has been isolated and identified as a retrovims. 

G. Siskiud, "Agiug and the Immune System," iu H. R. Warner, ed.. Modem Biological Theories ofMging Raven Press, New York, 1987, pp. 235-242. 

Human Immunodeficiency Virus. Human immunodeficiency vims (HIV) causes Acquired Immunodeficiency Syndrome (AIDS), which has no cure. HIV infects the cells of the human immune system, such as T-lymphocytes, monocytes, and macrophages. After a long period of latency and persistent infection, it results in the progressive decline of the immune system, and leads to full-blown AIDS, resulting in death. 

Adjuvants are substances which can modify the immune response of an antigen (139,140). With better understanding of the functions of different arms of the immune system, it is possible to explore the effects of an adjuvant, such that the protective efficacy of a vaccine can be improved. At present, aluminum salt is the only adjuvant approved for use in human vaccines. New adjuvants such as QS-21, 3D-MPL, MF-59, and other liposome preparations are being evaluated. Several of these adjuvants have been in clinical trial, but none have been approved for human use. IL-12 has been proposed as an adjuvant which can specifically promote T-helper 1 ceU response, and can be a very promising adjuvant for future vaccine development. 

The prophylactic stimulation of the immune system using vaccines and bacterins is time-consuming. Of even greater value would be the abiUty to activate the system to combat a disease attack already underway, or to be able to increase the response to abnormal cells and neutralize neoplasia in any organ of the body. Several compounds, some unique entities and some already in use for other purposes, have shown potential utiUty as such nonspecific immune stimulants. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

In the treatment of diseases where the metaboUtes are not being deUvered to the system, synthetic metaboUtes or active analogues have been successfully adrninistered. Vitamin metaboUtes have been successfully used for treatment of milk fever ia catde, turkey leg weakness, plaque psoriasis, and osteoporosis and renal osteodystrophy ia humans. Many of these clinical studies are outlined ia References 6, 16, 40, 51, and 141. The vitamin D receptor complex is a member of the gene superfamily of transcriptional activators, and 1,25 dihydroxy vitamin D is thus supportive of selective cell differentiation. In addition to mineral homeostasis mediated ia the iatestiae, kidney, and bone, the metaboUte acts on the immune system, P-ceUs of the pancreas (iasulin secretion), cerebellum, and hypothalamus. 

Among vertebrate species, the neuro-endocrine-immime system is responsible for many complex, inter-related physiological processes including neuronal, homeostatic, reproductive and immune functions. There are four main types of hormone polypeptides, eicosanoids, steroids and thyroid hormones. Reflecting the inter-dependency of the neiiro-endocrine and immune systems, hormones, neuropeptides and other neiirotransmitters are known to be produced by some immune cells and play a role in the regulation of the immune system, while endocrine and nervous tissues express receptors for many substances produced by the immune system. The major focus of interest in endocrine disruption has... 

The mammalian and avian immune systems function similarly both incorporate humoral and cell-mediated cytotoxic mechanisms, " and are thought to share a 160m year old relationship with the reptilian immune system. The immune system of mammals shows sexual dimorphism " a greater immune response is normally observed in females, which has been attributed to differences in steroid hormone concentration. In the toad Bufo regularis, sexual dimorphism of the immune system is also apparent. ... 

In addition to their endocrine disrupting properties, it must be appreciated that many of the chemicals in question possess more general toxic properties, which may be potentiated by metabolism by the organism. Several PAHs, PCBs and PCDDs are carcinogenic, while certain phthalate esters can enhance the excretion of zinc, potentially leading to zinc deficiency. Zinc, an essential element, plays a vital role in spermatogenesis and mature T-cell production. Deficiency may result in abnormalities of the male reproductive system, depletion of spermatogenesis and suppression of the immune system. 

The other global environmental problem, stratospheric ozone depletion, was less controversial and more imminent. The U.S. Senate Committee Report supporting the Clean Air Act Amendments of 1990 states, Destruction of the ozone layer is caused primarily by the release into the atmosphere of chlorofluorocarbons (CFCs) and similar manufactured substances—persistent chemicals that rise into the stratosphere where they catalyze the destruction of stratospheric ozone. A decrease in stratospheric ozone will allow more ultraviolet (UV) radiation to reach Earth, resulting in increased rates of disease in humans, including increased incidence of skin cancer, cataracts, and, potentially, suppression of the immune system. Increased UV radiation has also been shown to damage crops and marine resources."... 

The immune system in vertebrates provides a defense mechanism against foreign parasites such as viruses and bacteria. Three main properties are essential to its successful operation specific recognition of foreign molecules, the ability to destroy the foreign parasite, and a memory mechanism that allows a more rapid response to a second infection by the same microorganism. 

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