Immune system defects

Dioxins are of concern because they accumulate in the biosphere, where they have highly deleterious effects. Tests have shown that when the concentration of dioxins in the blood of laboratory animals reaches a critical level, reproductive and immune system defects result. Moreover, recent data indicate that the concentration of dioxins in the blood of the average U.S. resident has nearly reached that level. A major reason is that dioxins are not veiy water-soluble, so they accumulate in the body rather than being readily processed and excreted. Consequently, several groups, including the American Public Health Association, have issued calls for phasing out the use of industrial chlorine. 

First report of gene therapy cures for an inherited immune system defect. A few months later, several of the treated children developed a blood cancer... 

An immunocompromised host is a patient with defects in host defenses that predispose to infection. Risk factors include neutropenia, immune system defects (from disease or immunosuppressive drug therapy), compromise of natural host defenses, environmental contamination, and changes in normal flora of the host. 

Several cases of hepatotoxicity associated with chaparral use have been described (see Section 16.5). The mechanism of chaparral-associated hepatotoxicity is unknown. It is not known if chaparral is an intrinsic hepatotoxin (i.e., toxic to everyone if the dose is sufficient) or an idiosyncratic hepatotoxin (i.e., toxic only to those who have certain genetically aberrant metabolic pathways or immune system defects). Proposed mechanisms of chaparral-associated hepatotoxicity include (1) inhibition of cyclooxygenase or cytochrome P-450, (2) an immune-mediated reaction, (3) formation of a toxic metabolite, (4) impairment of liver function by phytoestrogens found in chaparral, and (5) cholestatic mechanisms causing impairment of bile formation or excretion. There is likely overlap between the two categories and the various mechanisms. In addition, toxicity may be influenced by age, weight, nutritional status, exposure to other drugs and chemicals, cumulative dose, and preparation (i.e., tea, dried plant parts, etc.) (Sheikh et al., 1997). 

VDUPl mice displayed immune system defects, including perturbed development and function of natural killer (NK) cells. There was a profound reduction in the numbers of NK cells and in NK activity in VDUP1 mice, which showed minimal changes in T and B cell development (Lee et al. 2005). The NK cell abnormality in the VDUP1 mice caused severe lymphoid hyperplasia in the small intestine and reduced tumor rejection (Lee et al. 2005). Moreover, the percentage of hepatic natural killer T (NKT) cells in VDUPl" " mice was decreased, and the percentage... 

WISCOTT-ALDRICH SYNDROME Inherited syndrome characterized by chronic skin disease and immune system defects. 

The Endocrine Society defines an endocrine disrupting substance as a compound either natural or synthetic, which, through environmental or inappropriate developmental exposures, alters the hormonal and homeostatic systems that enable the organism to communicate with and respond to its environment. Effects may include developmental, reproductive, neurological, and immune system defects. The field is a controversial one most of the data come from wildlife studies, and the dose/response effect is problematic. In laboratory studies, many anthropogenic compounds... 

However, several situations can be anticipated in which support of the immune system is required. These include congenital defects in the immune repertoire, acquired immune deficiencies such as in HIV infection, but also situations in which the immune system is compromised after treatment of patients, e.g., after radiation or chemotherapy. 

NF-kB regulates both innate and adaptive immune responses ( immune defense) [2]. Understanding the function of NF-kB in the development, maintenance, and activation of cells from the immune system (including hematopoietic cells, macrophages, dendritic cells, B and T lymphocytes) has greatly benefited from the analysis of knockout mice in which individual NF-kB family members were defective. 

Hibbs ML, Tarlinton DM. Armes J. Grail D. Hodgson G, Maghtto R, Stacker SA, Dunn AR Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 1995 83 301-311. Nishizumi H, Yamamoto T Impaired tyrosine phosphorylation and Ca + mobiUzation, but not degranulation, in Lyn-deficient bone marrow-derived mast cells. J Immunol 1997 158 2350-2355. 

Globally, undernutrition is widespread, leading to impaired growth, defective immune systems, and reduced work capacity. By contrast, in developed countries, there is often excessive food consumption (especially of fat), leading to obesity and to the development of cardiovascular disease and some forms of cancer. Deficiencies of vitamin A, iron, and iodine pose major health concerns in many countries, and deficiencies of other vitamins and minerals are a major cause of iU health. In developed countries, nutrient deficiency is rare, though there are vulnerable sections of the population at risk. Intakes of minerals and vitamins that are adequate to prevent deficiency may be inadequate to promote optimum health and longevity. 

There is clear evidence linking defects of the immune system to the development of NMSC. For example, it is observed that patients receiving chronic immunosuppressant therapy for organ transplantation have a 50% risk of developing SCC within 20 years of transplantation, and 30% of these cancers are highly aggressive.21 Additionally, patients with human immunodeficiency virus (HIV) infection are predisposed to melanoma.18 Data also support the idea that UV radiation... 

The receptor for RANKL is RANK, also known as ODAR (Anderson et al. 1997 Hsu et al. 1999). RANK is expressed in osteoclast precursors, mature osteoclasts, condrocytes, fibroblasts, and immune system cells (Anderson et al. 1997 Hsu et al. 1999). The binding of RANKL with RANK on preosteoclasts initiates the OCS and the activation of osteoclasts (Anderson et al. 1997 Hsu et al. 1999 Nakagawa et al. 1998). RANK-deficient mice display a phenotype characterized by osteopetrosis and several defects in the immune system similar to that observed in RANKL-deficient mice (Dougall et al. 1999). Consistent with this hypothesis, RANK-deficient mice are resistant to bone resorption induced by TNF-a, IL-l/J, or vitamin D3 (Li et al. 2000). In agreement with this, mice deficient in molecules implied in the transduction pathway from RANK like TRAF-6 or NF-/c Bl/NK-/c B2 also show an osteopetrotic phenotype,... 

Holsapple, M.P., West, L.J. and Landreth, K.S. Species comparison of anatomical and functional immune system development. Birth Defects Research, 68, 321, 2003. 

In patients infected with HIV, many nonspecific and certain specific cellular immune functions can be shown to be altered or decreased, and a number of seemingly healthy individuals may exhibit marked immunological abnormalities without evidence of clinical illness. As the individual begins to exhibit clinical symptoms associated with AIDS, the abnormalities in the immune system become more extreme. A factor that complicates the study of HIV-induced immunosuppression is that many of the infections patients develop may themselves induce marked changes in the immune system. For this reason, it has been difficult to dissociate the fundamental changes associated with prolonged HIV infection from epiphenomena caused by other infections. One basic defect in the immune system of HIV-infected patients has, however, been elucidated. This is the loss of function and ultimate destruction of a proportion of T lymphocytes. 

Infection with HIV affects every compartment of the immune system and results in a progressive decrease in the body s ability to eliminate other invading or normally nonpathogenic organisms. The immune defects observed in HIV seropositive patients are numerous. 

Recently, it has been possible to grow cells of the human immune system in special mice. These mice carry a genetic defect called severe combined immunodeficiency (SCID), which leaves them with crippled immune systems, much like those in AIDS patients. Because SCID mice lack functional cellular immunity, it is possible to implant them with human cells without tissue rejection taking place. Researchers have recently developed techniques to implant human fetal tissues containing stem cells for the blood into SCID mice. It is then possible to reconstitute these mice with functional human immune system cells, including T lymphocytes and B lymphocytes. They have also found that if these SCID mice are infected by HIV, the virus will establish infection in the human tissue and destroy the T helper lymphocytes, just as it does in humans. Thus, it may be possible to study some of the mechanisms by which HIV attacks the immune system in these mice. In addition, they may be very useful for testing potential antiviral drugs. 

Stem cell therapy is aimed at replacing, supplementing, repairing or reprogramming defective systems or cells in patients with immune system... 

The three targets that are the first point of contact between environmental chemicals and the body will be discussed first the gastrointestinal tract, the respiratory system, and the skin. Recall from Chapter 2 that chemicals enter the blood after absorption, so this fluid is the next target (see Figure 2.1). Then come the liver, the kidneys, and the nervous system. The chapter concludes with a discussion of some chemicals that can damage the reproductive system and some that can cause birth defects, the so-called teratogens, and other forms of developmental toxicity. Brief discussions of immune system, cardiovascular system, muscle, and endocrine system toxicities are also offered. 

Think how many carcinogens are household names asbestos, cigarette smoke (a mixture of several thousand chemical compounds), DES, dioxin, saccharin, arsenic, PCBs, radon, EDB, Alar. Hundreds more of these substances, some very obscure, are known to the scientific and medical community, and many of these are scattered throughout the land at thousands of hazardous waste sites similar to Love Canal. People are exposed to these dreadful substances through the air they breathe, the water they drink and bathe in, and the foods they eat. Chemicals can also produce many other types of health damage, some very serious, such as birth defects and damage to our nervous and immune systems. 

Tumors (see p. 400) arise from degenerated (transformed) cells that grow in an uncontrolled way as a result of genetic defects. Most transformed cells are recognized by the immune system and eliminated (see p. 294). If endogenous defense is not suf -ciently effective, rapid tumor growth can occur. Attempts are then made to inhibit growth by physical or chemical treatment. 

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