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Pauline E Jolly Yi Jiang William O Ellis Jia Sheng Wang Evans Afriyie Gyawu Timothy D Phillips and Jonathan H Williams

This chapter provides a brief review of the literature on immunomodulation by aflatoxin and other mycotoxins, examines immunomodulation by mycotoxins that co-occur in food, reviews possible mechanisms through which mycotoxins exert their effects, and considers future research in the field. Studies conducted in several species of animals and in animal and human cell cultures have shown that aflatoxins act as immunomodulators, primarily as immunosuppressors, of various aspects of cell-mediated immunity and phagocytic cell function. The effect of aflatoxin on humoral immunity in animals is less consistent. Recently, two studies have been published that show association between aflatoxin Bi albumin adduct levels in blood and antibody and cellular immune status of humans chronically exposed to aflatoxin in their diet. Several other immunotoxic mycotoxins co-occur with afla-toxin in foods, and are likely to have an additive, if not synergistic, effect on the immune system. Aflatoxin seems...

Investment distortions

Only 4.3 of the pharmaceutical R& D expenditure is targeted to the health problems that mainly concern low- and middle-income countries (World Health Organization, 1996 Commission on Macroeconomics and Health, 2001). Total pharmaceutical R& D in the private sector has more than doubled in the last decade to an estimated US 44 billion in 2000 (Scrips Pharmaceutical R& D Compendium, 2000 Global Forum for Health Research, 2002). It has been estimated that of 1393 drugs approved between 1975 and 1999, only 13 were specifically indicated for tropical diseases (Trouiller et al., 2002). Where diseases are common to both developed and developing countries, the picture is different. For example, the majority of human immunodeficiency virus (HIV) vaccines are being developed for genetic profiles of subtype B, prevalent in developed countries, but most acquired immune deficiency syndrome (AIDS) sufferers in developing countries are types A and C.

Common mycotoxicoses in farm animals

Aflatoxin exposure also results in effects on the immune system. Long-term exposure to low mycotoxin concentrations, which may produce no prominent signs of toxicity, can impair immune system functions. Subsequently, a lower immune response to vaccination programs and increased susceptibility to infectious diseases are noticed, as both, humoral and cellular immune responses are affected. Secondary effects include increased prevalence of Salmonella spp. and Campylobacter spp. infections in animals, unpredictable outbreaks of viral diseases and coccidiosis. Consequently, affected flocks require more medication, which in turn increases the risk for undesirable residues and the emergence of resistance to antimicrobials in poultry units and the products derived from the animals. The relationship between exposure to aflatoxins and the prevalence of hepatitis virus infections in human populations has been the subject of various epidemiological investigations, e.g., Groopman and Kensler...

Types of studies considered appropriate for biologicals

As shown in Table 6.5, many biologicals are intended to stimulate or suppress the immune system. The intended effects of these and other products on the immune system can be classified as immunopharmacology or as immunomodulatory effects. Adverse events can result from the intended immunomodulatory mechanism of action. For example, excessive down-regulation of the immune system can result in recrudescence of a previously inactive virus. Immunotoxicity, on the other hand, refers to adverse immune effects that occur with products that are not targeting the immune system or have unintended effects on the immune system. These effects include inflammatory reaction at the injection site and autoimmunity due to altered expression of surface antigens. Although immunogenicity is an immune response of the animal to a foreign protein, it is not viewed as immunotoxicity per se. ICH S6 does not provide detailed guidance on immunotoxicity testing. It states that immunotoxicologic testing strategies...

Chronic mycotoxicoses and immunosuppression

While growth retardation and reduced productivity are of economic importance, the intrinsic activity of many mycotoxins on the immune system of the animals is of increasing concern. The presence of moderate to low amounts of mycotoxins in daily feed rations increases the susceptibility of animals to viral, bacterial and parasitic diseases (Bondy and Pestka, 2000). This increased susceptibility requires increased therapeutic intervention with antibiotics and antiparasitic drugs. These interventions increase the costs for animal health care and the use of anti-infective agents, particularly antibiotics, at the farm level with a concomitant increase in the risk of induction and spread of antimicrobial resistance. The immu-nosuppressive effect of mycotoxins also may result in incomplete protection of farm animals following vaccination against viral diseases, as antibody formation is impaired. The impaired immune competence of animals following long-term exposure to mycotoxins has been...

Induction of oxidative stress and cancer

Induction of cellular oxidative stress, resulting from an increase in the production of oxygen and hydrogen radicals, and a depletion of cellular defense mechanisms such as glutathione, is a common following exposure to many mycotoxins (Surai and Dvorska, 2005). The pro-oxidant effect of mycotoxins is dose- and time-dependent and may go beyond glu-tathione depletion to include changes in the activity of glutathione peroxidase, catalase and superoxide dismutase. For example, glutathione depletion in the liver is one of the earliest signs of exposure to mycotoxins such as aflatoxins and ochratoxins, but the response is transient. After repetitive exposure to low amounts of mycotoxins, measurable glutathione levels increase again, as a sign of adaptation. Cellular oxidative stress and enhanced radical production cause lipid peroxidation and cellular necrosis. Many mycotoxins including the trichothecenes, aflatoxins and ochratoxins also affect the transport of tocopherol, carotino-ids and...

AIDSInfected Persons in the Veterinary Workplace

The American Veterinary Association had reminded veterinarians that acquired immune deficiency syndrome (AIDS) is a human disease and that human immunodeficiency virus (HIV) does not infect animals other than nonhuman primates. Veterinarians and their employees are no more at risk by reason of their employment than are workers in offices. Cautions for

Need for mycotoxin testing and monitoring Health effects of mycotoxin contamination

The effects of long term exposure to aflatoxins in humans are well documented and include damage to body organs such as the liver and suppression of the immune system, which increases the frequency of other health disorders (Williams et al., 2004). Cases of acute tox-icity have been reported and these often have been exacerbated by limited availability of food supplies, e.g., in the drought-stricken areas of Kenya where in 2004 over 100 people died from consuming aflatoxin-contaminated maize meals, the major cereal in African diets (Azziz-Baumgartner et al., 2005). Additional cases also were reported in 2005. High concentrations of aflatoxin in maize also were reported in Nigeria, Ghana and several other West African countries (Kpodo and Bankole, Chapter 9).

Bees Wasps And Hornets

Imported fire ants and the stings of bees, hornets, and wasps together cause over half the reported anaphylaxis cases (57). The cardinal signs are bronchial spasm, larangeal spasm, and hypotension. Within minutes of the sting, upper or lower airway obstruction occurs, the latter more frequent in asthmatics. Usually, pruritic wheals with red, raised, curved edges and white centers appear, focal or diffuse, that may become giant hives these usually resolve by the second day. Occasionally, soft tissue swelling, as angioedema, is also present. Shock is often present, with or without a secondary cardiac event. Aspirin, opioids, NSAIDs, and radiocontrast agents must be avoided, as they may worsen matters. Upon recognizing anaphylaxis, inject 0.2 to 0.5 mL of 1 1000 epinephrine subcutaneously. Remove any insect stinger. Initiate an intravenous line to administer at 5 to 10 minute intervals 1 10,000 epi-nephrine and, should hypotension ensue, volume expanders and vasopressor agents. Nasal...

Protein stability in In Vitro Digestibility Assays

Acids, providing great nutritional value and representing no safety concern associated with their consumption, whereas other proteins are relatively stable or they yield stable fragments (e.g., histone proteins).34 Many food allergens are stable to digestion with pepsin in a low-pH environment of the stomach,35 hence increasing a possibility that undigested allergens or their fragments would be presented to the intestinal immune system, leading to a variety of gastrointestinal and systemic manifestations of immune-mediated allergy36 (for allergenicity assessment, see Chapter 8). Adverse reactions to food that are not mediated by the immune system are usually caused by toxic and pharmacologically active proteins contained in the consumed food. These proteins have an ability to survive the acidic environment of the stomach and proteolytic degradation with pepsin and pancreatin in biologically active forms,37-39 thereby causing a severe adverse reaction in the gut or an adverse systemic...

Identify and articulate a compelling issue

The first step is to properly define, or perhaps redefine, the problem with respect to plant patents. Framing the initial issue is strategically important because public support can readily build from an issue that has broad appeal. Fundamental human rights, especially in combination with a compelling story, have been shown to be highly effective in redefining the scope of patent rights under TRIPS. For example, in the access to Acquired Immune Deficiency Syndrome (AIDS) medicines campaign, there was a clearly articulated right to human health that was recognized and endorsed by the UN, WHO and other established nongovernmental organizations (NGOs). Moreover, the story of profitable companies withholding life-saving drugs was more compelling than the drug companies' competing tale of patent protection as essential to promote innovation.

Kerstin Hell Pascal Fandohan Ranajit Bandyopadhyay Sebastian Kiewnick Richard Sikora and Peter J Cotty

Aspergillus flavus, Aspergillus parasiticus and, rarely, Aspergillus nomius produce af-latoxins as secondary metabolites in agricultural products prone to fungal infection. Afla-toxins may cause liver cancer, suppressed immune systems, and retarded growth and development by contributing to malnutrition. Children are the most sensitive to the effects of af-latoxin-contaminated food. The effects of chronic exposure to aflatoxin are common in Africa, but acute toxicity, leading to death of humans, also has been reported (Azziz-

Mycotoxins Mycotoxicosis and Mycotoxicology

Mycotoxin is a convenient generic term describing the toxic secondary metabolites produced by fungi. Myco means fungal (mold) and toxin represents poison. They encompass a considerable variety of low molecular weight compounds with diverse chemical structures and biological activities. Some mycotoxins could also be toxic to plants or other microorganisms but these compounds are not classified as antibiotics of fungal origin. Like most microbial secondary metabolites, the benefit of mycotoxins for the fungi themselves is still not clearly defined. In considering the effects of mycotoxins on animals, it is important to distinguish between mycotoxicosis and mycosis. Myco-toxicosis is used to describe the action of mycotoxin(s) and is frequently mediated through a number of organs, notably the liver, kidney, lungs, and the nervous, endocrine, and immune systems. On the other hand, mycosis refers to a generalized invasion of living tissue(s) by growing fungi (CAST 2003 Chu 1998). Due to...

In Vitro Digestibility Assays

One biophysical aspect shared by many, but not all, food allergens is resistance to pepsin digestion in a low-pH environment. The premise on which this assay is based is that the allergen or fragments of the allergen that contain IgE-binding epitopes must be resistant to digestion in the human gastrointestinal (GI) tract and, thus, be available to interact with immune system cells. Standard laboratory conditions have been described whereby proteins are evaluated for their resistance to pH 1.2-2 in the presence of pepsin. Pepsin-digested proteins are loaded onto SDS-PAGE gels and stained with Coomassie blue protein dye to observe peptide fragments that may remain after exposure to acidic conditions. This standard method is performed as part of a multistep assessment of allergens and is referred to as an in vitro simulated gastric fluid (SGF) test.32,33 The purpose of the SGF test is to provide some physical correlation to the probability that a food protein could function as an...

Peter J Cotty Claudia Probst and Ramon Jaime Garcia

Aflatoxins are a group of highly toxic, cancer-causing chemicals produced by several members of the fungal genus Aspergillus. The presence of these mycotoxins in human foods can cause acute and chronic health effects (aflatoxicoses) including immune-system suppression, growth retardation, cancer, and death (Wild and Turner, 2002 Gong et al., 2004 Williams et al., 2004 Azziz-Baumgartner et al., 2005). Aflatoxins are carcinogens and genotoxins that directly influence the structure of DNA (Williams et al., 2004) and, as a result, occurrence of aflatoxins in human foods is strictly regulated to very low concentrations in developed countries. Indeed, in developed countries the exposure of domestic animals, even pets, is of both regulatory and economic concern. Deaths of pets due to aflatoxins in U.S. pet foods has had international economic impact in terms of both trade and litigation (Anonymous, 2006). Thus, in developed countries, the drive to abate aflatoxin contamination is due to loss...

Economic impacts of aflatoxin

Human health impacts of chronic aflatoxin exposure are just now being evaluated (Jolly et al., Chapter 5 Gong et al., Chapter 6). The interaction of aflatoxins with Hepatitis B and Hepatitis C to increase the risk of hepatocellular carcinoma is well known. The risk af-latoxin imposes on children who fail to thrive when their diet is highly contaminated with the toxin appears to be large enough to account for a significant proportion of the deaths of children under age 5 in Sub-Saharan Africa. For older children and adults, immune system suppression appears to occur and may reduce the effectiveness of vaccines and lower innate resistance to seemingly unrelated diseases. These losses in mental and physical development, the quality and quantity of output from a worker, and the added costs to already overburdened health care systems will be both economically and socially significant but have yet to be quantified or examined in any detail. Aflatoxin is a major constraint affecting exports...

Importance of mycotoxins to economies and health

Ing the last six weeks of the crop's growth. Many farmers have irrigation to avoid this risk, even though simulations of response to irrigation in Florida (Williams and Boote, 1995) show that significant production losses attributable to drought at this stage of production seldom occur. These farmers are responding to the market's requirement for food low in aflatoxins and expect a quality premium on their produce in return. Similarly, there are one-time fixed costs of infrastructure for, and recurring costs associated with, taking samples and analyzing them for toxins. Investments in drying and electronic sorting after harvest to segregate potentially contaminated grains all increase the economic burden imposed by mycotoxins. Despite these investments there are times when a significant fraction of agricultural production is lost in developed countries because it is contaminated. In the United States these losses can be as high as 1.5 billion across all the range of mycotoxins (Robens...

Future studies on immune effects of aflatoxin and other mycotoxins

Currently, there is a scarcity of data on the immunosuppressive effects of mycotoxins in humans. Future research needs to be conducted to i) establish the association between my-cotoxin exposure in humans and modulation of various aspects of immune function ii) determine the mode of action of the different mycotoxins and their interaction and iii) evaluate immunomodulatory interactions between mycotoxins, nutritional factors and infectious agents, especially those that are immunosuppressive, such as HIV AIDS. The study by Jiang et al. (2005) was relatively small and exploratory in nature. The results suggest that additional larger investigations are needed on the association between aflatoxin levels and immune status function. Thus, large randomized follow-up studies to assess the association between aflatoxin levels, immune status, susceptibility to infectious diseases and failure to produce an effective immune response to vaccines need to be conducted. The availability of...

Immunogenicity of biological products

Overall, it is accepted that the administration of an exogenous protein to animals or humans has the potential to elicit an antibody response against the protein if the immune system recognizes the protein as foreign. Immunogenicity is a unique property of biological therapeutics that distinguishes biologicals from traditional small-molecule drug products. An immune response to a biological drug can occur in nonclinical animal species or in clinical trial subjects and patients, and the more the structure and amino acid sequence of the protein drug differs from the native protein, the greater the immunogenic potential of the drug.64 Immunogenic responses associated with protein drugs were first identified in diabetes patients administered insulins from animal (bovine or porcine) sources.65-67 In general, biological products that have a high degree of sequence homology to the native human protein are less likely to be immunogenic in humans however, induction of antibody responses has...

Nutrient utilization and effects of mycotoxins on the gut barrier

Based on the observation that mycotoxins reduce weight gain and feed conversion, mycotoxins were hypothesized to have a direct effect on the intestines (Li et al., 2005). A malabsorption syndrome is a common result of exposure to aflatoxins, ochratoxins or trichothecenes. Measurable signs of the malabsorption syndrome are decreased transport of soluble nutrients and (fat-soluble) vitamins. Aflatoxin Bj and ochratoxin A were the first toxins known to induce hypocarotinoedemia and reduced tissue levels of a-tocopherol (vitamin E). Comparable effects were seen in chickens, following exposure to T-2 toxin and aurofusarin. The reduced levels of vitamins with antioxidant properties are associated with an increase of reactive oxygen species and cellular oxidative stress, which impairs both normal cellular function and differentiated traits, such as intracellular killing of pathogens by cells of the immune system (see below).

Organic Dusts

Endotoxin from gram-negative bacteria has been particularly found to be an important causative agent in producing respiratory illness. Recent insights into the innate immune system from genetic research may help elucidate the biological mechanism(s) related to respiratory health effects from endotoxin and other inhaled toxins. The Toll-like group of receptors (TLRs) are receptors for specific components of pathogens such as lipopolysaccharide (LPS), peptidoglycan, and others. It appears that genetic variation in TLRs influences the response to inhaled endotoxin. Thus, variable pulmonary responses in individuals exposed to organic dusts may be due to polymorphisms in the TLR genes. For example, it has been demonstrated that common missense mutations in the Toll-like receptor 4 (TLR4) are associated with a blunted response to inhaled LPS (endotoxin). Consequently, some individuals may be more susceptible than others when exposed to organic dusts. Some authors...


The reaction to the allergen in the skin is of a type IV hypersensitivity nature. The immune system reacts to the allergen with lymphocytic T cells, causing a cell-mediated response. After contact with the skin, urushiol (from poison ivy, oak, or sumac) causes a delayed hypersensitivity reaction that humans do not have at birth. Persons exposed to urushiol before the age of five are not as likely to develop a sensitivity to it as is someone first exposed between five years of age and adulthood. Even if exposed during this time period, roughly 10 of the population cannot develop sensitivity to urushiol, and others will not if the level of exposure is not great enough (36,41,42).

Fire Ants

Systemic reactions occur in 16 and anaphylaxis in 2 of patients. The onset occurs within 45 minutes of a sting. It can include urticaria, chest tightness, pruritis, dysphagia, abdominal cramps, nausea, vomiting, diarrhea, wheezing, the changes of anaphylaxis (described later), syncope, convulsions, confusion, mononeuropathy and seizures (46-48). Therapy is directed towards the particular symptoms and signs the patient has. Immunotherapy is in its early stages but shows great promise (49,50).

Cutaneous Neoplasms

Surgery is the most popular treatment for BCC and SCC cryotherapy is the most common for AK. Excision completely removes the skin cancer but can leave unsightly scars. Other techniques for removal include laser removal techniques, carbon dioxide resurfacing of photo-damaged skin, cryotherapy techniques, topical antimetabolites, electrodesiccation, and irradiation. Treatment of melanomas may require a complicated combination of excision, adjunctive immunotherapy or chemotherapy, and irradiation (47,48).

Ionizing Radiation

Ionizing radiation is uncommon in agricultural settings. Ionizing radiation may be used in food sterilization and decontamination procedures. Excessive exposure to ionizing radiation may lead to acute or chronic radiation sickness. Rapidly dividing cells, such as the lining of the gastrointestinal tract and blood-generating cells in the bone marrow, are particularly sensitive to radiation exposure. Hence, acute radiation sickness is characterized by gastrointestinal disturbances, bleeding due to platelet loss, infections due to immune-system damage, and anemia. Exposed skin may suffer acute burns and subsequent scarification. Chronic radiation exposure may be associated with cancer and reproductive abnormalities. Prevention of illnesses and injuries from ionizing radiation involves eliminating or minimizing exposure. Radiation sources should be properly shielded and radiation exposures monitored. Persons not educated in working around such sources should not have access.