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By Drs. Ingrid Waldron, Department of Biology, University of Pennsylvania, CC-BY-NC 4.0.
Examines the correlation between the spread of infectious diseases and population growth.
- 7.1: Infectious Disease Protocol
- An infectious disease is any disease caused by germs that can be spread from one person to another. Germs include viruses, bacteria, and protozoa. This activity will simulate the spread of an infectious disease. A simulation is a simplified demonstration of a real biological process. Our simulation will show how an infectious disease can spread from one infected person to other people who, in turn, infect others.
- 7.2: Infectious Disease Teacher's Preparation Notes
- The spread of infectious disease from person to person in a population can result in an exponential increase in the number of infected people. Similarly, when population size doubles repeatedly, this results in exponential growth. The maximum population size that an environment can sustain is called the carrying capacity. As population size approaches the carrying capacity, the rate of growth in population size decreases, resulting in a logistic growth curve.
High School Biology : Immune System
The spleen is an intra-abdominal organ whose function is __________ .
related to the regulation of body fat metabolism
excretion of liquid wastes
related mostly to immunological abilities
the production of gastrin, which it delivers to the stomach
related mostly to immunological abilities
The spleen is like a giant lymph node, and it is organized in a somewhat similar manner. Although it can be surgically removed if it is damaged, such patients are at life-long risk of death from fairly ordinary infectious processes. The spleen is a reservoir of immune competence. Blood passes through the spleen for exposure to white blood cells. When the white blood cells detect antigens or foreign particles in the blood, they initiate the immune response. The spleen is essentially a screening center to check the blood for contaminants.
Example Question #2 : Immune System
When a person is exposed to an organism and produces specific antibodies against it, this type of immunity is referred to as __________ .
Adaptive immunity occurs when antibodies are produced as a result of exposure to a pathogen or immunization. These antibodies are specific for the particular microorganism and memory cells are produced. Cell-mediated immunity is a direct form of defense based on the action of lymphocytes to attack foreign cells and destroy them. Congenital immunity is immunity one is born with. This may result from antibodies received from the mother's blood. Innate immunity is not pathogen-specific and includes the secretion of proteins and the activities of natural killer cells. Passive immunity involves the introduction of preformed antibodies into an unprotected individual. This may occur through infusion of immune globulin or antibodies that pass from the mother to the fetus through the placenta.
Example Question #3 : Immune System
How is VDJ recombination indispensible for adaptive immunity?
It prevents integration of viral DNA into host DNA
VDJ recombination is not involved in adaptive immunity
It promotes clotting and macrophage recruitment to wounds
It allows for the generation of diverse and variable antibodies that are able to recognize a myraid of antigens
It allows for the generation of diverse antigens to recognize many antibodies
It allows for the generation of diverse and variable antibodies that are able to recognize a myraid of antigens
VDJ recombination occurs during early B- and T-cell maturation, resulting in diverse antibodies and T-cells. This DNA recombination occurs between the V, D, and J segments of the antibody or T-cell before transcription occurs. As a result, a unique sequence is generated, transcribed, and then translated to a functional protein. This recombination is responsible for creating the unique series of antibodies that the body is capable of producing in order to detect the various antigens represented by foreign pathogens.
Example Question #4 : Immune System
Which of the following is true regarding B cell and T cell interactions?
Both B cells and T cells can activate each other
B cells and T cells do not activate each other
T cells can activate B cells but B cells cannot activate T cells
B cells can activate T cells but T cells cannot activate B cells
T cells can activate B cells but B cells cannot activate T cells
B cells and T cells are both part of the adaptive immunity. B cells secrete antibodies that bind to foreign antigens. Upon binding to a specific antigen, B cells can be activated by T cells, which facilitate the synthesis of specific antibodies for the antigen. This enhances the antibody-antigen binding and allows for a better immune response. T cells have receptors on their surface that detect antigens. Once they detect the antigen, T cells can activate B cells and other immune system cells (such as macrophages and neutrophils) to eliminate the foreign antigen. B cells do not play a role in the activation of T cells.
Example Question #1 : Understanding Adaptive Immunity
A researcher is analyzing a specific immune complex that is made up of an antibody-antigen complex. What can the researcher conclude about this immune response?
It involves B cells and a cell-mediated immune response.
It involves T cells and a cell-mediated immune response.
It involves T cells and a humoral immune response.
It involves B cells and a humoral immune response.
It involves B cells and a humoral immune response.
The question states that the immune complex has antibodies bound to antigens. Recall that B cells eliminate pathogens by secreting antibodies. These antibodies bind to antigens and release factors called cytokines. Cytokines recruit phagocytic cells like macrophages and neutrophils that kill the infected cell. They also activate a part of the innate immune system called the complement, which aids in the elimination of the pathogen. This type of immune response is called a humoral immune response. Elimination of the pathogen using T cells is called a cell-mediated immune response.
Note that both the humoral and the cell-mediated immune responses are very specific responses that are part of the adaptive immunity. Innate immunity involves non-specific immune responses via macrophages, granulocytes (neutrophils, eosinophils, and basophils), complement system, and NK cells.
Example Question #6 : Immune System
Which of the following is/are characteristic(s) of T cells?
I. T cells can differentiate into plasma cells.
II. T cells can differentiate into cells that inhibit activity of other T cells.
III. HIV attacks helper T cells.
Plasma cells are circulating cells that form part of adaptive immunity that secrete antibodies to specific antigens. These cells arise from naïve B cells. Broadly specific naïve B cells have the ability to bind to several antigens. Once bound, these naïve B cells differentiate into plasma cells that secrete antibodies that are very specific to the antigen. T cells facilitate this differentiation, but only B cells give rise to plasma cells.
A naïve T cell has the ability to differentiate into three kinds of cells. First, it can differentiate into a helper T cell. These cells facilitate the activation of other immune cells such as B cells, macrophages, and granulocytes. Second, a naïve T cell can differentiate into a cytotoxic T cell. These cells bind to infected cells and induce their death. Third, a naïve T cell can differentiate into a regulatory T cell. These T cells bind to the same antigens as the first two cells however, instead of initiating an immune response, they regulate it by suppressing the activity of T cells.
HIV is a virus that likes to reside inside helper T cells. A person infected with HIV will have a decreased helper T cell count, which makes the person more susceptible to other opportunistic infections (infections that only occur in immune-compromised individuals). A patient with very low helper T cell count develops AIDS and often passes away due to these opportunistic infections.
Example Question #7 : Immune System
CD8 is a surface glycoprotein found in many T cells. Which of the following T cells will NOT have a CD8?
All of the these T cells will have CD8.
A T cell that participates in the elimination of extracellular bacterial cells
A T cell that participates in the elimination of virus infected cells
A T cell that participates in the elimination of cancer cells
A T cell that participates in the elimination of extracellular bacterial cells
There are three kinds of T cells: helper T cells, cytotoxic T cells, and regulatory T cells. All T cells have glycoproteins on their surfaces that act as receptors. CD4 and CD8 are two glycoproteins that can be found on T cells. Helper T cells and regulatory T cells have CD4 glycoproteins, whereas cytotoxic T cells have CD8. These glycoproteins serve as markers to distinguish between T cell types.
The question is asking about CD8, or cytotoxic, T cells. Recall that cytotoxic T cells bind to infected cells and induce their death. Typically, cytotoxic T cells bind to infected cells that have the pathogen inside them (meaning intracellular pathogens). Intracellular pathogens include viruses and intracellular bacteria therefore, T cells that attack these cells will be CD8 cells. In addition, cytotoxic T cells also attack cancer cells therefore, these T cells will also be CD8 cells.
Extracellular bacterial cells do not infect host cells therefore, these bacteria are eliminated via the helper T cells. These T cells bind to the bacteria and activate other immune cells such as B cells, macrophages, and granulocytes that eliminate the bacteria.
Example Question #1 : Understanding Innate Immunity
Which of the following is not considered a part of the innate immune response?
Innate immunity is defined as the general protection mechanisms from pathogens. Innate immunity will be present even when the body has not seen a specific pathogen. Antibodies are highly specific for one particular antigen, and only develop in the body after previous exposure to a pathogen. As a result, it is not considered innate. Instead, antibodies are considered a hallmark of adaptive immunity.
Physical barriers (like the skin), chemical barriers (like stomach acid), and non-specific immune cells (like phagocytes) help to protect against all pathogens, regardless of the type of pathogen or previous exposure.
Example Question #1 : Immune System
Which type of immunity is not pathogen-specific and does not create memory cells?
Innate immunity is non-specific immunity linked to general defenses in the body. These immune defenses include inflammation and phagocytosis, which are not determined by the specific responses of B- or T-lymphocytes. Physical barriers, such as tight junctions in the skin and the acidity of the stomach and vaginal canal, also act as innate immune mechanisms.
Acquired and active immunity only result from a prior exposure to an antigen. Antibodies are produced by B-cells. Cell-mediated immunity involves the regulatory and cytotoxic activites of T-cells during the specific immune response. Humoral immunity is the term used to describe the protective activities of antibodies against infection by common microorganisms.
Example Question #10 : Immune System
Which of the following is NOT an aspect of the innate immune system?
Enzymes in sweat, tears, and saliva that kill bacteria
The innate immune system is a general defense against infections. Antibodies are very specific to the type of infection they can fight. Thus antibodies are considered specific defense.
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It’s Got Agents Standing By
Other than your nervous system, your immune system is the most complex system in your body. It’s made up of tissues, cells, and organs, including:
- Your tonsils
- Your digestive system
- Your bone marrow
- Your skin
- Your lymph nodes
- Your spleen
- Thin skin on the inside of your nose, throat, and genitals
All of these help create or store cells that work around the clock to keep your whole body healthy.
A fever can help your immune system fight infections in two ways. A higher temperature in the body speeds up how cells work, including the ones that fight illness. They can respond to invading germs faster. Also, higher body temperatures make it harder for bacteria and viruses to thrive in your body.
How Fevers Help Our Immune System Hunt Down Infections
It’s an ironic fact of life that the symptoms of a cold or fever are actually our bodies’ attempts at a cure. Runny noses, high temperatures and vomiting are all strategies aimed at forcing dangerous microbes from our bodies so we can feel better again. But, how the elevated temperatures that so often accompany an infection help us recuperate has been something of a mystery.
“In spite of the fact that they are important to us, there remains very little understanding of what it is that fevers do to improve survival,” said JianFeng Chen, a cell biologist at the Shanghai Institute of Biochemistry and Cell Biology in China.“Understanding this could be important for people to fight against infections, allergy, autoimmune diseases, and even cancer.”
Now, Chen and colleagues have figured out how fevers unleash the immune system to fight off infections. The team’s work could mean new treatments that not only combat infection but also curb inflammation during allergic reactions.
Fevers raise body temps anywhere from 2 to 7 degrees Fahrenheit. Fever’s protective effects may be in part because ratcheting temps up is sometimes more uncomfortable for pathogens than it is for us. Poliovirus’ ability to multiply plummets in the face of a fever’s heat, for example. But some research has suggested the scorching conditions might also flush out infections by setting immune cells in action. Chen and colleagues wanted to find out how.
The researchers isolated immune cells from mice and then put them in incubators set to a normal body temperature (about 98.6 degrees F) or a feverish temp of 104 degrees F. They found the immune cells that grew in the febrile environment produced a suite of molecules called heat shock proteins. One of these proteins, known as Hsp90, quickly set in motion a cascade of events that eventually directed the immune cells to the infection, Chen and team report today in the journal Immunity .
“During infection, this mechanism can enhance the [movement of immune] cells to… sites of infection and facilitate the clearance of pathogens,” Chen said.
“This pathway is critical for animal survival during infection,” he added. Indeed, disrupting the pathway with a mutation in Hsp90 impaired the ability of mice infected with Salmonella to fight off the infection, the researchers found.
The discovery suggests that therapies to raise Hsp levels could help fight infections, while lowering them could help those with allergies or autoimmune diseases by slowing down inflammation, Chen said.
It also points to some new advice for people with a fever.
“People should avoid using fever-reducing drugs immediately once they have a fever,” Chen added. Instead he recommends taking a fever-reducing drug only after several hours with a high temperature. That way Hsp90 has had a chance to mobilize the immune system to clear the infection.
7: Immune System - Biology
Количество зарегистрированных учащихся: 260 тыс.
Learners who complete Science of Exercise will have an improved physiological understanding of how your body responds to exercise, and will be able to identify behaviors, choices, and environments that impact your health and training. You will explore a number of significant adjustments required by your body in order to properly respond to the physical stress of exercise, including changes in carbohydrate, fat and protein metabolism, nutritional considerations, causes of muscle soreness & fatigue, and the effectiveness and dangers of performance enhancing drugs. Active learning assessments will challenge you to apply this new knowledge via nutrition logs, heart rate monitoring, calculations of your total daily caloric expenditure and body mass index (BMI). Finally, learners will examine the scientific evidence for the health benefits of exercise including the prevention and treatment of heart disease, diabetes, cancer, obesity (weight loss), depression, and dementia.
Training, Nutrition, Fitness And Nutrition, Public Health
An exceptionally great course. I enjoyed every bit of it. Thanks to the organizers for making these as easy and simple as possible. Now I can live a more healthy lifestyle with the principles learned!
Totally enjoyed this course. It was informative and helped me to understand how my body works so that i can adapt my training and those in my family so we can live a much better life style. Thank you
Physiological Systems During Exercise
In this module you will learn how a number of key physiological systems (muscular, respiratory, cardiovascular, endocrine and immune systems) are regulated during exercise to help maintain homeostasis. These adjustments are critical for exercise to continue for any significant duration. This will include: how the respiratory system adjusts during exercise to ensure proper oxygen delivery and carbon dioxide removal from active muscles how the cardiovascular system responds to ensure adequate blood flow to various organs, including muscle, during exercise how the endocrine system plays a major role in regulating key biochemical and physiological responses to exercise and how exercise influences the immune system and your ability to fight infections.
Robert Mazzeo, Ph.D.
This video will examine the impact that both a single bout of exercise, as well as regular training, have on the immune system. The relatively new field of exercise immunology has emerged over that past 20 years, and has generated some exciting results. As the immune system is extremely complex, I will only address some of the key features as it pertains to exercise and one's susceptibility to infections. Our bodies are constantly exposed to a number of infectious agents that could potentially make us ill. Fortunately, for the most part, our immune system does an excellent job of neutralizing these pathogens upon exposure. The two major branches of the immune system are shown here. They are innate immunity and adaptive immunity. While exercise will affect both branches, in the interest of time I will only focus on adaptive immunity. Adaptive immunity will respond to a specific infectious agent such as a flu virus. And make immune cells specifically designed to neutralize and kill that specific virus. The two arms of adaptive immunity include both a humoral and cellular component. For the purpose of this video, the humoral arm is responsible for making specific antibodies that circulate in the blood, neutralizing infectious agents. The cellular arm is responsible for making t-cells that can kill cells that have all ready been infected. Thus when we look at the responses to exercise, I will discuss the ability to make both antibodies as well as these T killer cells. The impact that a single bout of exercise will have on the immune system will be very much dependent upon the exercise intensity. A moderate bout of exercise has only a small or marginal effect on immune function. However, heavy intense exercise can transiently suppress immune function up to three hours post-exercise. Here is one of many studies demonstrating that after an intense part of exercise. The humoral branch of adaptive immunity and specifically, antibody production is transiently suppressed at least one hour post exercise. This study was performed on eight well trained cyclists who exercised for two hours at 75% of their VOt max. Shown here is the typical response of the cellular branch of adaptive immunity to a single bout of intense exercise. Notice that after an intense training bout of exercise these marathon runners demonstrated a significant reduction in their ability to produce T-cells up to three hours after exercise. Again, this immunosuppression was transit as T-cell production returned to normal after six hours. Taking together the suppression in both humoral and cellular immunity immediately post exercise has lead to the Open Window Theory. Basically, this theory states that for several hours after an intense bought of exercise your immune system is transitory suppressed. Giving any opportunistic bacterial or virus the chance to get a foot hold leading to infection. You may have already been exposed to these infectious agent before the bout of exercise, but your immune system was effectively neutralizing them prior to the intense bout of exercise. Thus, one's susceptibility to infection is likely greater during the post exercise recovery period. Possible mechanisms for this transient suppression in immune function after exercise center around the elevation of several stress hormones. These include the adrenal hormones of cortisol, epinephrine, and norepinephrine, which are known to be immunosuppressive. Additionally, an increase in body temperature as occurs during exercise may also play a role in immunosuppression. Shown here is the cortisol and epinephrine response from those marathon runners described earlier in this video. You'll had a significant reduction in T-cell production three hours after a bath of intense training. Noticed that both cortisol and epinephrine levels remained elevated when compared to rest for several hours into the recovery period. So does this transient suppression and immune function actually translate into an increase susceptibility to infection? The answer appears to be yes. For the weeks following a big racing competition such as a marathon, Iron Man, or Tour de France, the incidents of infection is two to five fold greater an athletes who completed. When compared to individuals of similar fitness, that did not compete. Shown here is just one of many studies that demonstrates this point. Runners who competed in a 56-kilometer race had a two and a half-fold increase in contracting upper respiratory tract infection, when compared to their roommates. As their roommates were exposed to the same possible environmental infectious agents, this suggests that it was the bout of intense exercise that made the runners more susceptible to infection. Other factors that can contribute to an increased susceptibility to infection are shown here. I will briefly discuss the interaction between exercise and stress at the end of this video. People frequently ask me if they should exercise when they're sick. Some people believe that the work out will kill any bacteria or viruses and rid the body of toxins. This is absolutely false. In fact, as stated above, a single bout of exercise can suppress immune function during the post-exercise recovery period, thus making the matter worse. The general rule of thumb is not to exercise, but rest if your symptoms are below the neck. Such as muscle aches, fever, an upset stomach, and lung congestion. If you have symptoms above the neck, such as a simple head cold, it is generally okay to engage in light easy exercise as tolerated. However, if you find even easy exercise makes you feel worse, then you should stop exercising and rest until you have recovered. As you start to feel better, you can gradually return to your normal exercise pattern. Now let's examine how a training can influence your baseline immune function. The majority of studies clearly indicate that participation in regular moderate physical activity will improve overall immunity. Again, I will show you just one representative study of many demonstrating this outcome. In this study, three months of walking in previously sedentary individuals reduced the incidence of upper respiratory track infections by approximately 50%. Over a 15 week window of observation. The mechanisms responsible for this training adaptation remain to be determined, but likely involve both branches of the immune system. While moderate training can boost immune function, involvement in repeated high intensity training will have the opposite effect. As I've already stated in this video, a single bout of high intensity exercise is immunosuppressive. Frequent engagement in these types of training sessions will chronically suppress immune function, making the individual more susceptible to infections. As shown here, this can result in a weakened immune system that puts the individual at a greater risk for infection. Even when compared to their sedentary counterparts. The frequency of infections is a common complaint among many distance athletes. In fact, one of the classic symptoms of overtraining in athletes is an increase in the number of infections resulting from a chronically suppressed immune system. Finally, I would like to discuss the interaction of stress, immune function and regular exercise. It is well established that repeated or chronic stress can weaken the immune system. And can contribute to the onset of illness and disease. Here is just one example demonstrating that regular participation in moderate exercise can reduce the negative effects of other life stressors on the immune system. When sedentary animals are exposed to a stressor, their ability to mount an effective immune response is clearly blunted. However, endurance trained animals when exposed to the exact same stressor, show no reduction or impairment in immune function. Similar findings have been found in humans. Basically moderate exercise training can provide a degree of immune resilience, or stress resistance, protecting you from the adverse affects of other life stressors. In summary, a single bout of high-intensity exercise can transiently suppress immune function allowing an opportunistic virus or bacteria to make you ill. Participation in regular moderate exercise can improve baseline immune function, thereby, lowering the risk of infection. Chronic high-intensity training and overtraining can lower immune function, thereby increasing the rest risk of infection. Regular moderate exercise can reduce the negative effects of other life stressors on the immune system and, thus, your susceptibility to infections.
You Have an Unexplained Rash
"Don't ignore if you develop a skin rash that is not going away with time," says Laura McGevna Nelson, MD , board-certified dermatologist. "Rashes often flare when the immune system is going haywire."
The Rx: Many dermatologists are offering telemedicine consults. Contact yours if necessary.
Veterans and Agent Orange: Update 2012 (2014)
As in Veterans and Agent Orange: Update 2010 (IOM, 2012, hereafter referred to as Update 2010), immune-system disorders are being addressed in a separate chapter preceding those on other adverse health outcomes. In Veterans and Agent Orange (VAO) reports prior to Update 2010&mdashVeterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), and Update 2008 (IOM, 2009)&mdashpossible adverse health outcomes arising from disruptions of the immune system were included in the &ldquoOther Health Effects&rdquo chapter. The current committee elected to revisit comprehensively the limited epidemiologic evidence concerning association of immune disease with herbicide exposure in light of the substantial volume of toxicologic evidence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impairment of the immune systems of laboratory animals.
This chapter opens with an overview of the various types of health problems that can arise from malfunctioning of the human immune system. The standard VAO sections leading to the committee&rsquos assignment of a health outcome to a category of association follow, and they include a new tabulation of all the immune-related epidemiologic information that has been considered in this series and a synopsis of the information new in this update. The next section discusses factors that may lead the immune responses of animals exposed to the chemicals of interest (COIs) to be much more pronounced than any observed to date in humans. The chapter closes with the committee&rsquos thoughts regarding research on the possibility that immune perturbations in humans function as a mechanistic step in the development of disease processes in other organ systems.
The immune system plays three important roles in the body:
1. It defends the body against infection by viruses, bacteria, and other disease-producing microorganisms, known as pathogens.
2. It defends against cancer by destroying mutated cells that might otherwise develop into tumors and by providing immunity against tumors.
3. It provides resident immune cells that are specially adapted for different tissues and organs (such as microglia in the central nervous system and Kupffer cells in the liver) that help to regulate the functional activity and integrity of those tissues.
To recognize the wide array of pathogens in the environment, the immune system relies on many cell types that operate together to generate immune responses. Those cells arise from stem cells in the bone marrow they are found in lymphoid tissues throughout the body and they circulate in the blood as white blood cells (WBCs). The main types of WBCs are granulocytes, monocytes, and lymphocytes. Each type has many specialized cell populations that are responsible for specific functions connected to the production of specific mediators, such as immune hormones, cytokines, and other secreted factors. Imbalances in those specialized populations or in their level of functional activity can result in inadequate or improper immune responses, which may lead to pathologic outcomes. Diseases arising from immune dysfunction may be apparent immediately or observed only after an organism encounters an environmental challenge that causes immune cells to respond (such as an infection).
Immune dysfunctions are in four major categories that need not be mutually exclusive: immune suppression, allergy, autoimmunity, and inflammatory dysfunction (inappropriate or misdirected inflammation). Although immune suppression usually is seen as an increased incidence of infections or an increased risk of cancer, allergic, autoimmune, and inflammatory disorders can be manifested as diseases that affect virtually any tissue. It is often difficult to diagnose such diseases, so they may or may not be medically categorized as immune disorders.
Suppression of immune responses can reduce resistance to infectious disease and increase the risk of cancer. Infection with the human immunodeficiency virus (HIV) is a well-recognized example of an acquired immune deficiency in which a specific type of lymphocyte (CD4+ T cell) is the target of the virus. The decline in the number of CD4+ T cells after HIV infection correlates with an increased incidence of infectious diseases, including fatal opportunistic infections, and with
an increased incidence of several types of cancer. Treatment of cancer patients with toxic chemotherapeutic drugs suppresses the immune system by inhibiting the generation of new WBCs by the bone marrow and by blocking proliferation of lymphocytes during an immune response. Both those examples represent severe immune suppression in which the adverse outcome is easily detected with clinical measurements.
Immune suppression can also result from exposure to chemicals in the workplace or in the environment and be manifested as recurrent infections, opportunistic infections, a higher incidence of a specific category of infections, or a higher incidence of cancer. However, unless the immune suppression is severe, it is often difficult to obtain clinical evidence that directly links chemically induced changes in immune function to increased infectious disease or cancer because many confounding factors can influence a person&rsquos ability to combat infection. Such confounders include age, vaccination status, the virulence of the pathogen, the presence of other diseases (such as diabetes), stress, smoking, and the use of drugs or alcohol. Therefore, immunotoxicology studies are often conducted in laboratory animals to understand the scope and mechanism of chemical-induced immune suppression. Results of such studies can be used to develop biomarkers to assess effects in human populations. Infectious-disease models in animals can also be used to determine whether the pattern of disease changes with chemical exposure.
The immune system sometimes responds to a foreign substance that is not pathogenic. Such immunogenic substances are called allergens. Like most immune-based diseases, allergic diseases have both environmental and genetic risk factors. Their prevalence has increased in many countries in recent decades (CDC, 2004 Linneberg et al., 2000 Simpson et al., 2008 Sly, 1999). Major forms of allergic diseases are asthma, allergic rhinitis, atopic dermatitis, and food allergy. In immediate hypersensitivity, the response to some allergens, such as pollen and bee venom, results in the production of immunoglobulin E (IgE) antibodies. Once produced, IgE antibodies bind to mast cells, specialized cells that occur in tissues throughout the body, including lung airways, the intestinal wall, and blood-vessel walls. When a person is exposed to the allergen again, it binds to the antibodies on the mast cells and causes them to release histamine and leukotrienes, which produce the symptoms associated with an allergic response. In delayed-type hypersensitivity (DTH) reactions, also known as cell-mediated immunity, other allergens, such as poison ivy and nickel, activate allergen-specific lymphocytes at the site of contact (usually the skin) that (memory T cells) release substances that cause inflammation and tissue damage. Some allergic responses, such as those to food allergens, may involve a combination of allergen-specific lymphocyte-driven and IgE-driven inflammation. Allergic responses may be man-
ifested in specific tissues (such as skin, eyes, airways, and gastrointestinal tract) or may result in a system-wide response called anaphylaxis.
The National Institutes of Health Autoimmune Disease Coordinating Committee recognizes 80 diseases and conditions that affect the cardiovascular, respiratory, nervous, endocrine, dermal, gastrointestinal, hepatic, and excretory systems and are classified as autoimmune diseases (NIH Autoimmune Diseases Coordinating Committee, 2005). They affect both men and women, but most affect more women than men (Fairweather et al., 2008). Genetic predisposition, age, hormone status, and such environmental factors as infectious diseases and stress are known to affect the risk of developing autoimmune diseases, and different autoimmune diseases tend to occur in the same person and to cluster in families. The existence of some autoimmune diseases is also a risk factor for the development of other immune-related diseases, such as some types of cancer (Landgren et al., 2010).
Autoimmune disease is an example of the immune system&rsquos causing rather than preventing disease: the immune system attacks the body&rsquos own cells and tissues as though they are foreign. Inappropriate immune responses that result in autoimmune disease can be promoted by different components of the immune system (such as antibodies and lymphocytes) and can be directed against a wide variety of tissues or organs. For example, the autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system in Crohn&rsquos disease, the intestine is the target of attack in type 1 diabetes mellitus, the insulin-producing cells of the pancreas are destroyed by the immune response and rheumatoid arthritis arises from immune attack on the joints, but can also involve the lung, heart, and additional organs.
More generalized forms of autoimmune diseases also occur. Systemic lupus erythematosus (SLE) is an autoimmune disease that has multiple target organs of immune attack. Instead, patients have a variety of symptoms that often occur in other diseases, and this makes diagnosis difficult. A characteristic rash across the cheeks and nose and sensitivity to sunlight are common symptoms oral ulcers, arthritis, pleurisy, proteinuria, and neurologic disorders may be present. Almost all people who have SLE test positive for antinuclear antibodies in the absence of drugs known to induce them. The causes of SLE are unknown, but environmental and genetic factors have been implicated. Some of the environmental factors that may trigger it are infections, antibiotics (especially those in the sulfa and penicillin groups) and some other drugs, ultraviolet radiation, extreme stress, and hormones. Occupational exposures to such chemicals as crystalline silica, solvents, and pesticides have also been associated with SLE (Cooper and Parks, 2004 Parks and Cooper, 2005).
Inflammatory diseases (also referred to as auto-inflammatory diseases) make up a more recently identified category of immune-related disorders that are characterized by exaggerated, excessively prolonged, or misdirected dysfunctional inflammatory responses (usually involving immune cells). Tissue disease can result from this inappropriate inflammation, which can affect virtually any organ. Examples of diseases and other conditions that are most often included in other disease categories but are also considered to be inflammatory diseases are coronary arterial disease, asthma, eczema, chronic sinusitis, hepatic steatosis, psoriasis, celiac disease, and prostatitis. Inflammatory diseases often occur with one another, and this has resulted in the categorizing of different but linked inflammatory diseases together as a single chronic inflammatory disorder (Borensztajn et al., 2011) among these are atherosclerosis and chronic pulmonary obstructive disease. Inappropriate inflammation also appears to play a role in promoting the growth of cancer (Bornschein et al., 2010 Hillegass et al., 2010 Landgren et al., 2010 Porta et al., 2010 Winans et al., 2010) examples can be seen in the higher prevalence of specific cancers in patients who have such inflammatory diseases as inflammatory bowel disease (Lucas et al., 2010 Viennot et al., 2009 Westbrook et al., 2010), prostatitis (Sandhu, 2008 Wang et al., 2009), and psoriasis (Ji et al., 2009).
Ordinarily, inflammation can be advantageous in fighting infectious diseases. It is one component of the normal host response to infection and is mediated by innate immune cells. Inflammatory responses have evolved to speed the trafficking of macrophages, granulocytes, and some lymphocytes to the area of infection, where they produce toxic metabolites that kill pathogens. Interactions among innate immune cells and epithelial and endothelial cells are important in regulating the magnitude of inflammation. However, improperly regulated inflammation can contribute to diseases that arise in nonlymphoid tissues, such as the lungs, skin, nervous system, endocrine system, and reproductive system.
The following comments are restricted to findings related to the immune system that occur after adult human exposure. For a discussion of potential effects on the immune system arising from early-life (such as perinatal) exposures (which would not be directly applicable to the Vietnam veterans who are the target of this report), see Chapters 4 and 9. Studies that served as the basis of prior updates of VAO are shown in Table 7-1.
A handful of the direct studies of veterans listed in Table 7-1 reported a statistically significant difference in a single immune measure (Kim et al., 2003
Participants in 1997 examination cycle, Operation Ranch Hand veterans vs comparisons (incidence)
Participants in 1987 examination cycle, Operation Ranch Hand veterans vs comparisons (morbidity)
Participants in 1985 examination cycle, Operation Ranch Hand veterans vs comparisons (morbidity and mortality)
Morbidity&mdashDeployed vs nondeployed
Physical health and reproductive outcomes
Michigan Vietnam Veterans (deployed vs nondeployed)
New Jersey Agent Orange Commission
Texas Agent Orange Advisory Committee
Australian Vietnam Veterans&mdashlongitudinal cohort study of 67 conditions in randomly selected Vietnam veterans vs general population
1983&ndash1985&mdashAustralian Vietnam Veterans&mdashlongitudinal cohort study of 67 conditions in randomly selected Vietnam veterans vs general population
Antinuclear and sperm autoantibodies
IARC Phenoxy Herbicide Cohort&mdashSubset of Dutch workers (n = 85) from 2 plants that produced and formulated chlorophenoxy herbicides (high exposure = 47, low exposure = 38) serum collected 30 yrs after exposure
IARC Phenoxy Herbicide Cohort&mdashDutch workers from 2 plants that produced and formulated chlorophenoxy herbicides (Plant A, n = 1,167 Plant B, n = 1,143).
Cross-sectional study of 153 male workers in six chemical plants in Germany
138 surviving workers from a larger cohort of 254 exposed workers after an accident in a BASF TCP production facility
Updated and expanded evaluation of 158 workers in a German chemical plant with differing exposure studied in two trials
19 highly exposed chemical workers vs 28 unexposed controls in two chemical plants in Hamburg, Germany
192 workers in a German pesticide plant, including 29 highly exposed and 28 controls compared for immune functional tests
Comparison of 11 2,4,5-trichlorophenol production workers 20 years after exposure vs 10 unexposed age-matched workers in the same company
Examination of eight trichlorophenol production workers who developed chloracne and were reexamined 15&ndash25 years after initial exposure
89 volunteers involved in decontamination work at a chemical plant in Hamburg, Germany no control population
Cross-sectional study of 259 TCDD-exposed 2,4,5-trichlorophenate (and its derivatives) workers (mean serum TCDD, 223 ppt) and 243 unexposed residential controls (mean serum TCDD, 6 ppt)
1987 cross-sectional study of 281 chemical-plant workers in NJ and MO at least 15 years after exposure vs 260 unexposed controls
EUROPIT Study&mdashProspective multicenter cohort study (Bulgaria, Finland, Italy, The Netherlands) of 238 pesticide-exposed workers vs 198 unexposed workers
Comparison from the AHS of 534 cases of self-reported physician-diagnosed depression vs 17,051 controls
29,074 female spouses of pesticide applicators in the AHS
Nested case-control study of rheumatoid arthritis in agricultural families (57,000 pesticide applicators and their spouses)
Longitudinal study of 10 farmers during 1994 within 7 days before and 1&ndash12 days and 50&ndash70 days after exposure
Study of 101 chloracne cases vs 211 controls 20 years after the accident relatively low statistical power was available because the study examined the occurrence of individual diseases
Study of 62 people from a highly exposed zone and 53 from noncontaminated areas 20 years after the accident
45 children (3&ndash7 years of age) living in exposed areas vs 45 nonexposed children as controls
Regression analysis used for comparisons among 41 exposed people for adipose-tissue, TCDD vs immune measures three exposed groups defined by tissue dioxin
82 people in more highly contaminated areas vs 40 in low-risk exposure areas as controls
80 people in highly contaminated areas vs 40 controls in lower-risk areas
Pilot study of small numbers of people for comparisons, people were assigned to two environmental-exposure groups: those in high-risk areas (27 men, 23 women, and 15 children) and those in low-risk areas (12 men, 10 women, and 8 children)
A subset of the previously anergic persons in the Stehr-Green et al. (1987) study were reevaluated in the DTH test with a higher DTH test dose and highly trained, blinded readers
Small (ill-defined) samples were used comparisons of residents of the Quail Run Mobile Home Park with residents of St. Louis&ndasharea trailer parks as controls
154 people in highly contaminated area vs 155 in three low&ndashenvironmental-contamination areas as controls
80 people in a high&ndashexposure risk group vs 40 controls
154 people in the exposed area vs 155 nonexposed people in an uncontaminated area
|Other Environmental Studies|
|Belgium (Flanders)&mdash200 people 17&ndash18 yr of age in three areas of Flanders (Belgium) TEQ values were calculated from serum dioxin-like PCB concentrations and relationships with immune measures were examined||Dioxins and PCBs: Decreases in eosinophil and NK-cell counts with increasing TEQ IgE concentrations history of upper airway allergy, and odds of a positive RAST test correlated negatively with serum TEQ IgA concentrations correlated positively with TEQ||Van den Heuvel et al., 2002|
|Germany&mdashCross-sectional study of 221 teachers who worked in German day-care centers treated with wood preservatives vs 189 teachers who worked in untreated facilities||Dioxin in wood preservatives, exposure primarily via inhalation: No effects of inhaled dioxin were seen on T4 or T8 cell numbers or on the ratio some evidence of a dose&ndashresponse relationship was seen for risk of anergy (or hypoergy) in the DTH assay||Wolf and Karmaus, 1995|
|US (NHANES)&mdash1,721 adults were assessed for serum dioxin-like PCBs and self-reported arthritis||Dioxin-like PCBs: Association between serum dioxin-like PCBs and prevalence of arthritis particularly among women||Lee et al., 2007a|
|Norway&mdashblood samples from 24 Norwegian hobby fishermen were compared with those of 10 male referents as controls||PCDD, exposure from food: The study generally lacks experimental details no differences in an NK cell marker or in NK activity were seen apparently, some effects on lymphoid markers were observed but specific details are lacking||Lovik et al., 1996|
|Sweden&mdash23 high consumers of fatty fish from the Baltic Sea (containing low concentrations of PCDD) vs 20 low consumers or nonconsumers of fish as controls||PCDD, exposure from food: Blood PCDDs were significantly different between the groups mercury concentrations also differed NK cells correlated negatively with blood concentrations of persistent organic chemicals no other||Svensson et al., 1994|
|South Korea (Ansan)&mdashcomparison of immune measures in 31 waste-incineration workers vs 84 controls||TCDD (via waste incineration): Lymphoid subsets, IFN-gamma, and Ig not statistically different decrease in IL-4 and increase in T-cell activation (measured as combined CD3 and CD69 markers) associated with TCDD exposure||Oh et al., 2005|
|United Kingdom (Derbyshire)&mdash18 chemical workers in a 2,4,5-T in the Coalite Oils and Chemical, Ltd. factory exposed as a result of an industrial accident 17 years before study vs 15 matched controls||TCDD: No changes in serum Ig classes, increases in antinuclear antibodies and immune complexes, and increase in circulating NK cells (Leu7+) in exposed workers||Jennings et al., 1988|
|United States (California)&mdashtelephone interviews concerning environmental and occupational chemical exposures were conducted with 50 AIDS patients (with Kaposi sarcoma) and 50 homosexual men as controls||Chemical exposures, including pesticides, and Agent Orange: No significant differences were reported in a small study that generally lacked focus||Hardell et al., 1987|
NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid AHS, Agricultural Health Study CDC, Centers for Disease Control and Prevention CI, confidence interval COI, chemical of interest Con A, concanavalin A DTH, delayed-type hypersensitivity IFN-gamma, interferon-gamma Ig, immunoglobulin IL, interleukin MCPA, methyl-4-chlorophenoxyacetic acid MLR, mixed lymphocyte response MO, Missouri NHANES, National Health and Nutrition Examination Survey NIOSH, National Institute for Occupational Safety and Health NK, natural killer OR, odds ratio PCB, polychlorinated biphenyl PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines) PCDF, polychlorinated dibenzofurans PHA, polyhydroxyalkanoates RAST, radioallergosorbent SEA, Southeast Asia TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin TCP, trichlorophenol TEQ, total toxic equivalent TNF, tumor necrosis factor VA, Department of Veterans Affairs WBC, white blood cell.
Michalek et al., 1999a). But invariably the same effect was not found in other studies of Vietnam veterans, nor was support found in epidemiologic studies of other populations. Thus, there were no consistent findings indicative of immunosuppression, increased risk of autoimmunity (usually as measured with autoantibodies), or biomarkers of atopy or allergy (such as increased IgE concentrations). Much of the focus of the studies was on measuring T4:T8 ratios. The T4:T8 ratio is an effective biomarker of the progression of HIV-induced AIDS, but, on the basis of the TCDD-exposure animal data, it is not an immunologic index that is expected to be altered. The results of a survey of Australian Vietnam veterans (O&rsquoToole et al., 2009) included purportedly significant increases in the prevalence of a number of conditions in which immune function may play a prominent role, but the study&rsquos methods were deemed unreliable.
Occupational-exposure studies shown in Table 7-1 evaluated concentrations of lymphoid populations in circulation, such as CD4, CD8 (and the ratio of the two), and natural killer (NK) cells cell-mediated immunity (the delayed-hyper-
sensitivity response) serum concentrations of immunoglobulins, such as IgM, IgG, and IgA concentrations of complement, such as C3 and C4 and concentrations of cytokines, such as IL-1, IL-2, interferon-gamma, IL-4, IL-6, and tumor necrosis factor (TNF)-alpha. A few studies also included disease or condition endpoints, such as rheumatoid arthritis, SLE, and depression. Ex vivo analyses included measures of NK activity, lymphoid mitogen-induced proliferation, and the mixed lymphocyte response (MLR) against allogeneic cells. Some studies identified one or more dioxin-related shifts in immune measures, but many reported no significant differences in the same measures. That is particularly true of the study by Neubert et al. (2000), which measured toxicity equivalents (TEQs) for dioxin but found no immunoglobulin or cytokine alterations. In general, the spectrum of occupational-exposure findings does not provide a consistent or clear picture of alterations in immune measures that could be extrapolated to an increased risk of a single disease or even a broader category of diseases. The exception may be observations of pesticide-associated autoimmunity and depression. Immune depression was rather consistently associated with very high pesticide exposures or pesticide poisonings. However, because the studies generally concerned broad categories of pesticide exposure, their relevance to herbicide exposures in Vietnam is not clear.
Several environmental-exposure studies reported alterations, but findings were inconsistent among the studies (see Table 7-1). Some studies reported alterations in immune measures associated with TEQs for dioxin. For example, Van den Heuvel et al. (2002) reported that IgE, positive radioallergosorbent (RAST) tests in response to specific allergens, eosinophil counts, and NK-cell counts correlated negatively with dioxin TEQs but that IgA increased these alterations, however, were not seen consistently in other studies. Baccarelli et al. (2002) found no changes in IgA but saw changes in IgG in the Seveso population. Svensson et al. (1994) found that NK-cell numbers were reduced with increasing concentrations of persistent organic chemicals, but Lovik et al. (1996) found no difference in NK numbers or activity. Similarly, the occupational-exposure studies (see Table 7-1) that examined NK concentrations reported the full spectrum of results: no alterations (Halperin et al., 1998), a decrease (Faustini et al., 1996), and even an increase in NK numbers (Jennings et al., 1988) in dioxin-exposed people.
As seen in Table 7-1, some early studies of the Quail Run Mobile Home Park population exposures reported that dioxin exposure was associated with a reduced cell-mediated immune response, the delayed-type hypersensitivity (DTH) response (Andrews et al., 1986 Hoffman et al., 1986 Knutsen et al., 1987 Stehr-Green et al., 1987). But some of those studies had technical problems in assessment and in followup analyses. Dioxin-associated changes were not confirmed (Evans et al., 1988 Webb et al., 1989). In addition, several studies of the Times
Beach population did not find any alteration of the DTH response in dioxin-exposed populations (Knutsen, 1984 Stehr et al., 1986 Webb et al., 1987).
Analysis of National Health and Nutrition Examination Survey (NHANES) data found that exposure to dioxin-like polychlorinated biphenyls was associated with an increase in self-reported arthritis (Lee et al., 2007a), but De Roos et al. (2005b) had found no such association in their study.
Prior VAO updates have concluded that human data were either insufficient or inconsistent with respect to an increased risk of immunosuppression, allergic disease, or autoimmune disease.
Vietnam-Veteran and Case-Control Studies
No new case-control studies or studies of Vietnam veterans exposed to the COIs and adverse immunologic conditions have been published since Update 2010.
There were several small new studies of occupational cohorts. Endres et al. (2012) studied fungal sensitization in the Agricultural Health Study and reported that farmers had levels of fungal sensitization lower than the national levels found in the NHANES studies. It is difficult to interpret those data, although they do suggest that farmers as a group have a lower reactivity to fungal antigens.
Saberi Hosnijeh et al. (2011) studied Dutch phenoxy-herbicide workers, assessing their humoral immunity. The 45 TCDD-exposed workers had decreased concentrations of complement factor 4 but no other apparent changes in humoral immunity as measured by other complement factors or immunoglobulins. The same authors (Saberi Hosnijeh et al., 2012) reported that plasma TCDD concentrations were associated with decreases in cytokines, chemokines, and growth factors. The authors conclude that this work provided evidence of immunologic effects of TCDD.
No environmental studies of adverse immunologic conditions have been published since the 2010 review. However, a report of an investigation of the immune response of a single highly exposed person (Brembilla et al., 2011) reported some clearly TCDD-associated immune changes (such as IL-22 production by CD4+ T cells), confirming some TCDD-associated changes in immune measures. It is interesting that there was no measured effect of TCDD exposure on the
person&rsquos T regulatory cells. Earlier publications cited indicate that this patient was Victor Yuchenko, whose poisoning in 2004 has provided insight into human response to and biotransformation of an extremely high dose of TCDD, exceeding by orders of magnitude the exposures experienced by Vietnam veterans.
The literature searches for the current update found two epidemiologic studies (Jusko et al., 2011 Miyashita et al., 2011) that addressed immune-related outcomes in the children of mothers potentially exposed to the COIs (the topic of Chapter 10) that are not relevant to assessing immune consequences in Vietnam veterans of their own exposure.
There is an extensive body of evidence from experimental studies in animal-model systems that TCDD, other dioxins, and several dioxin-like chemicals (DLCs) are immunotoxic (Kerkvliet, 2009, 2012). Immunotoxicity is due primarily to changes in adaptive immune responses that result in suppression of both antibody-mediated and cell-mediated immunity. A new endogenous pathway, the tryptophan metabolic pathway, has recently been identified as affecting the aryl hydrocarbon receptor (AHR) and immune biology (Opitz et al., 2011). Dioxin and related chemicals with dioxin-like activity may induce a reduction in the ability to clear pathogenic infections and prevent tumor growth in a fashion that is mediated by endogenous pathways. Studies in laboratory mice have shown that the immunotoxicity of TCDD and DLCs depends on activation of the AHR. Most of the cell types involved in the immune system express the AHR, so there are many potential pathways to immunotoxicity. TCDD has also been shown to alter macrophages and neutrophils in a manner that exacerbates some forms of inflammation during infections and may contribute to the development of chronic inflammatory lung disease (Teske et al., 2005 Wong et al., 2010). Other recent work shows that the AHR is involved in hematopoiesis at multiple stages (Baba et al., 2012 Sibilano et al., 2012 Simones and Shepherd, 2011 Singh et al., 2011). Working with human B cells in vitro, Allan and Sherr (2010) demonstrated a new AHR-dependent mechanism by which exposure to environmental polycyclic aromatic hydrocarbons could suppress humoral immunity by blocking differentiation of B cells into plasma cells.
TCDD is a potent immunosuppressive chemical in laboratory animals. The relative potencies of given DLCs based on induction hepatic enzymes&mdashtheir toxicity equivalence factors (TEFs)&mdashappear to predict the degree of immunosuppression induced (Smialowicz et al., 2008). TCDD has also been shown to induce apoptosis in rabbit chondrocytes, and this supports a potential role of TCDD in contributing in a novel way to arthritis (Yang and Lee, 2010). Exposure of animals to dioxin not only suppresses some adaptive immune responses but also has been shown to increase the incidence and severity of various infectious diseases and to increase the development of cancer (Choi et al., 2003 Elizondo et al., 2011
Fiorito et al., 2010, 2011 Head and Lawrence, 2009 Jin et al., 2010 Sanchez et al., 2010). It is consistent with its immunosuppressive effects that TCDD exposure suppresses the allergic immune response of rodents this in turn results in decreased allergen-associated pathologic lung conditions and has recently been shown to suppress the development of experimental autoimmune disease (Quintana et al., 2008), to induce the suppression of autoimmune uveoretinitis (Zhang et al., 2010), and to affect colitis (Takamura et al., 2011), arthritis (Nakahama et al., 2011), and inflammatory lung diseases, such as silicosis (Beamer et al., 2012). A recent study of 18 people who had allergic asthma, 17 people whose asthma was controlled, and 12 controls showed that the plasma concentrations of IL-22 and the expression of the AHR in peripheral blood mononuclear cells was associated with the severity of allergic asthma this finding strengthened the possibility that the AHR is involved in allergic asthma, thereby implying a role for dioxin exposure in this condition (Zhu et al., 2011). Thus, depending on the disease, TCDD exposure could exacerbate or ameliorate symptoms.
Recent attention has focused on the ability of the AHR to induce regulatory T cells, or Tregs (Kerkvliet, 2012 Marshall and Kerkvliet, 2010). Tregs have potent suppressive activity in the immune system, and their inappropriate induction by TCDD could account for much of the immune suppression. AHR activation in dendritic cells has also been shown to promote the development of Tregs by inducing tryptophan metabolism. AHR activation in B cells can directly disrupt the production of antibodies (Sulentic and Kaminski, 2011). The recent demonstration that AHR activation by TCDD leads to the development of Tregs helps to explain the diversity of effects seen after exposure to TCDD (Funatake et al., 2008 Kerkvliet, 2012 Marshall et al., 2008 Quintana et al., 2008 Stockinger et al., 2011 Yamamoto and Shlomchik, 2010).
Recent data indicate that the AHR pathway plays an integral role in B-cell maturation, and that TCDD and DLC exposure may alter the function of these cells and result in critical changes in the immune response. Suppression of the immune response by TCDD and similar compounds in mice has been known for over 30 years, but the effect on human cells is less clear. Some recent reports indicate that TCDD and DLC elicit similar effects in humans. Activation of non-transformed human B cells results in an increase in expression of the AHR, indicating that this pathway has a role in normal B-cell function (Allan and Sherr, 2010). Furthermore, treatment of those cells with B[a]P suppresses B-cell differentiation. Lu et al. (2010) demonstrated that although human B cells appeared less responsive to TCDD in increasing expression of AHR battery genes, the ability of TCDD to decrease IgM production was similar in both mouse and human B cells. In addition, data from human hemopoietic stem cells (HSCs) and knockout AHR mouse models show that the AHR is critical in HSC maturation and differentiation (Fracchiolla et al., 2011 Singh et al., 2011). TCDD not only alters HSC maturation but also alters proliferation and migration in vivo and in
vitro (Casado et al., 2011), and this indicates that exposure may have multiple effects on immune-cell function.
One would expect exposure to substantial doses of TCDD to result in immune suppression in Vietnam veterans. However, several studies of various measures of human immune function failed to reveal consistent correlations with TCDD exposure, probably because the exposures were inadequate to produce immune suppression or because the characteristics measured were not among those most relevant with respect to biologic plausibility. No clear pattern of an increase in infectious disease has been documented in the studies of veterans exposed to TCDD or to the herbicides used in Vietnam. However, three occupational-exposure studies provide some support for the idea that exposure to TCDD may result in an altered immune response to some exposures and an increased frequency of infections. The study of a single highly exposed person (Brembilla et al., 2011) confirmed TCDD-associated changes in immune measures that may not be applicable to people whose exposure was considerably lower. Immune alteration and the frequency and duration of specific types of infections should therefore be a focus of future studies. Suppression of the immune response by TCDD might increase the risk of some kinds of cancer in Vietnam veterans, but there is no evidence to support the connection.
Allergic and Autoimmune Diseases
Epidemiologic studies have been inconsistent with regard to TCDD&rsquos influence on IgE production in humans. No human studies have specifically addressed the influence of TCDD on autoimmune disease, but several animal studies have shown that TCDD suppresses the development of autoimmune diseases. In studying postservice mortality, Boehmer et al. (2004) found no increase in deaths of Vietnam veterans that could be attributed to immune-system disorders. There is no experimental evidence to support that finding, but increased inflammatory responses could be involved. The study of people who had allergic asthma or controlled asthma strengthened the data and suggested that the AHR (and thus dioxin exposure) is involved in the disease (Zhu et al., 2011). Future studies are needed to determine a potential mechanism of TCDD-induced allergic and autoimmune disease, including rheumatoid arthritis.
Few effects of phenoxy herbicide or cacodylic acid exposure on the immune system have been reported in animals or humans, and no clear association between such exposure and autoimmune or allergic disease has been found.
Exposure of laboratory animals to phenoxy herbicides or cacodylic acid has not been associated with immunotoxicity.
There are no human data on the potential for dioxin or the herbicides of interest to induce dysregulation of inflammation that could contribute to an increased risk of inflammation-associated diseases.
Possible associations involving infectious or inflammation-related diseases should be a focus for the future. Examples of earlier studies whose results support the occurrence of such adverse outcomes are Baccarelli et al. (2002), Baranska et al. (2008), Beseler et al. (2008), Oh et al. (2005), O&rsquoToole et al. (2009), Tonn et al. (1996), and Visintainer et al. (1995).
On the basis of the evidence reviewed here and in previous VAO reports, the present committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and specific infectious, allergic, or autoimmune diseases.
Animal studies and in vitro studies with human cells and cell lines are important ways of trying to understand underlying biologic mechanisms associated with immunotoxic and other responses to xenobiotics, which are &ldquoforeign&rdquo substances that do not normally occur in biologic systems. However, as discussed above, despite the vast array of data supporting the immunotoxicity of TCDD in laboratory animals, little evidence from studies of Vietnam veterans or other human populations suggests that TCDD or the herbicides of concern produce immune alterations. Many factors must be considered in examining the relevance of animal and in vitro studies to human disease and disease progression, and they are discussed in Chapter 4. Here, we present the factors that are probably most important in considering differences between the results of laboratory studies and the findings of observational epidemiologic studies.
Magnitude and Timing of Exposure
In general, the TCDD exposures used in animal studies have been orders of magnitude higher than exposures that Vietnam veterans are likely to have received during military service. It is well known that the immune system is highly susceptible to xenobiotic exposure during critical stages of development,
A Duet of Bone and the Immune System
Over the past two decades, exciting research has provided an important new perspective on the biology of bone in health and disease, revealing an active and sometimes loud crosstalk between bone and the immune system. This perspective is a radical departure from the traditional view of the relationship of these tissues. In the traditional view, the bone and immune system represented separate functional realms despite their close physical relationship in the bone marrow. There, the bone houses immune cells and provides a sanctuary for key events in immune cell development and differentiation. Many of the important discoveries on the interactions between bone and the immune system arose from studies on arthritis, where immune cells and bone are closely juxtaposed in the joint microenvironment. 1&ndash4 The dimension and variety of these interactions, however, were unexpected and have spurred the creation of a dynamic new field of research.
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Explore This Issue
From a clinical perspective examining pathogenesis, bone seems to be the target and victim from damage inflicted at the hands of the immune system. Indeed, in inflammatory arthritis, bone erosion is the dreaded outcome of the immune system&rsquos destructiveness. As is now realized, however, this view is too simplistic because bone can drive the immune system as well as withstand its blows. Evidence for an active role of bone in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus and inflammatory arthritis, has accumulated rapidly. This evidence includes provocative new findings on the properties of bone marrow niches, which are specialized microenvironments for the maturation of immune cells and for the maintenance of immunological memory. This new research field is called osteoimmunology and addresses the mutual interactions of bone and the immune system. 5
Although pioneering works in the late 1970s identified potential interactions between bone and the immune system, the field truly emerged from landmark studies in the late 1990s. These studies demonstrated that T lymphocytes can trigger bone loss by inducing differentiation of osteoclasts. 4,6 In this article, we will discuss current concepts of osteoimmunology in the context of rheumatologic disease. We will focus on the processes of bone degradation and formation that are regulated by the immune system in inflammatory arthritides. We will also consider the role of bone and bone marrow as a niche for immune cells, a mostly unknown yet important facet for the interplay of bone and immune systems in the pathogenesis of autoimmune disease.
RANKL has been established as a key mediator of inflammatory bone loss and one of the key molecules in the interactions that characterize osteoimmunology.
Osteoclasts, Osteoblasts, and Inflammatory Cells
Bone is living tissue and not just an inert or rigid framework to organize other tissues in the body. Bone grows, heals, transforms, and constantly remodels as it adapts to external mechanical forces. Adult vertebrates replace approximately 10% of their total bone content per year, with adolescents showing even higher turnover rates. The cells mediating these dynamic processes are the osteoclasts that degrade bone and the osteoblasts that produce new bone. A tightly regulated balance of osteoclastic and osteoblastic activity maintains a steady state of total bone mass in healthy adults. Diseases affecting bone, however, can disturb this balance and lead to both the loss and gain of bone tissue. 7
To remodel bone efficiently, osteoclasts and osteoblasts interact extensively in fact, osteoblasts are important regulators of osteoclast differentiation. Elegant in vitro systems have demonstrated that bone marrow&ndashderived monocytes/macrophages differentiate into osteoclasts in the presence of osteoblast precursors or other mesenchymal cells such as synovial fibroblasts. 4 To induce osteoclastogenesis, osteoblast precursors and synovial fibroblasts release soluble factors, including macrophage colony&ndashstimulating factor, and express surface molecules, such as the long-sought osteoclast differentiation factor (see Figure 1, p. 37). 1,4 When cloned in 1998, the osteoclast differentiation factor surprisingly showed identity with a protein called the receptor activator of nuclear factor&ndash&kappaB ligand (RANKL). 8,9 RANKL had already been known for its role in the immune system, particularly for lymph node development, demonstrating clearly shared signalling mechanisms between bone and the immune system. 10
Since its discovery, RANKL has been established as a key mediator of inflammatory bone loss and one of the key molecules in the interactions that characterize osteoimmunology. When expressed on osteoblast precursors, synovial fibroblasts, and immune cells (see below), RANKL can bind to its receptor RANK on osteoclast precursors and induce osteoclastogenesis via intracellular signaling by NF-&kappaB and the activation protein (AP)&ndash1 transcription factor family. 1,4 Studies from mouse models have provided important insights into the role of RANKL in bone. For example, mice deficient for RANKL show an osteopetrotic phenotype and a defective development of osteoclasts and low bone resorption. Interestingly, the expression of RANKL in the body is induced by proinflammatory cytokines, in particular tumor necrosis factor (TNF) as well as interleukin (IL)-1 and IL-17 this pattern of regulation further highlights the involvement of the immune system and inflammation in RANKL-mediated effects on bone. 1,11
Filming how our immune system kill bacteria
To kill bacteria in the blood, our immune system relies on nanomachines that can open deadly holes in their targets. UCL scientists have now filmed these nanomachines in action, discovering a key bottleneck in the process which helps to protect our own cells.
The research, published in Nature Communications, provides us with a better understanding of how the immune system kills bacteria and why our own cells remain intact. This may guide the development of new therapies that harness the immune system against bacterial infections, and strategies that repurpose the immune system to act against other rogue cells in the body.
In earlier research, the scientists imaged the hallmarks of attack in live bacteria, showing that the immune system response results in 'bullet holes' spread across the cell envelopes of bacteria. The holes are incredibly small with a diameter of just 10 nanometres.
For this study, the researchers mimicked how these deadly holes are formed by the membrane attack complex (MAC) using a model bacterial surface. By tracking each step of the process, they found that shortly after each hole started to form, the process stalled, offering a reprieve for the body's own cells.
"It appears as if these nanomachines wait a moment, allowing their potential victim to intervene in case it is one of the body's own cells instead of an invading bug, before they deal the killer blow," explained Dr. Edward Parsons (UCL London Centre for Nanotechnology).So-called membrane attack complexes -- imaged on the back of a bacterium. The scale bars correspond to 800 (left) and 30 (right) nanometres. Credit: EMBO Journal (2019), 10.15252/embj.201899852.
The team say the process pauses as 18 copies of the same protein are needed to complete a hole. Initially, there's only one copy which inserts into the bacterial surface, after which the other copies of the protein slot into place much more rapidly.
"It is the insertion of the first protein of the membrane attack complex which causes the bottleneck in the killing process. Curiously, it coincides with the point where hole formation is prevented on our own healthy cells, thus leaving them undamaged," said Professor Bart Hoogenboom (UCL Physics & Astronomy).A video sequence of the formation of a hole in a bacterial surface, recorded at 6.5 seconds per frame. The scale bar (see first frame) corresponds to 30 nanometres. Credit: Edward S. Parsons et al.
To film the immune system in action at nanometre resolution and at a few seconds per frame, the scientists used atomic force microscopy. This type of microscopy uses an ultrafine needle to feel rather than see molecules on a surface, similar to a blind person reading Braille. The needle repeatedly scans the surface to produce an image that refreshes fast enough to track how immune proteins get together and cut into the bacterial surface.
Mutated virus may reinfect people already stricken once with covid-19, sparking debate and concernsIn any case, Murphy added, antibodies are only part of a person’s immune system response.
The adult trials paved much of the way, but researchers still need to study how kids’ immune system s react and to confirm the optimal dosage.
Changes in immune system markers, like antibodies, in people who are vaccinated comport with what scientists expect in a situation that prevents the virus from setting up shop in people’s airways.
The purpose of the vaccine is to trigger your immune system to respond.
Don’t buy into immune-boosting hacksSome companies are advertising vitamin regimens to strengthen the immune system and boost protection from the vaccine, but there’s no data to suggest any benefits from them.
There were no deaths on scheduled commercial aviation flights in 2014, in a system that operates 68,000 flights a day.
She fills her characters up—strong women beating back against a sexist system—with so much heart.
A hundred ultra-wealthy liberal and conservative donors have taken over the political system.
“Stay in formation,” a sergeant from the ceremonial unit said over a public address system to the cops along the street.
Both parties are now equal opportunity offenders when it comes to gaming the system.
Sweden excluded British goods, conformably to the continental system established by Bonaparte.
As Spain, however, has fallen from the high place she once held, her colonial system has also gone down.
The reformers of the earlier period were not indifferent to the need for centralized organization in the banking system.
Accordingly, the question "How far does the note issue under the new system seem likely to prove an elastic one?"
Thanks to Berthier's admirable system, Bonaparte was kept in touch with every part of his command.