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Gluten is not a single protein, but a complex mixture of related proteins that constitute the bulk of protein stores in many grains. These proteins belong to 2 main classes: prolamins and glutelins.
Gluten has unique viscosity properties that give the dough its elasticity. Because of its low costs, wheat gluten is widely used as a thickening or binding agent, and to fortify low-protein food products. For this reason, apart from obvious sources, gluten can also be found in a variety of processed foods, including meat and meat substitutes, as well as medications and nutrition supplements.
Prolamins are of most clinical significance when it comes to gluten-related disorders. In wheat they are called gliadin. Proteins similar to gliadin exist in rye, barley, oat, and their derivatives. These proteins are highly polymorphic, meaning there exist many variations of the same protein. Thus, not only different grains, but also different varieties or even different genotypes of the same grain can produce different gluten compounds. Composition of a particular gluten also varies depending on growing conditions and processing technologies.
Prolamins are the main causative agent of celiac disease. Prolamins are rich in the amino acids proline and glutamine, and are therefore highly resistant to digestion by enzymes of the gastrointestinal tract. Partial digestion of prolamins produces a family of small peptides, that can trigger inappropriate immune response in people with celiac disease. These peptides are known as epitopes. A given patient may react only to a few of these peptides. Different patients may react to different peptides. The most toxic epitope, responsible for strongest reactions in most patients, is a 33-amino acids peptide from wheat alpha-2-gliadin.
While it also contains gluten, oat is safe for most people with celiac disease. This is because the prolamin content in oat is significantly lower than that in the other 3 grains, and the number of people reacting to oat epitopes is relatively smaller.
People with celiac disease usually inherit a genetic predisposition to the disease. They have certain receptors that bind strongly to the epitopes and alert the immune system, specifically T-helper cells, to their presence. Activated T-helper cells release inflammatory cytokines, and attract cytotoxic T-cells to the small intestine. This results in inflammation of the mucosa, villous atrophy, and increased gut permeability. Common gastrointestinal symptoms include bloating and abnormal bowel habits.
Wheat gluten is also involved in wheat allergy. Allergy is an immediate abnormal immune response, usually within minutes of ingestion. The mechanism is similar to other food allergies and involves IgE-mediated release of histamine and other inflammatory chemicals from mast cells. Symptoms include itching, swelling, rash, vomiting, diarrhea, and in some cases, life‐threatening anaphylaxis. Gluten, however, is not always the culprit in wheat allergy. Some people react not to gluten, but to other wheat proteins and pollen proteins.
The most common gluten-related disorder is the so-called non-celiac gluten sensitivity. This term includes all reactions to gluten-containing grains that are not celiac disease or wheat allergy. Pathology is not yet understood, and the terminology maybe a misnomer, because other proteins and carbohydrates present in the grains may also be responsible for the symptoms.

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Allergy refers to abnormal reactions of the immune system to otherwise harmless substances. Normally, the immune system raises immune response to protect the body from foreign invaders, such as bacteria or viruses, but does not react to non-infectious environmental antigens. In people with allergies, however, the immune system also reacts to these substances, producing allergic reactions. Such substances, called allergens, can come from the patient’s natural environment, foods, medications, latex products, or insect bites.
Most allergies are mediated by a class of antibody called immunoglobulin E, IgE. IgE is produced when the body is first exposed to an allergen. Production of IgE is activated by a subtype of T-lymphocytes, known as type 2 helper T-cells, TH2. IgE molecules then bind to their receptors on the surface of mast cells and basophils. The first exposure is usually asymptomatic, but the body is now sensitized. Upon reexposure to the same antigen, the antigen binds to adjacent IgE molecules, bringing their receptors together, triggering a signaling cascade that induces the release of histamine and other inflammatory chemicals. These chemicals cause dilation and increased permeability of blood vessels, mucus secretion, stimulation of sensory nerves, smooth muscle spasms, and are responsible for allergic symptoms, which can range from mild to severe. Mild symptoms usually consist of watery eyes, runny nose, sneezing and a mild rash; while severe reactions may include swelling, hives, difficulty breathing due to bronchospasm, and digestive problems due to increased gastrointestinal motility. When released systemically, these chemicals can cause extensive vasodilation and smooth muscle spasms which may lead to anaphylaxis, a life-threatening condition in which blood pressure drops and airways narrow to a dangerous level.
The reactions are immediate, within minutes of contact with the allergen. There is also a late phase response, due to subsequent tissue infiltration with eosinophils and other inflammatory cells.
People who are sensitized to a specific allergen may also react to other substances that contain similar antigens. This is called cross-reactivity. For example, people who are allergic to birch pollen may also have reactions to certain fruits and vegetables such as apples or potatoes, consumption of which can cause itching and swelling of the lips and oral cavity.
Both genetic and environmental factors contribute to the development of allergic diseases.
Allergies tend to run in families. What is inherited is the susceptibility to allergic reactions, due to irregularities in the makeup of the immune system.
Early childhood exposures to bacterial and viral infections are thought to suppress TH2 cells and are therefore protective against allergic diseases. This theory, known as hygiene hypothesis, implies that living in too sterile an environment is a risk factor for allergic diseases. While still a hypothesis, it does partly explain the higher prevalence of allergies in developed countries. Other risks factors include exposure to allergens and stress.
Diagnosis is usually based on symptoms and patient’s history. Potential allergens may be identified with skin prick test or intradermal test, where small amounts of common allergens are introduced into the skin and local reactions are observed. A blood test, called allergen-specific serum IgE test, can also be performed. In this case, patient’s blood sample containing IgE is tested for binding to common allergens. If binding occurs, the person is allergic to that allergen.
Antihistamines are effective for treatment of mild allergies. Other drugs include mast cell stabilizers, corticosteroids and leukotriene modifiers. Severe reactions require immediate injection of epinephrine.
The best way to prevent allergies is to avoid the offending allergens. People with serious reactions to unavoidable allergens may benefit from immunotherapy. In immunotherapy, patients are injected weekly with gradually increasing doses of the allergen, starting with a tiny amount. This process desensitizes the immune system, reducing reactions to the allergen, but may take several years to complete.

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Hypersensitivity refers to abnormal reactions of the immune system against certain antigens. It includes exaggerated reactions to otherwise harmless environmental antigens, commonly known as allergies; and inappropriate reactions against the body’s own antigens, or autoimmune diseases.
Reactions can range from a mild rash, to damaged organs, to fatal anaphylactic shock.
There are 2 principal groups of factors contributing to hypersensitivity:
– Imbalance between effectors and regulators of immune response: in some people, mechanisms that normally moderate the immune system are compromised, causing it to overreact to harmless, non-infectious antigens.
– Self-reactivity of immune cells: during their development in the thymus and bone marrow, T-cells and B-cells learn to not react to the body’s own antigens; self-reactive cells are normally eliminated; but in some people, some of these cells escape and may attack their own tissues once activated.
Hypersensitivity reactions only occur in pre-sensitized individuals. Patients must have had a previous contact with the antigen, which produced no symptoms, but during which the body had started making antibodies or activated immune cells that may cause symptoms in subsequent exposures to the same antigen.
Hypersensitivity is classified into 4 types based on mechanisms of action:
In type I hypersensitivity, a previous exposure to the antigen results in production of a class of antibodies called IgE. IgE molecules bind to their receptors on the surface of mast cells and basophils. Upon re-exposure to the same antigen, or sometimes a similar antigen, the antigen binds to adjacent IgE molecules, bringing their receptors together, triggering a signaling cascade that induces the release of histamine and other inflammatory chemicals. These chemicals cause dilation of blood vessels, smooth muscle spasms, and are responsible for symptoms such as edema, rash, difficulty breathing due to bronchospasm, abdominal cramping, vomiting and diarrhea. The reactions are immediate, within minutes of contact with the antigen, and can range from mild to severe. Severe reactions may lead to anaphylactic shock, a life-threatening condition in which blood pressure drops and airways narrow to a dangerous level. Most allergies are type I hypersensitivity reactions.
In type II hypersensitivity, previously formed IgG or IgM antibodies bind to antigens on the surface of a particular cell type. Antibody binding marks the cells for destruction, either by the complement system or phagocytosis. The antibodies may also interfere with normal functions of the cells without killing them. Type II is at the basis of many autoimmune diseases, where the body produces antibodies to destroy its own cells. Another example is hemolytic disease of the newborn, where maternal antibodies bind to D-antigen on the surface of fetal red blood cells and destroy them.
Type III hypersensitivity reactions are also mediated by IgM or IgG, but in this case, the antibodies bind to free-floating antigens, forming antibody-antigen complexes. The complement system is activated and inflammation results, causing damage to the affected tissue. A typical example is serum sickness, induced by a large amount of antigens in the blood. Immune complexes are deposited in the walls of blood vessels, triggering their inflammation, or vasculitis.
Type IV hypersensitivity is a delayed reaction, mediated by T-cells. Pre-sensitized T-cells are produced during a previous contact with the antigen. Upon re-exposure to the same antigen, T-helper cells release inflammatory cytokines, while T-killers induce cytotoxic reactions. Typical examples are allergic reactions to substances that come into direct contact with the skin, known as contact dermatitis. Type IV is also the basis of the tuberculosis skin test.

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The major players of humoral immunity are B-cells. They develop in the bone marrow and complete their maturation in the spleen. Similar to T-cells, B-cells are formed in billions of variations, each carrying a unique surface protein, called B-cell receptor, BCR. Just like T-cells, they also learn to not react to the body’s own antigens; those that react to self-molecules are eliminated or ignored. The majority of mature B-cells, namely the follicular B-cells, circulate to secondary lymphoid organs – the same locations as mature T-cells, where they expect encounters with pathogens. T-cells and B-cells are usually separated into defined T-cell and B-cell zones within these organs.
Here again, specific immunity relies on the invading pathogen finding a match among these many variations of B-cells. Only cells that can bind to the pathogen, can be activated to produce antibodies. B-cell surface receptors, BCRs, are actually membrane-bound antibodies. The existence of BCR variations means that the body already has all the antibodies it can possible make right from the start. For resource management purposes, it makes sense not to produce all of them in large quantities. Instead, presence of an invading pathogen selectively activates the binding B-cell, which then multiplies and produces huge amounts of that particular antibody to combat the pathogen.
An antibody is basically a protein whose structure consists of variable and constant regions. The variable regions give the antibody its uniqueness, much like the bit, or blade, of a key. This is where it binds to a specific antigen, which is the lock.
There are several classes of antibodies, differing in their constant regions. Different antibody classes engage different mechanisms to neutralize the antigen. The surface receptors on B-cells are IgM and IgD molecules.
Each B-cell has thousands of identical copies of BCR on its surface. When a pathogen binds, it usually binds to several of these receptors, linking them together, triggering endocytosis of the pathogen. B-cells then cut the pathogen into pieces and display them on MHC-II molecules on their surface. Thus, B-cells now become antigen-presenting cells, but are not yet activated. In most cases, activation of antigen-primed B-cells does not happen until they are stimulated by antigen-specific T-helper cells.
Nearby, in the T-cell zone, T-helper cells are activated by dendritic cells carrying antigens of the same pathogen, and become effector T-helper cells. Some of these effector cells leave lymph nodes for the site of infection, while other, namely the follicular helper cells, migrate to T-cell B-cell borders, and bind to the antigens presented by B-cells. This interaction triggers T-cells to produce helper factors, which activate B-cells.
Activated B-cells undergo first rounds of proliferation and differentiation, giving rise to the first batch of plasma cells producing antibodies, mainly of IgM class; and a group of cells that are committed to become memory B-cells. The latter undergo antibody class switching; and form a so-called germinal center, where they go through cycles of multiplication and hypermutation in the immunoglobulin gene. This process produces slightly different variations of the same antibody, which are then subject to a binding test to the same antigen. Those that no longer bind are discarded, while the remaining compete for binding to antigen-specific T-helper cells. B-cells with the highest affinity to the antigen win the interaction with T-helpers and exit the germinal center. They can either become long-lived memory B-cells, or differentiate into antibody-producing plasma cells. This second batch of plasma cells produces better antibodies and lives longer than the first batch. They also make antibodies of different classes (predominantly IgG), which neutralize the pathogen in many different ways.
Upon reexposure to the same pathogen, memory B-cells mount a much faster immune response. Plasma cells form within hours, producing huge amounts of the best possible antibody within days, destroying the pathogen so quickly that no signs of illness are noticeable.

The adaptive immune response, also known as acquired or specific immunity, is the body’s defense system tailored to target a specific pathogen. It has two branches: cellular or cell-mediated immunity, and humoral, or antibody-mediated immunity.
The major players of cellular immunity are T-lymphocytes. They develop in the thymus, for which they are named. During the process of maturation, billions of variations of T-cells are formed, each carrying a unique surface protein, called T-cell receptor, TCR. In addition, a population of T-cells, called helper T-cells, also has a receptor named CD4; while a second population, of cytotoxic T-cells, carries CD8 receptor. In the process of development, T-cells also learn to not react to the body’s own antigens; those that react to self-molecules are eliminated. Mature T-cells then migrate to lymph nodes and other lymphoid tissues, where they await exposure to pathogens.
Basically, specific immunity relies on the invading pathogen finding a match among these billions of T-cell variations. Only the ones that can bind to the pathogen, are selectively activated. T-cells, however, cannot bind free-floating pathogens. They can only bind to pieces of the pathogen bound to a certain host molecule called major histocompatibility complex, or MHC, on the surface of so-called “antigen-presenting cells”. There are two classes of MHC:
– MHC class I molecules are expressed by all nucleated cells of the body. These molecules are constantly produced in the cytoplasm and, on their way to the cell membrane, pick up pieces of peptides and display them on the cell surface. If a cell is infected by a virus or is cancerous, a foreign or an abnormal antigen is displayed; and the cell can bind and activate a matching T-cell. MHC-I only binds CD8 receptor, thus activating only cytotoxic T-cells.
– MHC class II molecules occur exclusively on professional antigen-presenting cells, of which dendritic cells are most effective. Resident dendritic cells on the site of infection swallow up pathogens, cut them into pieces, and display them on MHC-II molecules on their surface. These dendritic cells then migrate to the nearest lymph node, where they present the antigens to a matching T-helper cell, whose CD4 receptor binds to MHC-II.
Activation of T-cells, however, requires a second binding between the two cells. This is the verification step, a safeguard mechanism serves to prevent the immune system from overreacting.
Once activated, T-cells undergo repeated cycles of mitosis in a process called clonal expansion. This process produces clones of identical cytotoxic and helper T-cells, both of which are specific to the pathogen. Some of these cells differentiate into effector cells, while other become memory cells.
Most effector T-cells leave the lymph node for the bloodstream and are delivered to the site of infection, where they carry out immune attack against the pathogen. Helper T-cells produce interleukins which help with the activation of cytotoxic T-cells, B cells, and other immune cells. With such diverse functions, helper T-cells are central to adaptive immunity. Cytotoxic T-cells, on the other hand, are the main actors of cellular immunity. They release toxins and directly kill infected or cancerous host cells.
While effector cells die during or shortly after the infection, memory cells live for much longer periods of time. Some of them remain in lymph nodes, while other circulate the blood or migrate to peripheral tissues. Memory T-cells are also more numerous than the original naïve T-cells. Upon reexposure to the same pathogen, they can mount a much faster immune response, destroying the pathogen so quickly that no signs of illness are noticeable.
It is important to note the role of a third T-cell population, known as regulatory, or suppressor T-cells, in dampening the immune response when it’s no longer needed. Once the pathogen is cleared, regulatory T-cells downregulate the proliferation of effector T-cells, keeping the immune reaction from running out of control. They also help differentiate between self and non-self antigens, and thus preventing autoimmune diseases.

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Fever, clinically known as pyrexia, is an abnormal increase in body temperature, usually due to an illness. Commonly thought as an undesirable side effect of diseases, fever is actually an effective way the body uses to fight infections. Patients usually recover faster when they allow fever to run its course rather than suppressing it with fever-reducing medications. This is because a higher temperature slows down the growth of most pathogens, as well as boosts the effectiveness of the body’s immune response. It also increases metabolic rates and thereby accelerating tissue repair.
Normally, the hypothalamus keeps the body’s temperature within a narrow range around 37 degrees Celsius, or 98.6 degrees Fahrenheit. The hypothalamus acts like a thermostat. It receives inputs from heat and cold receptors throughout the body, and activates heating or cooling, accordingly. When the body is too hot, the hypothalamus sends instructions for it to cool down, for example, by producing sweat. On the other hand, when temperature drops, the hypothalamus directs the body to preserve and produce heat, mainly via the release of norepinephrine. Norepinephrine increases heat production in brown adipose tissue and induces vasoconstriction to reduce heat loss. In addition, acetylcholine stimulates the muscles to shiver, converting stored chemical energy into heat.
Fever is part of the inflammatory response. When immune cells detect the presence of a pathogen, for example, upon binding to a component of bacterial cell walls, they produce inflammatory cytokines. Some of these cytokines are fever-inducers, or pyrogenic. Pyrogenic cytokines act within the hypothalamus to induce the synthesis of prostaglandin E2, PGE2, the major fever inducer. PGE2 acts on thermoregulatory neurons of the hypothalamus to raise the body’s temperature set point. In other words, PGE2 tricks the hypothalamus into thinking that the body is cold, while in fact the temperature did not change. In response, the hypothalamus instructs the body to actively produce heat to raise body temperature above normal. Fever-reducing medications, such as aspirin and ibuprofen, work by suppressing PGE2 synthesis.
Once infection is cleared, pyrogens are no longer produced and the hypothalamic thermostat is set back to normal temperature. Cooling mechanisms, such as sweating and vasodilation, are activated to cool the body down.
While fever is usually beneficial and need not be treated, precaution should be taken to prevent body temperature from running too high, which may cause confusion, seizures and irreversible damage to the brain.
Finally, it is important to differentiate between fever and hyperthermia, the latter is often caused by extended exposures to extreme heat, or heat stroke. Unlike fever, the body’s temperature set point in hyperthermia is unchanged and the body does not produce the extra heat; its cooling system is simply exhausted and fails to compensate for the excessive external heating. Hyperthermia is always harmful and must be treated with various cooling methods. Fever-reducing medications have no effect on hyperthermia as pyrogens are not involved.

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Inflammation is the body’s protective response against infections or injuries. Inflammation mobilizes defensive cells to the site of injury, limits the spread of pathogens, eliminates them, and initiates tissue repair. Inflammation can occur in any organ, but is most common, and also most easily observable in the skin and underlying tissues. Typical signs include redness, heat, swelling and pain.
Inflammation is an important defense mechanism, but it can be a double-edged sword when things go wrong. An autoimmune disease may result when inflammation targets and destroys the body’s own cells. An acute inflammation that fails to stop after the original insult is cleared, can become chronic and damaging to healthy tissues.
Acute inflammation is initiated when tissue-resident immune cells, such as macrophages, encounter an inflammatory stimulus. This stimulus can be a pathogen, a toxin, or an injured host cell. Binding of the stimulus to its receptor on the immune cell triggers a signaling cascade that activates production of cytokines and other inflammatory mediators.
Inflammatory chemicals dilate blood vessels, increasing blood flow and enhancing vessel permeability, allowing plasma fluid and more immune cells to seep through and accumulate in the inflamed tissue. This vasodilation is responsible for clinical signs of inflammation such as redness, heat and swelling.
The infiltration of blood components into the injured tissue occurs in 3 phases. The first phase is the exudation of plasma fluid containing various antimicrobial mediators, platelets and blood clotting factors. These factors can destroy microbes and stop any bleeding that may have occurred.
The second phase is the infiltration of neutrophils – the major phagocytes involved in first-line defense. Once activated by inflammatory mediators, endothelial cells of blood vessels become adhesive, they attach to neutrophils in blood flow, slowing them down, before getting them to squeeze through the vessel wall. Chemical cues guide neutrophils to the battle field, where they engulf bacteria and destroy them with enzymes or toxic peroxides. Neutrophils may also release highly reactive oxygen species in a phenomenon known as oxidative burst, which kills pathogens faster and more efficiently. The pathogen-laden neutrophils then die via apoptosis.
In the third phase arrive monocytes. Monocytes differentiate into macrophages, which then remove pathogens, injured cells and dying neutrophils by phagocytosis. Macrophages that have completed their mission are cleared from the tissue by the lymphatic system. Accumulation of fluid increases pressure on lymphatic capillaries, forcing open their one-way valves, facilitating lymphatic drainage. Lymph containing debris-laden macrophages passes through a number of lymph nodes and is filtered clean before it returns to the bloodstream.
Once the site is cleared from the original insult, immune cells stop producing pro-inflammatory chemicals and, instead, start producing anti-inflammatory mediators, which actively drive the termination of inflammation. Many of these anti-inflammatory molecules are lipids, some of which are synthesized from dietary omega-3 fatty acids. This step is essential in ensuring the favorable outcome of inflammation. Failure to resolve inflammation leads to development of chronic inflammation which continuously deals damage to healthy tissues. Chronic inflammation is a known contributing factor to pathogenesis of a wide variety of conditions including cardiovascular diseases, asthma, diabetes, arthritis, and even cancer.