15.4.1: 15.4T Allergies - Biology

15.4.1: 15.4T Allergies - Biology

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Immunologists, as well as the general public, use the term allergy in several different ways. Examples:

  • The windblown pollen released by orchard grass has no effect on me but produces a violent attack of hay fever (known to physicians as allergic rhinitis) in my wife.
  • She, on the other hand, can safely handle the leaves of poison ivy while if I do so, I break out in a massive skin rash a day or two later.

Antigens that trigger allergies are often called allergens.

Four different immune mechanisms can result in allergic responses.

  • Immediate Hypersensitivities: These occur quickly after exposure to the allergen. They are usually mediated by antibodies of the IgE class. Examples include hay fever, hives and asthma.
  • Antibody-Mediated Cytotoxicity: Cell damage caused by antibodies directed against cell surface antigens. Hence a form of autoimmunity. Examples include Hemolytic disease of the newborn (Rh disease) and Myasthenia gravis (MG)
  • Immune Complex Disorders: Damage caused by the deposit in the tissues of complexes of antigen and their antibodies. Examples include Serum sickness and Systemic lupus erythematosus (SLE)
  • Cell-Mediated Hypersensitivities: These reactions are mediated by CD4+ T cells. Examples:

The rash produced following exposure to poison ivy. Because it takes a day or two for the T cells to mobilize following exposure to the antigen, these responses are called delayed-type hypersensitivities (DTH). Those, like poison ivy, that are caused by skin contact with the antigen are also known as contact sensitivities or contact dermatitis.

  • certain autoimmune diseases, including
    • Type 1 diabetes mellitus
    • Multiple sclerosis (MS)
    • Rheumatoid arthritis (RA)

Immediate Hypersensitivities

Local Anaphylaxis

The constant region of IgE antibodies (shown in blue) has a binding site for a receptor present on the surface of basophils and their tissue-equivalent the mast cell. These cell-bound antibodies have no effect until and unless they encounter allergens (shown in red) with epitopes that can bind to their antigen-binding sites. When this occurs, the mast cells to which they are attached

  • explosively discharge their granules by exocytosis. The granules contain a variety of active agents including histamine;
  • synthesize and secrete other mediators including leukotrienes and prostaglandins.

Release of these substances into the surrounding tissue causes local anaphylaxis: swelling, redness, and itching. In effect, each IgE-sensitized mast cell is a tiny bomb that can be exploded by a particular antigen. The most common types of local anaphylaxis are:

  • allergic rhinitis (hay fever) in which airborne allergens react with IgE-sensitized mast cells in the nasal mucosa and the tissues around the eyes;
  • bronchial asthma in which the allergen reaches the lungs either by inhalation or in the blood
  • hives (physicians call it urticaria) where the allergen usually enters the body in food.

Leukotrienes are far more potent than histamine in mediating these reactions.

Leukotrienes and prostaglandins are derivatives of arachidonic acid (AA) an unsaturated fatty acid produced from membrane phospholipids. The principal pathways of arachidonic acid metabolism are

  • the 5-lipoxygenase pathway, which produces a collection of leukotrienes (LT) and
  • the cyclooxygenase pathway, which yields a number of prostaglandins (PG) and thromboxanes (Tx).

All three are synthesized by monocytes and macrophages. Mast cells and basophils generate a mixture of leukotrienes. The products of both pathways act in concert to cause inflammation with prostaglandins producing fever and pain. Aspirin, ibuprofen, and certain other nonsteroidal anti-inflammatory drugs (NSAIDs) achieve their effects (fever and pain reduction) by blocking the activity of cyclooxygenase.

Some people respond to environmental antigens (e.g., pollen grains, mold spores) with an unusually vigorous production of IgE antibodies. Why this is so is unclear; heredity certainly plays a role. In any case, the immune system of these people is tilted toward the production of T helper cells of the Th2 subtype. These release interleukin 4 (IL-4) and interleukin 13 (IL-13) on the B cells that they "help". These lymphokines promote class switching in the B cell causing it to synthesize IgE antibodies.

An inherited predisposition to making IgE antibodies is called atopy. Atopic people are apt to have higher levels of circulating IgE (up to 12 µg/ml) than is found usually (about 0.3 µg/ml). Whereas only 20–50% of the receptors on mast cells are normally occupied by IgE, all the receptors may be occupied in atopic individuals.

Skin Testing

When the problem allergen is not obvious, it can often be identified by skin testing. A panel of suspected allergens is injected into separate sites in the skin and each site is observed for the development of a "wheal and flare" reaction. The wheal is a sharply delineated soft swelling surrounded by the flare - a reddened area. Both are caused by the release of leukotrienes at the site, which increase the flow of blood to the site making it swollen and red.

A positive skin test occurs within minutes or even seconds (in contrast to patch testing for DTH responses).

Systemic Anaphylaxis

Some allergens can precipitate such a massive IgE-mediated response that a life-threatening collapse of the circulatory and respiratory systems may occur.

Frequent causes:

  • insect (e.g., bee) stings
  • many drugs (e.g., penicillin)
  • a wide variety of foods. Egg white, cow's milk, and nuts are common offenders in children; in fact, some school systems in the US now ban peanuts and peanut-butter sandwiches when they have a student at risk of systemic anaphylaxis from exposure to peanuts. Fish and shellfish are frequent causes of anaphylaxis in adults.

Treatment of systemic anaphylaxis centers on the quick administration of adrenaline, antihistamines, and if shock has occurred then intravenous fluid replacement.

An example of systemic anaphylaxis

The three graphs show the physiological responses of a physician (Dr. Vick) stung by a single bee while on a picnic with coworkers (fortunately some with medical training!). Dr. Vick required cardiac massage and intravenous injections of adrenaline at the times shown. He and his colleagues worked in a laboratory studying bee venom, but prior to this episode he had no idea that he had developed such extreme susceptibility. [Courtesy of Dr. J. Vick from L. M. Lichtenstein, "Allergic Responses to Airborne Allergens and Insect Venoms", Fed. Proc. 36:1727, 1977.]


So far, the most effective preventive for IgE-mediated allergies is to inject the patient with gradually-increasing doses of the allergen itself. The goal is to shift the response of the immune system away from Th2 cells in favor of Th1 cells. Unfortunately, this therapy takes a long time and the results are too often disappointing. Clinical trials are now underway to test the safety and efficacy of a complex of ragweed pollen allergen with chemically-modified DNA. This complex binds to the immune receptor TLR-9 causing a shift of the immune response from Th2 to Th1 much more rapidly than desensitization by the allergen alone.

Anti-IgE Antibodies

IgE molecules bind to mast cells and basophils through their constant region. If you could block this region, you could interfere with binding — hence sensitization of — these cells. Humanized monoclonal antibodies specific for the constant region of IgE are in clinical trials. They have shown some promise against asthma and peanut allergy, but such treatment will probably have to be continued indefinitely (and will be very expensive).

IgE-Independent Allergic Reactions

Mast cells have surface receptors in addition to IgE molecules. Binding of ligands to these other receptors can also trigger degranulation and immediate anaphylactic responses. Some culprits are:

  • pathogen-associated molecular patterns (PAMPs)
  • substance P
  • some components of wasp venoms
  • some antibiotics

Antibody-Mediated Cytotoxicity

In these disorders, the person produces antibodies directed against antigens present on the surface of his or her own cells. Thus these qualify as autoimmune disorders. Some examples:

  • hemolytic disease of the newborn (Rh disease)
  • immune hemolytic anemia
  • immune thrombocytopenic purpura
  • myasthenia gravis (MG)
  • thyrotoxicosis (Graves' disease)
  • pemphigus and pemphigoid, in which the antibodies are directed against the proteins in desmosomes (pemphigus) or hemidesmosomes (pemphigoid).
  • Goodpasture's Syndrome

Binding of antibodies to the surface of the cell can result in:

  • phagocytosis of the cell
  • lysis of the cell
  • damage to molecules on the cell surface (e.g., myasthenia gravis)
  • activation of cell-surface receptors (e.g., thyrotoxicosis)

Hemolytic Disease of the Newborn (Rh Disease)

Rh antigens are expressed at the surface of red blood cells. During pregnancy, there is often a tiny leakage of the baby's red blood cells into the mother's circulation. If the baby is Rh-positive (having inherited the trait from its father) and the mother Rh-negative, these red cells will cause her to develop antibodies against the Rh antigen. The antibodies, usually of the IgG class, may not develop fast enough to cause problems for that child, but can cross the placenta and attack the red cells of a subsequent Rh+ fetus. This destroys the red cells producing anemia and jaundice. The disease may be so severe as to kill the fetus or even the newborn infant.

Although certain other red cell antigens (in addition to Rh) sometimes cause problems for a fetus, an ABO incompatibility does not. Why is an Rh incompatibility so dangerous when ABO incompatibility is not? It turns out that most anti-A or anti-B antibodies are of the IgM class and these do not cross the placenta. In fact, an Rh-/type O mother carrying an Rh+/type A, B, or AB fetus is resistant to sensitization to the Rh antigen. Presumably her anti-A and anti-B antibodies destroy any fetal cells that enter her blood before they can elicit anti-Rh antibodies in her.

This phenomenon has led to an extremely effective preventive measure to avoid Rh sensitization. Shortly after each birth of an Rh+ baby, the mother is given an injection of anti-Rh antibodies. The preparation is called Rh immune globulin (RhIG) or Rhogam. These passively acquired antibodies destroy any fetal cells that got into her circulation before they can elicit an active immune response in her.

Rh immune globulin came into common use in the United States in 1968, and within a decade the incidence of Rh hemolytic disease became very low.

Immune Hemolytic Anemia

Some people synthesize antibodies against their own red blood cells, and these may lyze the cells producing anemia. Infections, cancer, or an autoimmune disease like systemic lupus erythematosus (SLE) are often involved. Many drugs (e.g. penicillin, quinidine) can also trigger the disorder. In these cases, stopping the drug usually brings about a quick cure.

Immune Thrombocytopenic Purpura

This is an autoimmune disorder in which the patient develops antibodies against his or her own platelets (thrombocytes). The life span of the platelets may be reduced from the normal of 8 days to as little as 1 hour, and platelet counts may drop from a normal of 140,000–440,000/µl to 20,000/µl or less. This greatly interferes with normal clotting, causing

  • external bleeding (e.g., from the nose)
  • internal bleeding into the skin causing purple patches (called purpura)

The fact that antibodies are the culprit was dramatically demonstrated by using a patient's serum to passively — but only temporarily —transfer the disorder to a normal recipient. The graph shows the decline and recovery in the platelet count of a normal human subject receiving two transfusions of serum from a patient with thrombocytopenic purpura. [From W. Harrington et al., J. Lab. Clin. Med. 38:1, 1951.]

Often no cause of the disorder can be found (the physicians call it "idiopathic"). Some cases are triggered by drugs like quinine, aspirin, digitoxin, and sulfa drugs. These cases can be cured by stopping the drug. The idiopathic cases can sometimes be helped by giving corticosteroids and/or removing the patient's spleen. Rituximab, a monoclonal antibody directed against B cells is also used. If these treatments are inadequate, attempts can be made to increase the platelet count by giving synthetic agonists (e.g., Romiplastin [Nplate®]) that stimulate the production of thrombopoietin.

Myasthenia Gravis (MG)

The hallmark of this autoimmune disorder is weakness of the skeletal muscles, especially those in the upper part of the body. It is caused by antibodies that attack the acetylcholine (ACh) receptors at the subsynaptic membrane of neuromuscular junctions. As the number of receptors declines, the ACh released with the arrival of a volley of nerve impulses is inadequate to generate end-plate potentials (EPPs) of the normal size. After repeated stimulation, the EPPs fail to reach the threshold needed to generate an action potential and the muscle stops responding.

The signs and symptoms of myasthenia gravis can be quickly but only temporarily relieved by injecting a drug that inhibits the action of cholinesterase. This prolongs the action of ACh at the neuromuscular junction. The immunosuppressant action of corticosteroids, like prednisone, can provide long-term improvement for patients. The exclusive role of antibodies (of the IgG class) in this disorder is demonstrated by the presence of the disease in the newborn babies of mothers with the disorder. As these antibodies, which the fetus had received from the mother's circulation, disappear (in 1–2 weeks), so do all signs of the disease.

Thyrotoxicosis (Graves' disease))

In this disorder, the patient has antibodies that bind to the TSH receptors on the thyroxine-secreting cells of the thyroid. These antibodies mimic the action of TSH itself (thus they behave as a TSH agonist) and trigger secretion of thyroxine (T4) and T3 by the thyroid gland. The role of antibodies (of the IgG class) in this disorder is demonstrated by the presence of the disease in the newborn babies of mothers with the disorder. As these antibodies, which the fetus had received from the mother's circulation, disappear (in 1–2 weeks), so do all signs of the disease.

Immune Complex Disorders

While binding of antibody to antigen is often a helpful — even life-saving — response, in some circumstances it causes pathological changes.

Serum Sickness

In passive immunization, an antiserum containing needed antibodies is injected into the patient. At one time, these antisera were prepared by immunizing horses or sheep. While they did their intended work (usually to provide immediate protection to a person exposed to diphtheria or tetanus), they also often later lead to a syndrome called serum sickness. The patient developed fever, hives, arthritis and protein in the urine. After a week or two, the symptoms would disappear spontaneously.

Serum sickness is caused by the many extraneous proteins present in the antiserum. Being foreign to the recipient, an active immunity develops against these proteins. The resulting antibodies bind to them forming immune complexes. These are carried by the blood and deposited in the walls of blood vessels as well as in the glomeruli of the kidneys (see figure).

Antigen-antibody complexes

  • bind to Hageman factor — one (XII) of the blood clotting factors. This activates inflammatory kinins.
  • bind to a system of serum proteins collectively known as complement. This generates
    • complement factor C3a, an anaphylatoxin which activates basophils and mast cells and causes them to release their histamine and leukotrienes producing inflammation.
    • complement factor C5a, another anaphylatoxin which also attracts neutrophils to the site.

Thanks to nearly universal active immunization against both tetanus and diphtheria, serum sickness is now quite rare. However, kidney damage (called glomerulonephritis) produced by deposits of immune complexes is found in some persistent infections.


  • the protozoans that cause malaria
  • the flatworms that cause schistosomiasis and the filarial worms that cause elephantiasis and other diseases in humans.
  • the virus that causes hepatitis B.

In these cases, the continued presence of the pathogen provides a renewable source of antigen to combine with antibodies synthesized by the host resulting in deposits of immune complexes.

Systemic Lupus Erythematosus (SLE)

Humans with SLE develop (for unknown reasons) antibodies against a wide variety of self components:

  • their own double-stranded DNA
  • nucleosomes
  • red blood cells
  • platelets
  • NMDA receptors in the brain
  • even their own IgG molecules. (These "anti-antibodies" are called rheumatoid factors. They are also found in people with rheumatoid arthritis (hence the name) and, for a time, in people with mononucleosis.)

In all these cases of autoimmunity, immune complexes form and are deposited in the skin, joints, and kidneys where they initiate inflammation.

Farmer's Lung

Repeated exposure to airborne organic particles, like mold spores, can elicit formation of antibodies. When these interact with inhaled antigen, inflammation of the alveoli occurs. The sufferer develops a cough, fever, and difficulty in breathing. Once removed from the source of antigen, the attack subsides within a few days.

Farmers exposed to moldy hay often develop this problem (technically known as extrinsic allergic alveolitis). Sugarcane workers, cheese makers, mushroom growers, pigeon fanciers, and a number of other occupational or hobby groups are apt to develop allergic alveolitis from exposure to the spores and dusts associated with their activities.

Cell-Mediated Hypersensitivities

Cell-mediated hypersensitivities can occur with extrinsic antigens or with internal ("self") antigens.

Extrinsic Antigens

The most common example of cell-mediated hypersensitivity to external antigens is the contact dermatitis caused in some people when their skin is exposed to a chemical to which they are allergic. Some examples:

  • the catechols found in poison ivy, poison oak, and poison sumac
  • nickel (often used in jewelry)
  • some dyes
  • certain organic chemicals used in industry

In every case, these simple chemicals probably form covalent bonds with proteins in the skin, forming the antigen that initiates the immune response. Dendritic cells in the skin take up the complex, process it, and "present" it to CD4+ T cells in nearby lymph nodes. Because it takes a day or two for the CD4+ T cells to mobilize to the affected area of skin, these cases are examples of delayed-type hypersensitivity (DTH).

When a patient is unsure of what chemical is causing the dermatitis, the physician can try a patch test. Pieces of gauze impregnated with suspected allergens are placed on the skin. After 48 hours, they are removed and each site is examined for a positive response (a reddened, itching, swollen area).

Intrinsic ("self") Antigens

Cell-mediated hypersensitivities to "self" cause autoimmune diseases. Examples:

  • Type 1 diabetes mellitus
  • Multiple sclerosis (MS)
  • Rheumatoid arthritis (RA)

Type 1 diabetes mellitus

In this disease, T cells initiate the destruction of the insulin-producing beta cells of the islets of Langerhans in the pancreas. The chief culprits are CD8+ cytotoxic T lymphocytes (CTL) aided and abetted by CD4+ helper T cells of the Th1 subset. Although antibodies against beta cell antigens are also found, these appear to be a secondary effect. Evidence: a diabetic boy with X-linked agammaglobulinemia so unable to make any antibodies at all.

Multiple Sclerosis (MS)

In this case, T cells — again mostly Th1 cells — initiate an attack that destroys the myelin sheath of neurons. As the disease progresses, other cells (e.g. macrophages) as well as antibodies participate in causing the damage.

Rheumatoid Arthritis (RA)

In this disorder, antibodies and T cells — again probably Th1 cells — react to antigens in the joints and release tumor necrosis factor-alpha (TNF-α) with resulting inflammation and damage to the joints.

A genetically engineered fusion protein consisting of the TNF receptor fused to the constant region of human IgG1 has shown promise as a treatment for RA. Given by injection, the fusion protein binds TNF-α and interferes with its action.

Autoimmune disorders are more common in females than in males

Graves' disease, systemic lupus erythematosus (SLE), multiple sclerosis, and rheumatoid arthritis are all more common in women than in men. The sex bias ranges from 9:1 for SLE to >2:1 for multiple sclerosis and rheumatoid arthritis. Why?

The answer is unclear, but hormones are probably involved.

A few clues:

  • In mice susceptible to Type 1 diabetes, testosterone seems to play a key role.
    • Castration causes male mice to become as susceptible as females.
    • Giving androgens like testosterone to females protects them.
  • High levels of estrogen and progesterone suppress Th1 responses (cell-mediated immunity).
  • Pregnant women — with extra-high levels of these hormones — produce large numbers of immunosuppressive regulatory T cells. Together these two responses may account for the improvement that often occurs in multiple sclerosis and rheumatoid arthritis during pregnancy (an improvement that ends after birth).
  • High levels of these hormones promote Th2 responses (antibody-mediated immunity). SLE results from antigen-antibody complexes and so it is not surprising that pregnancy does not help — and in some women actually exacerbates — this autoimmune disorder.

The Hygiene Hypothesis

Allergies, like asthma and hay fever, and some autoimmune diseases are more common in regions with good sanitation.

For example,

  • Crohn's disease, an inflammation of the small intestine and
  • ulcerative colitis, an inflammation of the large intestine

are rare in developing countries with poor sanitation but have become more common in developed regions with good sanitation.


No one knows for certain, but one intriguing possibility, called the hygiene hypothesis, is that infection by parasitic worms (helminths) shifts the balance of the immune response:

  • promoting regulatory T cells (Treg) with their anti-inflammatory cytokines IL-10 and TGF-β and
  • inhibiting pro-inflammatory effector T cells, e.g., Th17 cells.

Small clinical trials of feeding whipworm (a nematode) eggs to patients with Crohn's disease or ulcerative colitis have begun. After the eggs develop into mature worms in their intestine, most patients showed marked improvement of their symptoms.

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15.4.1: 15.4T Allergies - Biology

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The eosinophil count measures the amount of eosinophils in your blood.

The key is for eosinophils to do their job and then go away. But if you have too many eosinophils in your body for a long time, doctors call this eosinophilia. It can cause chronic inflammation, which could damage tissues.

Conditions where too many eosinophils are in the body include eosinophilic esophagitis (a disorder in your esophagus) and eosinophilic colitis (in your large intestine). Eosinophilic disorders also can happen in your stomach, small intestine, blood, or other organs. Sometimes, a biopsy will show that you have a high amount of eosinophils in your tissues, but you might not have a high amount in your blood.


About the Author

STEPHEN PRYKE, FRICS, MSc, PhD, PGCertEd, DipS, MCMI, is Professor of Supply Chain and Project Networks, and Course Director of the MSc Project and Enterprise Management at the Bartlett School of Graduate Studies, University College London. He is also Director of Postgraduate Teaching and Learning at the Bartlett School of Graduate Studies, UCL and Director of the Centre for Organisational Network Analysis (CONA@UCL). Stephen worked closely with the leading exponents of supply chain management worldwide before joining UCL full time. He previously provided project management training and consultancy to a number of major European companies and has been a consultant with Durland Consulting in Chicago. His main research interests involve supply chain management and the application of social network analysis in the study of construction project networks.


The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper-reactivity. In AD, IL-31 has been identified as one of the main “drivers” of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2-associated cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL-31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL-31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future.



The United States Centers for Disease Control and Prevention (CDC) recommends these criteria for diagnosis: [13]

  1. Greatly lowered ability to do activities that were usual before the illness. This drop in activity level occurs along with fatigue and must last six months or longer.
  2. Worsening of symptoms after physical or mental activity that would not have caused a problem before the illness. The amount of activity that might aggravate the illness is difficult for a person to predict, and the decline often presents 12 to 48 hours after the activity. [25] The 'relapse', or 'crash', may last days, weeks or longer. This is known as post-exertional malaise (PEM).
  3. Sleep problems people may still feel weary after full nights of sleep, or may struggle to stay awake, fall asleep or stay asleep.

Additionally, one of the following symptoms must be present: [13]

  • Problems with thinking and memory (cognitive dysfunction, sometimes described as "brain fog")
  • While standing or sitting upright lightheadedness, dizziness, weakness, fainting or vision changes may occur (orthostatic intolerance)

Other common symptoms Edit

Many, but not all people with ME/CFS report: [13]

  • Muscle pain, joint pain without swelling or redness, and headache
  • Tender lymph nodes in the neck or armpits
  • Sore throat
  • Irritable bowel syndrome
  • Chills and night sweats
  • Allergies and sensitivities to foods, odors, chemicals, lights, or noise
  • Shortness of breath
  • Irregular heartbeat

The CDC proposes that persons with symptoms resembling those of CFS consult a physician to rule out several treatable illnesses: Lyme disease, [26] [ failed verification ] "sleep disorders, major depressive disorder, alcohol/substance abuse, diabetes mellitus, hypothyroidism, mononucleosis (mono), lupus, multiple sclerosis (MS), chronic hepatitis and various malignancies." [27] [ failed verification ] Medications can also cause side effects that mimic symptoms of CFS. [26] [ failed verification ] Central sensitization, or increased sensitivity to sensory stimuli such as pain have been observed in CFS. Sensitivity to pain increases after exertion, which is opposite to the normal pattern. [28]

Onset Edit

Gradual or sudden onset of the illness may occur, and studies have mixed results as to which occurs more frequently. [2] : 158 : 181

Physical functioning Edit

The functional capacity of individuals with CFS varies greatly. [29] Some persons with CFS lead relatively normal lives others are totally bed-ridden and unable to care for themselves. [30] For the majority of persons with CFS, work, school, and family activities are significantly reduced for extended periods of time. [31] The severity of symptoms and disability is the same regardless of gender, [32] and many experience strongly disabling chronic pain. [33] Persons report critical reductions in levels of physical activity. [34] Also, a reduction in the complexity of activity has been observed. [35] Reported impairment is comparable to other fatiguing medical conditions [36] including late-stage AIDS, [37] lupus, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and end-stage kidney disease. [38] [ failed verification ] CFS affects a person's functional status and well-being more than major medical conditions such as multiple sclerosis, congestive heart failure, or type II diabetes mellitus. [39] [40]

Often, courses of remission and relapse of symptoms occur, which make the illness difficult to manage. Persons who feel better for a period may overextend their activities, and the result can be a worsening of their symptoms with a relapse of the illness. [25]

About 25% of people with CFS are house-bound or bed-ridden for long periods during their illness, often for decades. [2] : 32 [4] An estimated 75% are unable to work because of their illness. [41] More than half were on disability benefits or temporary sick leave, and less than a fifth worked full-time. [30] Children who become ill with CFS are a major cause of school absence. [2] : 183

People with CFS have decreased scores on the SF-36 quality-of-life questionnaire, especially in the sub scales on vitality, physical functioning, general health, physical role, and social functioning however, the sub scales for "role emotional" and mental health in CFS patients were consistent with or not substantially lower than healthy controls. [42] Direct healthcare costs are estimated at between $9 and $14 billion annually in the U.S. alone. [41]

Cognitive functioning Edit

Cognitive dysfunction is one of the more disabling aspects of CFS due to its negative impact on occupational and social functioning. 50 to 80 % of persons with CFS are estimated to have serious problems with cognition. [43] Cognitive symptoms are mainly due to deficits in attention, memory, and reaction time. Measured cognitive abilities are found to be below projected normal values and likely to affect day-to-day activities for example, increases in common mistakes, forgetting scheduled tasks, or having difficulty responding when spoken to are observed. [44]

Simple and complex information-processing speed, and functions entailing working memory over long time periods are moderately to extensively impaired. These deficits are generally consistent with the patient's perceptions. Perceptual abilities, motor speed, language, reasoning, and intelligence do not appear to be significantly altered. When poorer health status was reported, a person's perception of their cognitive problems was frequently greater. Better physical functioning in people with CFS is associated with less visuoperceptual difficulty and fewer language-processing complaints. [44]

Inconsistencies of subjective and observed values of cognitive dysfunction reported across multiple studies are likely caused by a number of factors. Differences of research participants' cognitive abilities pre and post illness onset are naturally variable, and are difficult to measure because of a lack of specialized analytical tools that can consistently quantify the specific cognitive difficulties in CFS. [44]

The frequency of neuropsychiatric and neuropsychological symptoms is increased in the population of persons with CFS the understanding of why this occurs is unresolved. Various hypotheses have been advanced to try to explain the relationship between the cognitive symptoms and the illness. Some researchers believe psychiatric causes underlie or contribute to the illness, while other researchers believe the illness causes biochemical and sociological changes in people that produce the symptoms. [43]

The cause of CFS is unknown. [42] Genetic, physiological, and psychological factors are thought to work together to precipitate and perpetuate the condition. [15] A 2016 report by the Institute of Medicine states that CFS is a biologically based illness, but that the biologic abnormalities are not sensitive or specific enough to be useful as a diagnosis. [42]

Because it may begin as an influenza-like illness with a sudden onset, various infectious causes have been proposed, but evidence is insufficient to support such causation. [45] [2] Infections proposed include mononucleosis, Chlamydophila pneumoniae, human herpesvirus 6, and Lyme disease. Inflammation may be involved. [46] Often, the illness will follow a viral illness, such as mononucleosis or gastroenteritis. [47]

Risk factors Edit

All ages, ethnic groups, and income levels are susceptible to the illness. The CDC states that Caucasians may be diagnosed more frequently than other races in America, [4] but the illness is at least as prevalent among African Americans and Hispanics. [3] A 2009 meta-analysis showed that compared with Caucasians, African Americans, and Native Americans have a higher risk of CFS, though it specifically excluded other more common ethnicities worldwide, and it acknowledged that studies and data were limited. [48]

More women than men get CFS. [4] A large 2020 meta-analysis estimated that between 1.5 and 2.0 times more cases are women. The review acknowledged that different case definitions and diagnostic methods within datasets yielded a wide range of prevalence rates. [10] The CDC estimates CFS occurs up to four times more often in women than in men. [3] The illness can occur at any age, but most frequently in persons between the ages of 40 and 60. [3] CFS is less prevalent among children and adolescents than among adults. [22]

Blood relatives of those who have CFS appear to be more predisposed, implying that genetic factors may increase the risk of susceptibility to the illness. [12]

Psychological stress, childhood trauma, perfectionist personalities, old age, lower middle education, low physical fitness, preexisting psychological illness, and allergies may be risk factors for developing chronic fatigue syndrome. This has led some to believe that stress-related visceral responses underlie CFS. [49] [50] Pre-existing depressive and anxiety disorders, as well as high expectation of parents and family history were predisposing factors identified in another review. [51]

People with CFS and their relatives tend to attribute their illness to physical causes (such as a virus or pollution) rather than to psychological causes, [15] [52] and these attributions are associated with increased symptoms and impairment, and worse outcomes over time. [15] According to the CDC, "CFS is a biological illness, not a psychologic disorder", and those affected "are neither malingering nor seeking secondary gain". [53] The World Health Organization (WHO) classifies CFS as a neurological disease in the ICD-11 for Mortality and Morbidity Statistics (ICD-11). [54]

Viral and other infections Edit

The term post-viral fatigue syndrome (PVFS) is used to describe CFS-like symptoms that occur after a viral infection. [6] A recent review found Epstein-Barr Virus (EBV) antibody activity to be higher in patients with CFS, and that a subset of patients with CFS were likely to have increased EBV activity compared to controls. [55] Viral infection is a significant risk factor for CFS, with one study finding 22% of people with Epstein-Barr virus experience fatigue six months later, and 9% having strictly defined CFS. [56] A systematic review found that fatigue severity was the main predictor of prognosis in CFS, and did not identify psychological factors linked to prognosis. [57] One review found risk factors for developing CFS after mononucleosis, dengue fever or the bacterial infection Q-fever include longer bed-rest during the illness, poorer pre-illness physical fitness, attributing symptoms to physical illness, belief that a long recovery time is needed, as well as pre-infection distress and fatigue. The same review found biological factors such as CD4 and CD8 activation and liver inflammation are predictors of sub-acute fatigue, but not CFS, [58] however these findings are not generally accepted due to the use of the Oxford criteria in selecting patients. The CDC does not recognize attribution of symptoms as a risk factor. [5]

A study comparing diagnostic labels found that people labelled with ME had the worst prognosis, while those with PVFS had the best. Whether this is due to those with more severe or longer lasting symptoms results in a label with the description of ME, or if being labelled with ME adversely causes a more severe or prolonged illness is unclear. [59]

Neurological Edit

A range of neurological structural and functional abnormalities is found in people with CFS, including lowered metabolism at the brain stem, and reduced blood flow to areas of the brain these differences are consistent with neurological illness, but not depression or psychological illness. [6] The World Health Organization classes chronic fatigue syndrome as a central nervous system disease. [60]

Some neuroimaging studies have observed prefrontal and brainstem hypometabolism however, sample size was limited. [61] Neuroimaging studies in persons with CFS have identified changes in brain structure, and correlations with various symptoms. Results were not consistent across the neuroimaging brain structure studies, and more research is needed to resolve the discrepancies found between the disparate studies. [62] [61]

Tentative evidence suggests a relationship between autonomic nervous system dysfunction and diseases such as CFS, fibromyalgia, irritable bowel syndrome, and interstitial cystitis. However, it is unknown if this relationship is causative. [63] Reviews of CFS literature have found autonomic abnormalities such as decreased sleep efficiency, increased sleep latency, decreased slow wave sleep, and abnormal heart rate response to tilt table tests suggesting a role of the autonomic nervous system in CFS. However, these results were limited by inconsistency. [64] [65] [66]

Immunological Edit

Immunological abnormalities are frequently observed in those with CFS. Decreased NK cell activity is found more often in people with CFS and this correlates with severity of symptoms. [5] [67] People with CFS have an abnormal response to exercise, including increased production of complement products, increased oxidative stress combined with decreased antioxidant response, and increased Interleukin 10, and TLR4, some of which correlates with symptom severity. [68] Increased levels of cytokines have been proposed to account for the decreased ATP production and increased lactate during exercise [69] [70] however, the elevations of cytokine levels are inconsistent in specific cytokine, albeit frequently found. [2] [71] Similarities have been drawn between cancer and CFS with regard to abnormal intracellular immunological signaling. Abnormalities observed include hyperactivity of Ribonuclease L, a protein activated by IFN, and hyperactivity of NF-κB. [72]

Endocrine Edit

Evidence points to abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) in some, but not all, persons with CFS, which may include slightly low cortisol levels, [73] a decrease in the variation of cortisol levels throughout the day, decreased responsiveness of the HPA axis, and a high serotonergic state, which can be considered to be a "HPA axis phenotype" that is also present in some other conditions, including post-traumatic stress disorder and some autoimmune conditions. [74] It is unclear whether or not decreased cortisol levels of the HPA axis plays a primary role as a cause of CFS, [75] [76] [77] or has a secondary role in the continuation or worsening of symptoms later in the illness. [78] In most healthy adults, the cortisol awakening response shows an increase in cortisol levels averaging 50% in the first half-hour after waking. In people with CFS, this increase apparently is significantly less, but methods of measuring cortisol levels vary, so this is not certain. [79]

Autoimmunity Edit

Autoimmunity has been proposed to be a factor in CFS, but there are only a few relevant findings so far. A subset of patients with increased B cell activity and autoantibodies, possibly as a result of decreased NK cell regulation or viral mimicry. [80] In 2015, a large German study found 29% of ME/CFS patients had elevated autoantibodies to M3 and M4 muscarinic acetylcholine receptors as well as to ß2 adrenergic receptors. [81] [82] [83] A 2016 Australian study found that ME/CFS patients had significantly greater numbers of single nucleotide polymorphisms associated with the gene encoding for M3 muscarinic acetylcholine receptors. [84] [ non-primary source needed ]

Energy metabolism Edit

Studies have observed mitochondrial abnormalities in cellular energy production, but recent focus has concentrated on secondary effects that may result in aberrant mitochondrial function because inherent problems with the mitochondria structure or genetics have not been replicated. [85]

No characteristic laboratory abnormalities are approved to diagnose CFS while physical abnormalities can be found, no single finding is considered sufficient for diagnosis. [86] [6] Blood, urine, and other tests are used to rule out other conditions that could be responsible for the symptoms. [87] [88] [2] The CDC states that a medical history should be taken and a mental and physical examination should be done to aid diagnosis. [87]

Diagnostic tools Edit

The CDC recommends considering the questionnaires and tools described in the Institute of Medicine report, which include:

  • The Chalder Fatigue Scale
  • Multidimensional Fatigue Inventory
  • Fisk Fatigue Impact Scale
  • The Krupp Fatigue Severity Scale
  • DePaul Symptom Questionnaire
  • CDC Symptom Inventory for CFS
  • Work and Social Adjustment Scale (WSAS)
  • SF-36 / RAND-36 [2] : 270

A two-day cardiopulmonary exercise test (CPET) is not necessary for diagnosis, although lower readings on the second day may be helpful in supporting a claim for social security disability. A two-day CPET cannot be used to rule out chronic fatigue syndrome. [2] : 216

Definitions Edit

Notable definitions include: [89]

    (1994), [90] the most widely used clinical and research description of CFS, [15] is also called the Fukuda definition and is a revision of the Holmes or CDC 1988 scoring system. [91] The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight. [92][93] states: "A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations and the illness persists for at least 6 months".
  • The Myalgic Encephalomyelitis International Consensus Criteria (ICC) published in 2011 is based on the Canadian working definition and has an accompanying primer for clinicians [94][6] The ICC does not have a six months waiting time for diagnosis. The ICC requires post-exertional neuroimmune exhaustion (PENE) which has similarities with post-exertional malaise, plus at least three neurological symptoms, at least one immune or gastrointestinal or genitourinary symptom, and at least one energy metabolism or ion transportation symptom. Unrefreshing sleep or sleep dysfunction, headaches or other pain, and problems with thinking or memory, and sensory or movement symptoms are all required under the neurological symptoms criterion. [94] According to the ICC, patients with post-exertional neuroimmune exhaustion but only partially meet the criteria should be given the diagnosis of atypical myalgic encephalomyelitis. [6]
  • The 2015 definition by the National Academy of Medicine (then referred to as the "Institute of Medicine") is not a definition of exclusion (differential diagnosis is still required). [2] "Diagnosis requires that the patient have the following three symptoms: 1) A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and 2) post-exertional malaise* 3) Unrefreshing sleep* At least one of the two following manifestations is also required: 1) Cognitive impairment* 2) Orthostatic intolerance" and notes that "*Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half the time with moderate, substantial, or severe intensity." [2]

Clinical practice guidelines are generally based on case descriptions, with the aim of improving diagnosis, management and treatment. An example is the CFS/ME guideline for the National Health Services in England and Wales, produced in 2007, [92] (presently being updated). [95] Other guidance can be found at the New York Department of Health. [96]

Differential diagnosis Edit

Certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of CFS can be given. Hypothyroidism, anemia, [97] coeliac disease (that can occur without gastrointestinal symptoms), [98] diabetes and certain psychiatric disorders are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms. [92] [90] [97] Other diseases, listed by the Centers for Disease Control and Prevention, include infectious diseases (such as Epstein–Barr virus, influenza, HIV infection, tuberculosis, Lyme disease), neuroendocrine diseases (such as thyroiditis, Addison's disease, adrenal insufficiency, Cushing's disease), hematologic diseases (such as occult malignancy, lymphoma), rheumatologic diseases (such as fibromyalgia, polymyalgia rheumatica, Sjögren's syndrome, giant-cell arteritis, polymyositis, dermatomyositis), psychiatric diseases (such as bipolar disorder, schizophrenia, delusional disorders, dementia, anorexia/bulimia nervosa), neuropsychologic diseases (such as obstructive sleep apnea, parkinsonism, multiple sclerosis), and others (such as nasal obstruction from allergies, sinusitis, anatomic obstruction, autoimmune diseases, some chronic illness, alcohol or other substance abuse, pharmacologic side effects, heavy metal exposure and toxicity, marked body weight fluctuation). [97] Ehlers Danlos syndromes (EDS) may also have similar symptoms. [99]

Persons with fibromyalgia (FM, or fibromyalgia syndrome, FMS), like those with CFS, have muscle pain, severe fatigue and sleep disturbances. The presence of allodynia (abnormal pain responses to mild stimulation) and of extensive tender points in specific locations differentiates FM from CFS, although the two diseases often co-occur. [100]

Depressive symptoms, if seen in CFS, may be differentially diagnosed from primary depression by the absence of anhedonia, decreased motivation, and guilt and the presence of somatic symptoms such as sore throat, swollen lymph nodes, and exercise intolerance with post exertional exacerbation of symptoms. [97]

There is no approved pharmacological treatment, therapy or cure for CFS [7] [92] although various drugs have been or are being investigated. [101] A 2014 report prepared by the Agency for Healthcare Research and Quality stated that there are wide variations in patient management, that many receive a multifaceted approach to treatment, and that no medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ME/CFS, although several have been used off label. The report concluded that although counseling and graded exercise therapy (GET) have shown some benefits, these interventions have not been studied fully enough to recommend them for all persons affected. The report expressed concern that GET appears to be associated with worsening symptoms in some. [102] The CDC no longer recommends these interventions, and there is some evidence of patient harm. [103] [104]

The CDC guide for the management of CFS states that while there is no cure, a number of methods might improve symptoms. [7] Treatment strategies for sleep problems, pain, (depression, stress, and anxiety) dizziness and lightheadedness (orthostatic Intolerance), and memory and concentration problems are enumerated. Other useful topics mentioned that patients and doctors might discuss include carefully monitoring and managing activity to avoid worsening of symptoms, counseling to cope with the impact the illness may have on quality of life, proper nutrition and nutritional supplements that may support better health, complementary therapies that might help increase energy or decrease pain. [7]

The United Kingdom's National Institute for Health and Clinical Excellence (NICE) 2007 guideline directed toward clinicians, specifies the need for shared decision-making between the patient and healthcare professionals, and acknowledges the reality and impact of the condition and the symptoms. The NICE guideline covers illness management aspects of diet, sleep and sleep disorders, rest, relaxation, and pacing. Referral to specialist care for cognitive behavioural therapy, graded exercise therapy and activity management (pacing) programmes are recommended to be offered as a choice to patients with mild or moderate CFS. [105] In 2017 NICE announced its guidance for CFS/ME needed to be updated, [106] and publication is expected in December 2020. [107]

Comorbid conditions can occur in CFS which may interact with and exacerbate the symptoms of CFS. Appropriate medical intervention for these conditions may be beneficial. The most commonly diagnosed include: fibromyalgia, irritable bowel syndrome, depression, anxiety, as well as allergies and chemical sensitivities. [108]

Pacing Edit

Pacing, or activity management, is an illness management strategy based on the observation that symptoms tend to increase following mental or physical exertion, [7] and was recommended for CFS in the 1980s. [109] It is now commonly used as a management strategy in chronic illnesses and in chronic pain. [110]

Its two forms are: symptom-contingent pacing, where the decision to stop (and rest or change an activity) is determined by a self awareness of an exacerbation of symptoms and time-contingent pacing, which is determined by a set schedule of activities that a patient estimates he or she is able to complete without triggering postexertional malaise (PEM). Thus, the principle behind pacing for CFS is to avoid overexertion and an exacerbation of symptoms. It is not aimed at treating the illness as a whole. Those whose illness appears stable may gradually increase activity and exercise levels, but according to the principle of pacing, must rest if it becomes clear that they have exceeded their limits. [109] Use of a heart-rate monitor with pacing to monitor and manage activity levels is recommended by a number of patient groups and the UK's 2007 NICE guideline. [111] [106] [ failed verification ]

Energy envelope theory Edit

Energy envelope theory is considered to be consistent with pacing, and is a management strategy suggested in the 2011 international consensus criteria for ME, which referred to using an "energy bank budget". Energy envelope theory was devised by psychologist Leonard Jason, a former sufferer of CFS. [112] Energy envelope theory states that patients should stay within the envelope of energy available to them, and avoid pushing through, which will reduce the postexertional malaise "payback" caused by overexerting and may help them make "modest gains" in physical functioning. [113] [114] Several studies have found energy envelope theory to be a helpful management strategy, noting that it reduces symptoms and may increase the level of functioning in CFS. [115] [116] [114] Energy envelope theory does not recommend unilaterally increasing or decreasing activity and is not intended as a therapy or cure for CFS. [115] It has been promoted by various patient groups. [117] [118] Some patient groups recommend using a heart rate monitor to increase awareness of exertion, and allow patients to stay within their aerobic threshold envelope. [119] [120] Despite a number of studies showing positive results for energy envelope theory, randomized controlled trials are lacking. [ citation needed ]

Exercise Edit

Stretching, movement therapies, and toning exercises are recommended for pain in patients with CFS, and pain medication is also suggested. In many chronic illnesses, aerobic exercise is beneficial, but in chronic fatigue syndrome, the CDC does not recommend it. The CDC states: [7]

"Any activity or exercise plan for people with ME/CFS needs to be carefully designed with input from each patient. While vigorous aerobic exercise can be beneficial for many chronic illnesses, patients with ME/CFS do not tolerate such exercise routines. Standard exercise recommendations for healthy people can be harmful for patients with ME/CFS. However, it is important that patients with ME/CFS undertake activities that they can tolerate. "

Counseling Edit

The CDC states that counseling may help patients cope with pain caused by CFS, and that talking with a professional counselor or therapist may help people to more effectively manage the symptoms that affect their quality of daily life. [7]

Nutrition Edit

A proper diet is a significant contributor to the health of any individual. Medical consultation about diet and supplements are recommended for persons with CFS. [7] Persons with CFS may benefit from a balanced diet and properly supervised administration of nutritional support if deficiencies are detected by medical testing. Risks of nutritional supplements include interactions with prescribed medications. [121] [7]

Cognitive behavioral therapy Edit

The CDC states that speaking with a therapist may help people cope with the illness. [7] A 2015 National Institutes of Health report concluded that while counseling and behavior therapies could produce benefits for some people, they may not yield improvement in quality of life, and because of this limitation such therapies should not be considered as a primary treatment, but rather should be used only as one component of a broader approach. [122] This same report stated that although counseling approaches have shown benefit in some measures of fatigue, function and overall improvement, these approaches have been inadequately studied in subgroups of the wider CFS patient population. Further concern was expressed that reporting of negative effects experienced by patients receiving counseling and behavior therapies had been poor. [102] A report by the Institute of Medicine published in 2015 states that it is unclear whether CBT helps to improve cognitive impairments experienced by patients. [2] : 265 The rationale behind the use of CBT to change beliefs about the illness is disputed. [103]

A 2014 systematic review reported that there was only limited evidence that patients increased levels of physical activity after receiving CBT. The authors concluded that, as this finding is contrary to the cognitive behavioural model of CFS, patients receiving CBT were adapting to the illness rather than recovering from it. [123]

Patient organisations have long criticised the use of CBT as a treatment for CFS, and the rationale behind the model is disputed. [104] [124] In 2012 the ME Association (MEA) commenced an opinion survey of 493 patients who had received a CBT treatment in the UK. Based on the finding of this survey, in 2015 the MEA concluded that CBT in its current form should not be recommended as a primary intervention for people with CFS [125] In a letter published online in the Lancet in 2016, Dr Charles Shepherd, medical advisor to the MEA, expressed the view that the contention between patients and researchers lay in "a flawed model of causation that takes no account of the heterogeneity of both clinical presentations and disease pathways that come under the umbrella diagnosis of ME/CFS". [126] In 2019, a large UK survey of people with ME/CFS reported that CBT was ineffective for more than half of people, and Graded Exercise Therapy caused deterioration in most people. [127]

Graded exercise therapy Edit

Previously, a 2014 National Institutes of Health report concluded that while graded exercise therapy (GET) could produce benefits, it may not yield improvement in quality of life and because of this limitation, GET should not be considered as a primary treatment, but instead be used only as one component of a broader approach. The report also noted that a focus on exercise programs had discouraged patient participation in other types of physical activity, due to concerns of precipitating increased symptoms. [122] A July 2016 addendum to this report recommended that the Oxford criteria not be used when studying ME/CFS. If studies based on the Oxford criteria were excluded, there would be insufficient evidence of the effectiveness of GET on any outcome. [104]

A 2002 Cochrane review updated in 2019 stated that exercise therapy probably has a positive effect on fatigue in adults, and slightly improves sleep, but the long-term effects are unknown, and this has limited relevance to current definitions of ME/CFS. [128] [8] Cochrane have announced that a new review to look at exercise therapies in chronic fatigue syndrome is to start in 2020. [8] [129] As with CBT, patient organisations have long criticised the use of exercise therapy, most notably GET, as a treatment for CFS. [124] In 2012 the MEA commenced an opinion survey of patients who had received GET. Based on the findings of this survey, in 2015 the MEA concluded that GET in its current delivered form should not be recommended as a primary intervention for persons with CFS. [125]

Adaptive pacing therapy Edit

Adaptive pacing therapy (APT) was popularised by the PACE trial, a study that has caused much controversy among both patients and practitioners. [20] [ failed verification ] APT, not to be confused with pacing, [130] is a therapy rather than a management strategy. [131] APT is based on the idea that CFS involves a person only having a limited amount of available energy, and using this energy wisely will mean the "limited energy will increase gradually". [131] : 5 A large clinical trial known as the PACE trial found APT was no more effective than usual care or specialized medical care. [132] Unlike pacing, APT is based on the cognitive behavioral model of chronic fatigue syndrome and involves increasing activity levels, which it states may temporarily increase symptoms. [133] In APT, the patient first establishes a baseline level of activity, which can be carried out consistently without any postexertional malaise ("crashes"). APT states that persons should plan to increase their activity, as able. However, APT also requires patients to restrict their activity level to only 70% of what they feel able to do, while also warning against too much rest. [131] This has been described as contradictory, and Jason states that in comparison with pacing, this 70% limit restricts the activities that patients are capable of and results in a lower level of functioning. [130] Jason and Goudsmit, who first described pacing and the energy envelope theory for CFS, have both criticized APT for being inconsistent with the principles of pacing and highlighted significant differences. [130] APT was promoted by Action for ME, the patient charity involved in the PACE trial, until 2019. [133]

Rintatolimod Edit

Rintatolimod is a double-stranded RNA drug developed to modulate an antiviral immune reaction through activation of toll-like receptor 3. In several clinical trials of CFS, the treatment has shown a reduction in symptoms, but improvements were not sustained after discontinuation. [134] Evidence supporting the use of rintatolimod is deemed low to moderate. [20] The US FDA has denied commercial approval, called a new drug application, citing several deficiencies and gaps in safety data in the trials, and concluded that the available evidence is insufficient to demonstrate its safety or efficacy in CFS. [135] [136] Rintatolimod has been approved for marketing and treatment for persons with CFS in Argentina, [137] and in 2019, FDA regulatory requirements were met for exportation of rintatolimod to the country. [138]

A systematic review which looked at the course of CFS without systematic biological or psychological interventions found that "the median full recovery rate was 5% (range 0–31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8–63%). Return to work at follow-up ranged from 8 to 30% in the three studies that considered this outcome." . "In five studies, a worsening of symptoms during the period of follow-up was reported in between 5 and 20% of patients." A good outcome was associated with not attributing illness to a physical cause, and having a sense of control over symptoms. Other factors were occasionally, but not consistently, related to outcome, including age at onset, a longer duration of follow-up, and less fatigue severity at baseline. The review concludes that "irrespective of the biology of CFS, patients’ beliefs and attributions about the illness are intricately linked with the clinical presentation, the type of help sought and prognosis" [139] Another review found that children have a better prognosis than adults, with 54–94% having recovered by follow-up compared to less than 10% of adults returning to pre-illness levels of functioning. [140]

The prevalence rates for CFS/ME vary widely depending on "case definitions and diagnostic methods". [10] Based on the 1994 CDC diagnostic criteria, the global prevalence rate for CFS is 0.89%. [10] In comparison, the prevalence rate for the stricter criteria, such as the 1988 CDC "Holmes" criteria for CFS and the 2003 Canadian criteria for ME (both of which, for example, exclude patients with psychiatric diagnoses), produce an incidence rate of only 0.17%. [10] For an example of how these rates impact a nation: the CDC website states that "836,000 to 2.5 million Americans suffer from ME/CFS", but most remain undiagnosed. [1]

Females are diagnosed about 1.5 to 2.0 times more often with CFS than males. [10] An estimated 0.5% of children have CFS, and more adolescents are affected with the illness than younger children. [2] : 182 [141]

Myalgic encephalomyelitis Edit

  • From 1934 onwards, outbreaks of a previously unknown illness began to be recorded by doctors. [142][143] Initially considered to be occurrences of poliomyelitis, the illness was subsequently referred to as "epidemic neuromyasthenia". [143]
  • In the 1950s, the term "benign myalgic encephalomyelitis" was used in relation to a comparable outbreak at the Royal Free Hospital in London. [144] The descriptions of each outbreak were varied, but included symptoms of malaise, tender lymph nodes, sore throat, pain, and signs of encephalomyelitis. [145] The cause of the condition was not identified, although it appeared to be infectious, and the term "benign myalgic encephalomyelitis" was chosen to reflect the lack of mortality, the severe muscular pains, symptoms suggesting damage to the nervous system, and to the presumed inflammatory nature of the disorder. Björn Sigurðsson disapproved of the name, stating that the illness is rarely benign, doesn't always cause muscle pain, and is possibly never encephalomyelitic. [142] The syndrome appeared in sporadic as well as epidemic cases. [146]
  • In 1969, benign myalgic encephalomyelitis appeared as an entry to the International Classification of Diseases under Diseases of the nervous system. [147]
  • In 1986, Ramsay published the first diagnostic criteria for ME, in which the condition was characterized by: 1) muscle fatiguability in which, even after minimal physical effort, 3 or more days elapse before full muscle power is restored 2) extraordinary variability or fluctuation of symptoms, even in the course of one day and 3) chronicity. [148]
  • By 1988, the continued work of Ramsay had demonstrated that, although the disease rarely resulted in mortality, it was often severely disabling. [2] : 28–29 Because of this, Ramsay proposed that the prefix "benign" be dropped. [144][149][150]

Chronic fatigue syndrome Edit

  • In the mid-1980s, two large outbreaks of an illness that resembled mononucleosis drew national attention in the United States. Located in Nevada and New York, the outbreaks involved an illness characterized by "chronic or recurrent debilitating fatigue, and various combinations of other symptoms, including a sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias". An initial link to the Epstein-Barr virus had the illness acquire the name "chronic Epstein-Barr virus syndrome". [2] : 29 [91]
  • In 1987, the CDC convened a working group to reach a consensus on the clinical features of the illness. The working group concluded that CFS was not new, and that the many different names given to it previously reflected widely differing concepts of the illness's cause and epidemiology. [151] The CDC working group chose "chronic fatigue syndrome" as a more neutral and inclusive name for the illness, but noted that "myalgic encephalomyelitis" was widely accepted in other parts of the world. [91]
  • In 1988, the first definition of CFS was published. Although the cause of the illness remained unknown, several attempts were made to update this definition, most notably in 1994. [90]
  • The most widely referenced diagnostic criteria and definition of CFS for research and clinical purposes were published in 1994 by the CDC. [59]
  • In 2006, the CDC commenced a national program to educate the American public and health-care professionals about CFS. [152]

Other medical terms Edit

A range of both theorised and confirmed medical entities and naming conventions have appeared historically in the medical literature dealing with ME and CFS. These include:

  • Epidemic neuromyasthenia was a term used for outbreaks with symptoms resembling poliomyelitis. [142][153]
  • Iceland disease and Akureyri disease were synonymous terms used for an outbreak of fatigue symptoms in Iceland. [154]
  • Low natural killer syndrome, a term used mainly in Japan, reflected research showing diminished in vitro activity of natural killer cells isolated from patients. [155][156] has been proposed as an historical diagnosis that occupied a similar medical and cultural space to CFS. [157]
  • Royal Free disease was named after the historically significant outbreak in 1955 at the Royal Free Hospital used as an informal synonym for "benign myalgic encephalomyelitis". [158]
  • Tapanui flu was a term commonly used in New Zealand, deriving from the name of a town, Tapanui, where numerous people had the syndrome. [159]

Naming Edit

Many names have been proposed for the illness. Currently, the most commonly used are "chronic fatigue syndrome", "myalgic encephalomyelitis", and the umbrella term "ME/CFS". Reaching consensus on a name is challenging because the cause and pathology remain unknown. [2] : 29–30

The term "chronic fatigue syndrome" has been criticized by some patients as being both stigmatizing and trivializing, and which in turn prevents the illness from being seen as a serious health problem that deserves appropriate research. [160] While many patients prefer "myalgic encephalomyelitis", which they believe better reflects the medical nature of the illness, [148] [161] there is resistance amongst some clinicians toward the use of myalgic encephalomyelitis on the grounds that the inflammation of the central nervous system (myelitis) implied by the term has not been demonstrated. [162] [163]

A 2015 report from the Institute of Medicine recommended the illness be renamed "systemic exertion intolerance disease", (SEID), and suggested new diagnostic criteria, proposing post-exertional malaise, (PEM), impaired function, and sleep problems are core symptoms of ME/CFS. Additionally, they described cognitive impairment and orthostatic intolerance as distinguishing symptoms from other fatiguing illnesses. [2] [164] [165] [ dead link ]

Economic impact Edit

Reynolds et al. (2004) [166] estimated that the illness caused about $20,000 per person with CFS in lost productivity, which totals to $9.1 billion per year in the United States. [167] This is comparable to other chronic illnesses that extract some of the biggest medical and socioeconomic costs. [168] A 2008 study [169] calculated that the total annual cost burden of ME/CFS to society in the US was extensive, and could approach $24.0 billion. [170] A 2017 estimate for the annual economic burden in the United Kingdom from ME/CFS was 3.3 billion Pounds Sterling. [12]

Awareness day Edit

May 12 is designated as ME/CFS International Awareness Day. [171] The day is observed so that stakeholders have an occasion to improve the knowledge of "the public, policymakers, and health-care professionals about the symptoms, diagnosis, and treatment of ME/CFS, as well as the need for a better understanding of this complex illness." [172] It was chosen because it is the birthday of Florence Nightingale, who had an illness appearing similar to ME/CFS or fibromyalgia. [171] [173]

Doctor–patient relations Edit

Some in the medical community do not recognize CFS as a real condition, nor does agreement exist on its prevalence. [174] [175] [176] There has been much disagreement over proposed causes, diagnosis, and treatment of the illness. [177] [178] [179] [180] [181] This uncertainty can significantly affect doctor-patient relations. A 2006 survey of GPs in southwest England found that despite more than two-thirds of them accepting CFS/ME as a recognizable clinical entity, nearly half did not feel confident with making the diagnosis and/or treating the disease. Three other key factors that were significantly, positively associated with GPs' attitudes were knowing someone socially with CFS/ME, being male, and seeing more patients with the condition in the last year. [182]

From the patient perspective, one 1997 study found that 77% of individuals with CFS reported negative experiences with health-care providers. [39] In a more recent metaanalysis of qualitative studies, a major theme identified in patient discourses was that they felt severely ill, yet were blamed and dismissed. [183] A study of themes in patient newsgroup postings noted key themes relating to denial of social recognition of suffering and feelings of being accused of "simply faking it". Another theme that emerged strongly was that achieving diagnosis and acknowledgement requires tremendous amounts of "hard work" by patients. [176] [184]

Blood donation Edit

In 2010, several national blood banks adopted measures to discourage or prohibit individuals diagnosed with CFS from donating blood, based on concern following the 2009 claim of a link, [185] between CFS and a retrovirus which was subsequently shown to be unfounded. Organizations adopting these or similar measures included the Canadian Blood Services, [186] the New Zealand Blood Service, [187] the Australian Red Cross Blood Service [188] and the American Association of Blood Banks, [189] In November 2010, the UK National Blood Service introduced a permanent deferral of donation from ME/CFS patients based on the potential harm to those patients that may result from their giving blood. [190] Donation policy in the UK now states, "The condition is relapsing by nature and donation may make symptoms worse, or provoke a relapse in an affected individual." [191]

Controversy Edit

Much contention has arisen over the cause, pathophysiology, [50] nomenclature, [192] and diagnostic criteria of CFS. [177] [178] Historically, many professionals within the medical community were unfamiliar with CFS, or did not recognize it as a real condition nor did agreement exist on its prevalence or seriousness. [175] [176] [193] Some people with CFS reject any psychological component. [194]

In 1970, two British psychiatrists, McEvedy and Beard, reviewed the case notes of 15 outbreaks of benign myalgic encephalomyelitis and concluded that it was caused by mass hysteria on the part of patients, or altered medical perception of the attending physicians. [195] Their conclusions were based on previous studies that found many normal physical test results, a lack of a discernible cause, and a higher prevalence of the illness in females. Consequently, the authors recommended that the disease should be renamed "myalgia nervosa". This perspective was rejected in a series of case studies by Dr. Melvin Ramsay and other staff of the Royal Free Hospital, the center of a significant outbreak. [196] The psychological hypothesis posed by McEvedy and Beard created great controversy, and convinced a generation of health professionals in the UK that this could be a plausible explanation for the condition, resulting in neglect by many medical specialties. [162] The specialty that did take a major interest in the illness was psychiatry. [197]

Because of the controversy, sociologists hypothesized that stresses of modern living might be a cause of the illness, while some in the media used the term "Yuppie flu" and called it a disease of the middle class. People with disabilities from CFS were often not believed and were accused of being malingerers. [197] The November 1990 issue of Newsweek ran a cover story on CFS, which although supportive of an organic cause of the illness, also featured the term 'yuppie flu', reflecting the stereotype that CFS mainly affected yuppies. The implication was that CFS is a form of burnout. The term 'yuppie flu' is considered offensive by both patients and clinicians. [198] [199]

In 2009, the journal Science [185] published a study that identified the XMRV retrovirus in a population of people with CFS. Other studies failed to reproduce this finding, [200] [201] [202] and in 2011, the editor of Science formally retracted its XMRV paper [203] while the Proceedings of the National Academy of Sciences similarly retracted a 2010 paper which had appeared to support the finding of a connection between XMRV and CFS. [204]

Research funding Edit

United Kingdom Edit

The lack of research funding and the funding bias towards biopsychosocial studies and against biomedical studies has been highlighted a number of times by patient groups and a number of UK politicians. [205] A parliamentary inquiry by an ad hoc group of parliamentarians in the United Kingdom, set up and chaired by former MP, Dr Ian Gibson, called the Group on Scientific Research into CFS/ME, [106] : 169–186 [206] was addressed by a government minister claiming that few good biomedical research proposals have been submitted to the Medical Research Council (MRC) in contrast to those for psychosocial research. They were also told by other scientists of proposals that have been rejected, with claims of bias against biomedical research. The MRC confirmed to the group that from April 2003 to November 2006, it has turned down 10 biomedical applications relating to CFS/ME and funded five applications relating to CFS/ME, mostly in the psychiatric/psychosocial domain. [206]

In 2008, the MRC set up an expert group to consider how the MRC might encourage new high-quality research into CFS/ME and partnerships between researchers already working on CFS/ME and those in associated areas. It currently lists CFS/ME with a highlight notice, inviting researchers to develop high-quality research proposals for funding. [207] In February 2010, the All-Party Parliamentary Group on ME (APPG on ME) produced a legacy paper, which welcomed the recent MRC initiative, but felt that far too much emphasis in the past had been on psychological research, with insufficient attention to biomedical research, and that further biomedical research must be undertaken to help discover a cause and more effective forms of management for this disease. [208]

Controversy surrounds psychologically oriented models of the disease and behavioral treatments conducted in the UK. [209]

United States Edit

In 1998, $13 million for CFS research was found to have been redirected or improperly accounted for by the United States CDC, and officials at the agency misled Congress about the irregularities. The agency stated that they needed the funds to respond to other public-health emergencies. The director of a U.S. national patient advocacy group charged the CDC had a bias against studying the disease. The CDC pledged to improve their practices and to restore the $13 million to CFS research over three years. [210]

On 29 October 2015, the National Institutes of Health declared its intent to increase research on ME/CFS. The NIH Clinical Center was to study individuals with ME/CFS, and the National Institute of Neurological Disorders and Stroke would lead the Trans-NIH ME/CFS Research Working Group as part of a multi-institute research effort. [211]

Notable cases Edit

In 1989, The Golden Girls (1985–1992) featured chronic fatigue syndrome in a two-episode arc, "Sick and Tired: Part 1" and "Part 2," in which protagonist Dorothy Zbornak, portrayed by Bea Arthur, after a lengthy battle with her doctors in an effort to find a diagnosis for her symptoms, is finally diagnosed with CFS. [212] American author Ann Bannon had CFS. [213] Laura Hillenbrand, author of the popular book Seabiscuit, has struggled with CFS since age 19. [214] [215]

The different case definitions used to research the illness influence the types of patients selected for studies, [86] and research also suggests subtypes of patients may exist within a heterogeneous population. [167] [216] [217] [218] In one of the definitions, symptoms are accepted that may suggest a psychiatric disorder, while others specifically exclude primary psychiatric disorders. [89] The lack of a single, unifying case definition was criticized in the Institute of Medicine's 2015 report for "creating an unclear picture of the symptoms and signs of the disorder" and "complicating comparisons of the results" (study results). [2] : 72

More robust diagnostic methods are being investigated with the aim of identifying unique biomarkers that may be used in clinical testing. In 2019, two different papers were published proposing blood-based biomarkers for CFS. [219] [220] One found that blood cells of CFS patients could be distinguished from healthy controls by their response to hyperosmotic stress. [221] Another found that the red blood cells of CFS patients were stiffer, and thus less able to deform in order to pass through capilliaries. [222]

Test Details

How does a Bravo pH test work?

The Bravo pH monitoring test is a system that includes:

  • A pH-sensing wireless capsule that is placed into esophageal tissue to measure pH levels.
  • A recorder you wear to capture the data from the capsule
  • A software system that makes it all work.

A small capsule, about the size of a gel cap, is temporarily attached to the wall of the esophagus during an upper endoscopy. The capsule measures pH levels in the esophagus and transmits readings to a receiver (about the size of a pager) worn on your belt or waistband.

The receiver has several buttons on it that you will press to record symptoms of GERD such as heartburn (a caregiver will tell you what symptoms to record). You will be asked to maintain a diary to keep track of events like when you start and stop eating and drinking, when you lie down and when you get back up. This will be explained by your caregiver.

Who performs a Bravo pH monitoring test?

The capsule will be placed by a digestive disease provider skilled in gastrointestinal endoscopy. The upper endoscopy process uses thin tubing with cameras to look into your gastrointestinal system through your esophagus and down toward your stomach. The process can be used both to examine your system and to treat certain conditions.

How do you prepare for the Bravo pH test?

Let your doctor know if you have a pacemaker or implantable heart defibrillator, a history of bleeding problems, dilated blood vessels, and any other previously known problems with your esophagus.

  • Seven days before the monitoring period, don’t take proton pump inhibitors such as omeprazole (Prilosec®), lansoprazole (Prevacid®), rabeprazole (Aciphex®), pantoprazole (Protonix®), esomeprazole (Nexium®).
  • Two days (48 hours) before the monitoring period, don’t take the H2 blockers ranitidine (Zantac®), cimetidine (Tagamet®), famotidine (Pepcid®), nizatidine (Axid®) or the promotility drug, metoclopramide (Reglan®).
  • Six hours before the monitoring period, don’t take antacids (such as Alka-Seltzer®, Gaviscon®, Maalox®, Milk of Magnesia®, Mylanta®, Phillips®, Riopan®, Tums® or any other brands).
  • Four to six hours before your appointment, don’t eat or drink.

Please note: Occasionally, your doctor may want you to continue taking a certain medication during the monitoring period to determine if it is effective.

What happens on the day of the Bravo pH test?

You should wear comfortable clothing. You might be asked to change into a gown at the hospital or outpatient facility.

Leave your jewelry and credit cards at home. You won’t be able to wear your glasses or dentures during the procedure.

You should have a responsible person to drive you home.

Your healthcare provider will again explain the procedure and what to expect. This procedure is done under twilight sleep. They will tell you about possible complications or side effects.

Your provider will apply a local anesthetic (pain-relieving medication) at the back of your throat.

The provider will insert an endoscope into your mouth and into your esophagus (the "food pipe" leading from your mouth into your stomach). The endoscope does not interfere with your breathing.

The provider will attach the capsule to tissue on your esophagus and make sure that the capsule is sending signals to the recorder.

The procedure lasts only a few minutes.

Does the Bravo pH monitoring test hurt?

You’re probably wondering what your Bravo test experience will be like. Your throat might be a little sore. You might feel like something is in your throat. If you have any symptom that is extreme or that concerns you, contact your healthcare provider.

What happens during the Bravo pH monitoring test after the capsule is placed?

Here’s what you need to know about what happens during the study.

  • Activity: Follow your usual daily routine. Don’t reduce or change your activities during the monitoring period. If you change things, the monitoring results aren’t as useful. Note: Don’t get the receiver wet because it’s not waterproof.
  • Eating: Eat your regular meals at the usual times. If you don’t eat during the monitoring period, your stomach won’t produce acid as usual, and the test results won’t be accurate. Eat at least 2 meals a day. Eat foods that tend to increase your symptoms (without making yourself miserable). Avoid snacking. Don’t suck on hard candy or lozenges and don’t chew gum during the monitoring period.
  • Lying down: Remain upright throughout the day. Don’t lie down until you go to bed (unless napping or lying down during the day is part of your daily routine).
  • Medications: Continue to follow your doctor’s advice regarding medications to avoid during the monitoring period.
  • Recording symptoms: Press the appropriate button on the receiver when symptoms occur (as discussed with the nurse). Record the time you start and stop eating and drinking (anything other than plain water). Record the time you lie down (even if you’re just resting) and when you get back up. Someone on your healthcare team will explain all of this. .
  • Unusual symptoms or side effects: If you think you may be experiencing any unusual symptoms or side effects, call your doctor.

You’ll return the receiver and diary when the monitoring period is over. The information on the receiver and diary will be downloaded to a computer and the results will be analyzed.

What are the risks and benefits of the Bravo pH monitoring test?

Finding out if you have acid reflux is important. If you do have the more severe version (GERD), it could be causing damage to your esophagus, which could mean you could develop problems that are more serious. These include Barrett’s esophagus or esophageal cancer.

Finding out that you don’t have acid reflux is also important. Many people are taking medication like PPIs that aren’t working. You don’t need to take medication that is not indicated. If you don’t have acid reflux, your healthcare team can then help you find out what is really causing your symptoms.

Any procedure has risks, but the Bravo test has had few complications. These have included problems with the equipment that make the results unreliable. The capsule might fail to stay in place for the full testing period. Or, it might not detach when it’s supposed to do so.

Rarely, people having this test might feel some discomfort when they swallow, chest pain or back pain. You may have a sore throat from the endoscopy for a day or so.

There are other possible, though very unlikely, risks. These include damage to the tissue of your esophagus or intestines, possible bleeding or aspiration (breathing in) of the capsule.

15.4.1: 15.4T Allergies - Biology

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An allergy is a hypersensitive immune response to a normally harmless substance. The first process necessary for establishing an allergy is sensitization.

For example, individuals who are allergic to grass pollen have undergone sensitization. Their immune cells lining the respiratory passage take up and degrade the allergens into fragments.

These immune cells are called antigen presenting cells, or APCs because they display the degraded allergen fragments on their surface.

The APCs activate another encountered cell, type two T helper cells, abbreviated as Th2.

The activated Th2 then release chemical signals that cause another type of immune cell, B cells, to develop into antibody producing plasma cells which make immunoglobulin E, or IgE, a class of antibodies.

In this case, exposure to grass pollen will produce an IgE specific to this pollen, causing an allergic reaction distinct to grass pollen and no other type.

Once created, IgE binds to the surface of specialized cells called mast cells, found in tissues like the mucous membranes and skin.

Following sensitization, an allergic reaction occurs each time an individual encounters the allergen to which they are allergic after the allergen binds to its specific IgE on mast cells.

For instance, when the grass pollen allergen binds to its IgE, it causes the release of allergy symptom causing chemicals, such as leukotrienes and histamines that lead to sneezing, runny noses, and nasal passage inflammation.

Allergen exposure also causes mast cells and Th2 to release chemical signals that recruit and activate other inflammation inducing immune cells such as eosinophils and basophils to further amplify symptoms.

24.7: Allergic Reactions


We speak of an allergy when the immune system triggers a response against a benign foreign structure, like food, pollen or pet dander. These elicitors are called allergens. If the immune system of a hypersensitive individual was primed against a specific allergen, it will trigger allergic symptoms during every subsequent encounter of the allergen. Symptoms can be mild, such as hay fever, to severe, such as potentially fatal anaphylactic shock.

Sensitization Is the First Step of an Allergy

The immune system is crucial for defending an organism against bacteria, viruses, fungi, toxins, and parasites. However, in a hypersensitive response, it can be triggered by harmless substances and cause unpleasant or potentially life-threatening overreactions, called allergies. The first step toward establishing an allergy is sensitization. For instance, an individual becomes allergic to the pollen of ragweed when, for the first time, immune cells in the respiratory passage take up the pollen and degrade the allergens into fragments. These immune cells are called antigen-presenting cells, or APCs, because they display the degraded allergen fragments on their surface. Examples of APCs are dendritic cells, macrophages and B cells.

Subsequently, APCs activate encountered Type 2 helper T cells (Th2). The activated Th2 then release chemical signals (e.g., cytokines) that cause B cells to differentiate into antibody-producing plasma cells. Plasma cells, in turn, produce immunoglobulin E (IgE), a class of antibodies.

Once created, IgE binds to the surface of mast cells. Mast cells are especially prevalent in tissues that separate the outside and inside of an organism, such as the skin, mucosa of the lungs, digestive tract, mouth, and nose. The binding of IgE to the mast cells finalizes sensitization.

Repeated Allergen Exposure Induces an Inappropriate Immune Response

The next time the body encounters ragweed pollen, the IgE stimulates the mast cells to produce inflammatory chemicals, such as histamines, leukotrienes, and cytokines. These chemicals produce the typical allergic symptoms of hay fever: sneezing, runny nose, and nasal passage inflammation. Allergen exposure also causes mast cells and Th2 to release chemical signals that recruit and activate other inflammation-inducing immune cells, such as eosinophils and basophils, further amplifying symptoms.

The IgE that have been produced in response to ragweed pollen during sensitization are specific to ragweed. This means that these IgE will trigger an immune response (i.e., allergic reaction) whenever they encounter ragweed pollen. In some cases, the ragweed pollen-specific IgE might also trigger an allergic reaction in response to other allergens. This process is called cross-reactivity.

An Anaphylactic Shock Is a Potentially Fatal Systemic Allergic Reaction

While some allergic episodes may present merely a nuisance, others have potentially fatal consequences if not treated quickly. Although the prevalence of anaphylaxis varies regionally, an estimated 0.05-2% of people suffer from an anaphylactic shock&mdashthe rapid onset of a systemic allergic response. Triggers can be food, medication, latex, and venom from insects. Within minutes of allergen exposure, mast cells release a large number of mediators into the bloodstream. The mediators, such as histamines, leukotrienes, and tryptase, lead to restriction of airways (bronchoconstriction), widening of blood vessels (vasodilation), increased mucus production, changes in heart rate, and vascular permeability.

To diagnose anaphylaxis, one should, therefore, look for rashes, a rapid increase of mucus, difficulty breathing, reduced blood pressure and gastrointestinal symptoms over a time course ranging from several minutes to hours after allergen exposure. Epinephrine is the only potent medication known to counteract the complex physiological changes during anaphylaxis. It initiates constriction of blood vessels, increases heart rate, stabilizes heart contractility, and increases airflow through the airways. Epinephrine is usually auto-applied using an EpiPen, as a fast response after the onset of anaphylaxis is critical.

Reber, Laurent L., Joseph D. Hernandez, and Stephen J. Galli. &ldquoThe Pathophysiology of Anaphylaxis.&rdquo Journal of Allergy and Clinical Immunology 140, no. 2 (August 2017): 335&ndash48. [Source]

Valenta, Rudolf, Heidrun Hochwallner, Birgit Linhart, and Sandra Pahr. &ldquoFood Allergies: The Basics.&rdquo Gastroenterology 148, no. 6 (May 1, 2015): 1120-1131.e4. [Source]

33.4 Disruptions in the Immune System

In this section, you will explore the following questions:

  • What is hypersensitivity?
  • What is autoimmunity, and what is an example of an autoimmune disease?

Connection for AP ® Courses

Much of the information in this section is not within the scope for AP ® . Immune systems can, at times, be defeated by pathogens. For example, some bacteria, including Streptococcus pneumoniae, surround themselves with a capsule that inhibits phagocytes from engulfing them and displaying antigens to the adaptive immune system. Human immunodeficiency virus (HIV), the virus that causes AIDS, infects helper T-cells via their CD4 surface molecules, gradually depleting the number of TH cells in the body this inhibits the adaptive immune system’s capacity to sufficiently respond to infection or tumors that persons with healthy immune systems can defend against. Allergies to pollen or pet dander occur when the immune system attacks the body’s own cells or tissues. Other example of autoimmune diseases include type I diabetes and ALS. In the rejection of transplanted organs, the immune system is responding to unmatched MHC proteins on the cells of the donated (“non-self”) organ. However, the immune system usually responds as it should, defending you against infection and getting you back to your AP ® Biology class as soon as possible.

Information presented and the examples highlighted in the section support concepts outlined in Big Idea 2 of the AP ® Biology Curriculum Framework. The AP ® Learning Objectives listed in the Curriculum Framework provide a transparent foundation for the AP ® Biology course, an inquiry-based laboratory experience, instructional activities, and AP ® exam questions. A learning objective merges required content with one or more of the seven science practices.

Big Idea 2 Biological systems utilize free energy and molecular building blocks to grow, to reproduce, and to maintain dynamic homeostasis.
Enduring Understanding 2.D Growth and dynamic homeostasis of a biological system are influenced by changes in the system’s environment.
Essential Knowledge 2.D.3 Biological systems are affected by disruptions to their dynamic homeostasis.
Science Practice 1.4 The student can use representations and models to analyze situations or solve problems qualitatively and quantitatively.
Learning Objective 2.28 The student is able to use representations or models to analyze quantitatively and qualitatively the effects of disruptions to dynamic homeostasis in biological systems.


Failures, insufficiencies, or delays at any level of the immune response can allow pathogens or tumor cells to gain a foothold and replicate or proliferate to high enough levels that the immune system becomes overwhelmed. Immunodeficiency is the failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including certain medical treatments), malnutrition, or possibly by extreme stress. For instance, radiation exposure can destroy populations of lymphocytes and elevate an individual’s susceptibility to infections and cancer. Dozens of genetic disorders result in immunodeficiencies, including Severe Combined Immunodeficiency (SCID), Bare lymphocyte syndrome, and MHC II deficiencies. Rarely, primary immunodeficiencies that are present from birth may occur. Neutropenia is one form in which the immune system produces a below-average number of neutrophils, the body’s most abundant phagocytes. As a result, bacterial infections may go unrestricted in the blood, causing serious complications.

Everyday Connection for AP® Courses

This is a white severe combined immunodeficiency (SCID) mouse. SCID mice are used to study the immune system.


Maladaptive immune responses toward harmless foreign substances or self antigens that occur after tissue sensitization are termed hypersensitivities. The types of hypersensitivities include immediate, delayed, and autoimmunity. A large proportion of the population is affected by one or more types of hypersensitivity.


The immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a harmless antigen is called an allergy. In the United States, 20 percent of the population exhibits symptoms of allergy or asthma, whereas 55 percent test positive against one or more allergens. Upon initial exposure to a potential allergen, an allergic individual synthesizes antibodies of the IgE class via the typical process of APCs presenting processed antigen to TH cells that stimulate B cells to produce IgE. This class of antibodies also mediates the immune response to parasitic worms. The constant domain of the IgE molecules interact with mast cells embedded in connective tissues. This process primes, or sensitizes, the tissue. Upon subsequent exposure to the same allergen, IgE molecules on mast cells bind the antigen via their variable domains and stimulate the mast cell to release the modified amino acids histamine and serotonin these chemical mediators then recruit eosinophils which mediate allergic responses. Figure 33.27 shows an example of an allergic response to ragweed pollen. The effects of an allergic reaction range from mild symptoms like sneezing and itchy, watery eyes to more severe or even life-threatening reactions involving intensely itchy welts or hives, airway contraction with severe respiratory distress, and plummeting blood pressure. This extreme reaction is known as anaphylactic shock. If not treated with epinephrine to counter the blood pressure and breathing effects, this condition can be fatal.

Delayed hypersensitivity is a cell-mediated immune response that takes approximately one to two days after secondary exposure for a maximal reaction to be observed. This type of hypersensitivity involves the TH1 cytokine-mediated inflammatory response and may manifest as local tissue lesions or contact dermatitis (rash or skin irritation). Delayed hypersensitivity occurs in some individuals in response to contact with certain types of jewelry or cosmetics. Delayed hypersensitivity facilitates the immune response to poison ivy and is also the reason why the skin test for tuberculosis results in a small region of inflammation on individuals who were previously exposed to Mycobacterium tuberculosis. That is also why cortisone is used to treat such responses: it will inhibit cytokine production.


Autoimmunity is a type of hypersensitivity to self antigens that affects approximately five percent of the population. Most types of autoimmunity involve the humoral immune response. Antibodies that inappropriately mark self components as foreign are termed autoantibodies. In patients with the autoimmune disease myasthenia gravis, muscle cell receptors that induce contraction in response to acetylcholine are targeted by antibodies. The result is muscle weakness that may include marked difficultly with fine and/or gross motor functions. In systemic lupus erythematosus, a diffuse autoantibody response to the individual’s own DNA and proteins results in various systemic diseases. As illustrated in Figure 33.28, systemic lupus erythematosus may affect the heart, joints, lungs, skin, kidneys, central nervous system, or other tissues, causing tissue damage via antibody binding, complement recruitment, lysis, and inflammation.

Autoimmunity can develop with time, and its causes may be rooted in molecular mimicry. Antibodies and TCRs may bind self antigens that are structurally similar to pathogen antigens, which the immune receptors first raised. As an example, infection with Streptococcus pyogenes (bacterium that causes strep throat) may generate antibodies or T cells that react with heart muscle, which has a similar structure to the surface of S. pyogenes. These antibodies can damage heart muscle with autoimmune attacks, leading to rheumatic fever. Insulin-dependent (Type 1) diabetes mellitus arises from a destructive inflammatory TH1 response against insulin-producing cells of the pancreas. Patients with this autoimmunity must be injected with insulin that originates from other sources.