Hypersensitivity results from damage done to the body by an immune response. Many immune responses damage the body during antigen removal, causing swelling and pain from inflammation or lysis of virus-infected cells by cytotoxic T cells. When the damage is too great, however, hypersensitivity can become life-threatening. Hypersensitivities are classified into four types based on the mechanism of tissue damage. Most of what we call "allergy" is Type I hypersensitivity, in which IgE is produced in response to an antigen called an allergen.
Type I (immediate) hypersensitivity is mediated by IgE and mast cells. IgE-mediated allergic reactions include hay fever, skin inflammation (urticaria), food allergies, asthma, and systemic anaphylaxis.
The risk of developing a Type I hypersensitivity (atopy) is linked to family history and IgE levels. A child's risk of becoming atopic is greater if s/he has parents who are atopic. People with higher IgE levels tend to be atopic more often than people with lower IgE levels, although the linkage is not absolute.
Serum IgE has CH2 domains that bind FceRI on mast cells and basophils without previous antigen binding. (Remember that IgG must bind antigen to effectively bind FcgRI.) Most IgE is present on mast cell membranes in the connective tissues around the respiratory and digestive tracts. IgE production requires T cell help, especially IL-4 production by Th2 cells. Eosinophils stimulated by antigen-IgE binding to FceRI provide the most effective immune response to helminth parasites, so in locales with high helminth burdens, IgE production probably provides a selective advantage to people who produce it.
It is not clear what makes certain molecules allergens for atopic people. Allergens do fall into groups of molecules, such as grasses, pollens, animal dander, and foods that usually reach mucosal surfaces at very low doses. They are protein, since only protein molecules can be presented to T cells and elicit T cell help. Several are proteases. Since helminth parasites often secrete proteases to allow them to invade tissues by digesting connective tissue, an IgE responses to these proteolytic enzymes may be part of the normal protective response to worm parasites. Other enzymes which induce allergic reactions are one from house dust mites, papain from papaya (used in meat tenderizer), chymopapain (used clinically to destroy discs putting pressure on spinal nerves), and the bacterial enzyme subtilisin (used in some laundry detergents).
Exposure to allergens generally occurs at mucosal membranes in the respiratory and digestive tracts. Antigen dose is generally low, favoring activation of Th2 responses. The allergen is usually low molecular weight and very soluble, so it can diffuse through the mucus. It is also chemically stable. People who are atopic may have particular Class II MHC alleles that bind allergen peptides tightly and present them efficiently to Th cells.
When a person responds to an antigen by synthesizing IgE, some of the IgE binds to mast cell FceRI and remains after the antigen has been cleared from the body. Initial exposure to allergen, which results in IgE binding to mast cells in smooth muscle, blood vessels, and mucosal linings, is called sensitization and does not usually result in allergic symptoms. Subsequent exposure to antigen allows it to cross-link IgE molecules on mast cell FceRI and immediately trigger allergic symptoms.
Immediate hypersensitivity symptoms are caused by preformed mast cell molecules stored in cytoplasmic granules for rapid release as soon as antigen cross-links membrane FceRI receptors. Among these compounds are histamine, which causes smooth muscle contraction, mucus release, vasodilatation, and increased capillary permeability; proteolytic enzymes, which break down tissue matrix proteins; and TNFa, which up-regulates adhesion molecule expression on vascular endothelial cells to promote leukocyte extravasation. Increased blood flow and fluid release at mucus membranes and into tissues is designed to wash away antigen or permit phagocytes and antibodies to eliminate it.
Depending on the site of antigen contact, release of these mediators results in different clinical symptoms. In the respiratory tract, mucus production and smooth muscle contraction leads to runny nose, watery eyes, sneezing, coughing, sinus congestion and constructed airways. In the gastrointestinal tract, smooth muscle contraction and fluid release cause cramping, diarrhea, and vomiting. In the skin, localized swelling causes hives (urticaria).
Mast cells are stimulated by antigen binding to IgE-FceRI complexes to synthesize another group of mediators, which cause prolonged symptoms (late-phase response) several hours after initial antigen binding. These mediators include chemokines and platelet-activating factors to attract leukocytes, cytokines (including IL-4) to activate eosinophils and stimulate their synthesis in the marrow, and leukotrienes (SRS-A) to promote blood flow, smooth muscle constriction, and mucus secretion.
People whose airways are particularly sensitive to mast cell products may develop asthma, where constriction of airways is so severe that air cannot be expelled and suffocation is possible. Late phase products enhance airway constriction. Systemic allergic reactions can also result in immediate life-threatening systemic anaphylaxis, leading to vascular shock, cardiac arrhythmias, blocked airways, and fluid accumulation in the respiratory system.
Type I hypersensitivity can be measured by skin testing or by RAST, a specialized RIA (see ToolBox). The best treatment for allergy is complete allergen avoidance. Medications to prevent or lessen allergic symptoms include sodium cromoglycate to block mast cell degranulation, antihistamines and epinephrine to block mediator actions on the tissues, and immunosuppressive drugs like steroids to block Th2 activity.
Atopic individuals may also receive chronic desensitization, injected administration of allergen beginning with very low doses that are increased over many months. Desensitization is not effective for every allergen or for every individual, and its mechanism of action is unresolved. Current hypotheses are that the immune response is switched from IgE to IgG, which binds allergen before it can trigger mast cells, or that the treatment induces suppressor T cells (probably Th1 cells) which block B cell activation and IgE synthesis in response to allergen.
Both Type II and Type III hypersensitivities are mediated by IgG (or occasionally IgM) antibody. Type II hypersensitivity results when antibody binds to cell surface antigen. The surface antigen-antibody complexes activate complement or bind to FcgRI on cells that can perform antibody-dependent cell-mediated cytotoxicity (ADCC). Both processes result in lysis of the target cell.
Complement-mediated and ADCC-mediated lysis are normally directed against pathogens and are important protective mechanisms of the immune system. Classical complement activation by IgG releases inflammation-promoting anaphylatoxins and leads to formation of membrane attack complex (MAC) and lysis of the antibody-coated cell. Cells which mediate ADCC (K cells) include NK cells, neutrophils, eosinophils, and macrophages. K cells have FcgRI specific for antigen-bound IgG; they are not antigen specific. MHC is not involved in K cell recognition of ADCC targets. The cytotoxic mechanism depends on the particular K cell involved: NK cells use perforins, as they do for natural killing, while macrophages and granulocytes use proteases and toxic oxygen products.
Clinical examples of Type II hypersensitivities are numerous. They include hyperacute graft rejection, in which preformed antibodies to blood group antigens or transplantation antigens cause immediate, severe, and non-reversible damage to the graft. Drugs like aspirin and penicillin, which often complex with erythrocyte membrane proteins, may induce synthesis of IgG antibodies which then bind drug-coated erythrocytes and damage them. Other examples of Type II hypersensitivity are autoimmune diseases in which antibodies are produced to membrane proteins: acetylcholine receptor in myasthenia gravis, thyroid hormone receptor in Graves' disease, and erythrocyte membrane proteins in autoimmune hemolytic anemia. Type II Hypersensitivities to blood typing antigens A, B, and Rh are discussed in the clinical correlation below.
Type II Hypersensitivities can be detected by hemagglutination (see ToolBox). Clinical interventions for Type II hypersensitivities include prevention (blood and tissue crossmatching), discontinuing the offending drugs, supportive therapy, and immune suppressants. Autoimmune Type II hypersensitivities are obviously the most difficult to treat because antigen cannot be removed.
Type III hypersensitivity is caused by immune complex deposition in the tissues, where the classical complement cascade results in tissue damage. Normally, numerous immune complexes too small to bind FcR are removed from the circulation by erythrocytes bearing complement receptor CR1 before they can do any damage. Under certain conditions, often when antigen persists in the body for long periods or high levels of antigen are encountered at one time, immune complexes reach such high levels that they are no longer soluble. Common sites of deposition and tissue damage are blood vessel walls, kidney, and joints. Once cells are damaged and an inflammatory response is initiated, release of cytoplasmic enzymes and influx of inflammatory cells prolong the hypersensitivity.
A local inflammatory response (Arthus reaction) can be demonstrated in the skin of people with antibodies to the sensitizing antigen. Antigen injected into the skin binds antibody and the complexes bind FcgRIII on skin mast cells. Release of mast cell mediators and complement activation result in local inflammation, with swelling and reddening at the injection site.
Clinical examples of Type III hypersensitivity include serum sickness. Serum sickness is a systemic Type III hypersensitivity which occurs in response to passive immunization with foreign antiserum, i.e., horse neutralizing antibodies to rattlesnake venom. A person receiving horse antibodies for the first time makes a primary response to the foreign IgG protein. After 7-10 days, enough IgG anti-horse antibody has been produced to form immune complexes in the circulation that deposit in small vessels and activate complement and macrophages. Symptoms of serum sickness include fever, chills, rash, arthritis, and sometimes kidney damage. On second exposure to horse antibodies, the patient would begin experiencing serum sickness within a couple of days since isotype switching to IgG had already occurred. Serum sickness also occurs as a reaction to anti-lymphocyte globulin used as an immune suppressant for transplant recipients. Serum sickness can be fatal; however, symptoms usually disappear once the immune complexes are cleared.
Other examples of Type II hypersensitivity diseases are occupational diseases (i.e., Farmer's Lung) in which antibody is produced to soluble environmental antigens that are encountered repeatedly. Rheumatoid factor detectable in the serum of patients with rheumatoid arthritis is an IgM anti-IgG antibody that is thought to contribute to arthritic joint inflammation, and autoantibodies produced in Systemic Lupus Erythematosis cause tissue damage. Infectious diseases with persistent pathogens, including malaria, some virus infections, leprosy, and Lyme disease, can lead to Type III hypersensitivity.
Type III hypersensitivity can be detected by immunofluorescence of tissue biopsies and precipitation of serum immune complexes (see ToolBox). Type III Hypersensitivities are treated by supportive therapy until the antigen has been cleared by the antibody, by plasmapheresis to reduce immune complex levels, and by immunosuppressive therapy.
Type IV hypersensitivity, also called delayed-type hypersensitivity (DTH) because it occurs 48-72 hours after antigen contact, is mediated by antigen-specific Th1 cells and activated macrophages. DTH responses are seen in allergic reactions to poison ivy and metals, but the same reactions occur in normal immune responses against intracellular parasites. In DTH, Th1 cells secrete chemokines to attract macrophages, IFNg to activate macrophages, TNFa and TNFb to upregulate adhesion molecules on local blood vessels, and IL-3 and GM-CSF to increase bone marrow output of monocytes. Although macrophages are not antigen specific, they are activated only in the vicinity of an antigen-activated T cell. Initial contact with antigen can produce memory Th1 lymphocytes. As in Type I hypersensitivity, the initial response is called sensitization and may not result in symptoms.
Clinical examples of DTH include local skin reactions to proteins in insect venom and injected Mycobacterial proteins used in skin testing (see below). Other Type IV Hypersensitivities include contact sensitivities to poison ivy, latex, nickel in coins and jewelry, and cleaning products which come in contact with the skin. Small non-protein antigens either penetrate the skin or are scratched into the dermis in response to itching. They form complexes with skin proteins and peptides of the altered self proteins are taken up by Langerhans cells in the skin and migrate to regional lymph nodes to become dendritic cells. DC activate Th1 cells or Tc cells and generate memory T cells that migrate to the skin. Second contact with antigen results in activation of memory T cells with IFNg and IL-17 release. In response to these cytokines, skin keratinocytes secrete IL-1, IL-6, TNFa, GM-CSF, and chemokines that attract macrophages and more T cells into the site for development of the characteristic itchy rash. Celiac disease is a type IV hypersensitivity to gliadin, a product of the storage protein gluten found in wheat, barley and oats. Hypersensitivity causes atrophy of the intestinal villi, malabsorption of nutrients, and diarrhea. Allograft rejection and graft-versus-host reactions also have elements of DTH.
DTH can be measured by skin testing, for example the TB skin test (see ToolBox). Sensitization during prior exposure to Mycobacterium tuberculosis results in production of memory Th1 cells to Mycobacterial proteins. When purified tuberculin is injected into the skin, memory Th1 cells secrete cytokines to attract macrophages and granulocytes and cause induration and erythema. A positive test indicates that there has been exposure at some time to M. tuberculosis, not necessarily that active infection currently exists. DTH is treated by antigen avoidance and by anti-inflammatory and immunosuppressive drugs.
Practice Quiz
Pick the one BEST answer for each question by clicking on the letter of the co0rrect choice.
1. Upon initial exposure to allergen, plasma cells secrete antigen-specific IgE that binds to mast cell FceRI. The mast cells are said to be
a. activated.
b. allergenic.
c. anaphylactic.
d. sensitized.
e. tolerized.
2. An immediate allergic mediator released by mast cells is
a. epinephrine.
b. IgE.
c. IL-4.
d. histamine.
e. prostaglandin.
3. Humans probably make IgE responses because
a. IgE binds more efficiently to low doses of antigen than IgG
b. IgE is protective against dangerous pollens.
c. IgE triggers eosinophils to release products toxic to helminth parasites
d. their T cells were not properly tolerized to self IgE in the thymus.
e. they cannot produce enough IgG to protect themselves against allergens.
4. All of the following are Type I hypersensitivities EXCEPT
a. an allergy to peanuts.
b. an anaphylactic reaction to bee stings.
c. a blood transfusion reaction.
d. asthma induced by cat dander.
e. hay fever.
5. Fran walks outside on a beautiful day and takes a deep breath of ragweed pollen, to which she has a strong Type I hypersensitivity. Which event below will NOT occur within 30 minutes due to this hypersensitivity?
a. A local inflammatory response in the nose is induced, resulting in a runny or stuffy nose.
b. IgE specific for ragweed pollen is synthesized by B cells in the local lymph nodes.
c. Mast cells respond to the antigen-IgE signal by releasing preformed histamine
d. Ragweed pollen antigen binds to IgE present on mast cell FceRI in the respiratory tract.
e. Systemic effects of hypersensitivity such as anaphylactic shock may occur.
6. Type II hypersensitivities involve
a. anaphylactic shock.
b. complement-mediated lysis of antibody-coated cells.
c. cytotoxic T cell mediated lysis of antibody coated cells
d. chemotaxis of eosinophils.
e. IgE-mediated degranulation of mast cells.
7. All of the following are Type II hypersensitivities EXCEPT
a. a blood transfusion reaction to AB antigens on erythrocytes.
b. autoimmune hemolytic anemia, production of autoantibodies to erythrocyte antigens.
c. drug-induced hemolytic anemia, production of antibodies to medications which can bind to erythrocytes.
d. Grave's disease, production of autoantibodies to TSH receptor on thyroid cells.
e. serum sickness, production of antibodies to passively administered foreign antibodies.
8. Type II hypersensitivity results in all of the following EXCEPT
a. attraction and activation of inflammatory cells.
b. increased vascular permeability.
c. lysis of antibody coated cells by NK cells.
d. mediator release by CTL.
e. release of cytokines by macrophages.
9. A Type III hypersensitivity reaction is mediated by
a. antibody reacting with membrane antigen epitopes.
b. autoimmune reactions to self tissue antigens.
c. complement activation by immune complexes deposited in the blood vessel walls, kidneys, and joints.
d. cytokine release by Th1 cells.
e. the cell-mediated branch of the immune system.
10. As he cleared brush near his home, Frank was bitten by a rattlesnake. He went to the emergency room for treatment with horse IgG anti-rattlesnake venom. About a week after the treatment, Frank experienced a rash, fever, swollen lymph nodes, and pains in his joints, all symptoms of serum sickness. These symptoms are probably due to
a. a T cell memory response to horse IgG.
b. cross reactivity between horse IgG and human IgG.
c. late phase damage caused by the rattlesnake venom
d. production of IgG anti-horse immunoglobulin, which triggered a Type III hypersensitivity.
e. production of IgG anti-rattlesnake venom, which triggered a Type III hypersensitivity.
11. In the situation described in Question 10 above, Frank can be treated with
a. antiserum to complement to block its activation.
b. human anti-horse IgG to more quickly clear the horse antibody.
c. immunosuppressive drugs to block B cell production of antibody.
d. plasmapheresis to remove antigen-antibody complexes from the blood.
e. rattlesnake venom to absorb the horse anti-venom antibody.
12. Type IV hypersensitivity (DTH)
a. can be passively transferred with CD4 T cells.
b. causes chicken pox.
c. involves cell damage induced by IgG antibodies which are produced late in an immune response.
d. is mediated by memory macrophages.
e. occurs 1-2 weeks after antigen exposure.
13. During Delayed Type Hypersensitivity reactions, macrophages
a. are not antigen specific.
b. are stimulated by IFNg.
c. do not depend on antibody for antigen recognition.
d. kill neighboring cells, whether infected or not.
e. all of the above are true.
14. A positive skin reaction to tuberculin means that one has
a. an active case of tuberculosis.
b. an allergy to Mycobacterium tuberculosis.
c. antibodies specific for M. tuberculosis.
d. macrophages containing M. tuberculosis in their phagolysosomes.
e. memory CD4 T cells specific for M. tuberculosis.
15. A common feature of all hypersensitivities is
a. activation of CTL.
b. activation of Th2 cells.
c. antibody synthesis.
d. inflammation.
e. all of the above.
Problems
1. Could one simultaneously develop both Type I and Type II hypersensitivities to aspirin? EXPLAIN your answer.
2. Some people are "allergic" to hot or cold temperatures; they experience swelling in their extremities or difficulty in breathing. Other people experience asthma following vigorous exercise. Can you propose a mechanism for these allergic attacks?
3. How could you modify horse anti-rattlesnake venom to prevent serum sickness if Frank (Question 10 above) is bitten again by a rattlesnake?
4. Susan, nine months pregnant with her first child, was rushed into emergency cesarean section when she began to bleed heavily about a week before her child was due. The baby girl was delivered successfully, and Susan was given a transfusion of three units of whole blood. Shortly after the third unit was transfused, Susan experienced fever, chills, nausea and hemoglobin in her urine. A quick check of the blood crossmatching showed that one unit of type AB negative blood had been given to Susan, who is type A negative. Susan was given supportive therapy and she recovered without further incident.Blood types are based on the presence of antigens on the surface of red blood cells. The A and B antigens are complex carbohydrates which are part of erythrocyte membrane glycolipids. Susan, with type A blood, has A antigen. Type B blood cells have B antigen; type AB cells have both A and B antigens; and type O blood cells have neither A nor B antigen on their surface.
The same carbohydrates as those on the A and B antigens are found on normal bacterial flora of the intestine, which colonize shortly after birth. Humans make IgM antibodies to only those bacterial antigens not shared with their own erythrocyte antigens. Susan's blood contains IgM anti-B.
Susan's daughter Sara appeared somewhat pale and her lips and fingernail beds were blue even several minutes after she was born. A blood count showed that her erythrocyte numbers were only 80% of normal; her blood type was AB positive; and her erythrocytes agglutinated with anti-human IgG. Based on these results, the pediatrician diagnosed hemolytic disease of the newborn (erythroblastosis fetalis). Sara was given supportive oxygen and an exchange transfusion of AB negative erythrocytes.
Erythrocytes have another blood typing antigen, a membrane protein called Rh (Rhesus) factor. Hemolytic disease of the newborn can occur when the mother is Rh- (her cells do not have the protein) and the baby is Rh+. If some of the baby's blood enters the mother's circulation during pregnancy, the mother can make IgG antibodies to Rh which cross the placenta and bind the baby's red blood cells, triggering their lysis and causing anemia.
Hemolytic disease of the newborn does always usually occur with first pregnancies, but with repeated exposure of the mom to fetal Rh+ erythrocytes, she produces increased levels of IgG anti-Rh. Once the pediatrician informed the obstetrician that Sara was Rh+, Susan was given an injection of Rhogam, human anti-Rh antibody, to prevent future children from being born anemic. Susan should be monitored during future pregnancies for levels of IgG anti-Rh.
What type of hypersensitivity was induced in Susan by transfusing AB blood? Why did Sara's RBC agglutinate with anti-human IgG? Why was Sara given Rh negative blood, when her own type was Rh positive? Why didn't Susan's anti-B antibodies harm Sara's red blood cells? How does Rhogam prevent Susan from making more anti-Rh antibodies? How would you test Susan for IgG anti-Rh antibodies?
