Allergies

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

An allergy is a harmful immune response elicited by an antigen that is not itself intrinsically harmful.

• 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.

Four different immune mechanisms can result in allergic responses.

1. Immediate Hypersensitivities.

These occur quickly after exposure to the allergen. They are usually mediated by antibodies of the IgE class.

• hay fever
• hives
• asthma

2. Antibody-Mediated Cytotoxicity

Cell damage caused by antibodies directed against cell surface antigens. Hence a form of autoimmunity.

• Hemolytic disease of the newborn (Rh disease).
• Myasthenia gravis (MG)

3. Immune Complex Disorders

• Serum sickness
• Systemic lupus erythematosus (SLE)

4. Cell-Mediated Hypersensitivities

• 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.

• 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.

• 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 [Further discussion of asthma];
• 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. [Discussion]

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.

• 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 described below). In the example shown here, the antigen was 0.1 µg of protein from guinea pig hair. In some patients, a response can be elicited by as little as 0.1 ng of allergen. (Image reprinted, with permission, from B. D. Davis et al., Microbiology, 3rd ed., Harper & Row, 1980.)

Systemic Anaphylaxis

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 U. S. 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.

An example of systemic anaphylaxis

Desensitization

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.

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.

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

Antibody-Mediated Cytotoxicity

• 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). [More]
• Goodpasture's Syndrome

• 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)

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) and
• 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. J. 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))

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

Serum Sickness

Irregular, lumpy deposits of immune complexes (antigen + antibody + complement components) in a glomerulus. (Courtesy of Dr. Frank J. Dixon.)

• fever
• hives
• arthritis and
• protein in the urine.

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).

• bind to Hageman factor — one (XII) of the blood clotting factors [Link]. 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.

Systemic Lupus Erythematosus (SLE)

• 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.)

"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

Extrinsic Antigens

• 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

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

Type 1 diabetes mellitus

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)

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.

• the TNF receptor fused to
• the constant region of human IgG1

Patients with RA also develop antibodies (mostly IgM) against their IgG antibodies. The binding of these "rheumatoid factors" to IgG creates immune complexes, so RA is also an immune complex disorder.

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 3:1 for multiple sclerosis. Men and women are equally susceptible to Type 1 diabetes.

Why?

The answer is unclear, but hormones are probably involved.

• 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.

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

Why?

• 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.

Another Example

It has been recognized for some time that the incidence of asthma in European children raised on farms is substantially lower than in those children raised in an urban environment.

In the August 4, 2016 issue of The New England Journal of Medicine, Stein, et. al. provide clues to this phenomenon. They studied 30 children raised on Amish farms (where the incidence of childhood asthma is very low) to 30 children on Hutterite farms where the incidence of asthma is similar to that in children not raised on farms. Both the Amish and Hutterites came to the United States from the same area of Europe, have avoided breeding outside the group, and thus have very similar genomes.

However, their farming methods are quite different . The Amish live on small farms with horses, cows, etc. in close proximity. The Hutterites farm large communal tracts using motorized equipment.