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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

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Review the major players in the immune system, both cellular and humoral. Be sure you can explain what a hapten is.

For each of the following, describe the essential mechanism and mention some real-life illustrations: Type I, Type II, Type III, and Type IV hypersensitivity injury.

Briefly describe each of the following:

Type I (immediate, anaphylactic)

common hay fever / asthma
urticaria
systemic anaphylaxis
food allergy

Type II (fixed antigens)

Complement-mediated

ABO-mismatched transfusion reaction
Rh-mismatched delayed transfusion reaction
Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Goodpasture's disease of the lung and kidney
Pemphigus family of skin diseases
Hyperacute and acute transplant rejection (also some type III)

Cell-mediated ("antibody-dependent cell-mediated cytotoxicity")

Autoimmune gastritis
Hashimoto's thyroiditis
juvenile-onset diabetes mellitus
Lots more


Antibody-mediated dysfunction

circulating anticoagulants
excitatory and inhibitory antibodies (Graves', many others)

Type III (immune complex disease; soluble antigens)

Arthus reaction -- serum sickness
aches and pains of the "'flu"
Immune-complex induced thrombocytopenia (AIDS, idiopathic)
vasculitis (hepatitis B, rheumatoid arthritis)

Type IV (delayed hypersensitivity, generally without antibody involvement)

tuberculin skin test
nickel skin allergy
acute cellular transplant rejection
graft-versus-host diseases
"anergy" (explain the idea)

Describe and recognize the various anatomic signs of transplant rejection and graft versus host disease.

Critique the following statement, overheard at a party: "By strengthening our immune system, we prevent or cure most diseases. We strengthen our immune system by nutritional supplements and mental imagery to reduce stress."

Immune Disease Iowa Virtual Microscopy Have fun

Immune Pathology Photos, explanations, and quiz Indiana U.

QUIZBANK

Immuno (all; this covers these 4 lectures)
Metabolic (amyloid) #'s 93-111
Clinical immunology lab (all)

LEARN FIRST: TYPES OF IMMUNE INJURY ("HYPERSENSITIVITY")

Okay. These divisions are artificial.

Type I... Havoc resulting from IgE and mast-cell degranulation

Type II... Antibodies bind to cells. This can cause

• cell death by complement fixation or phagocytosis


• cell death by subsequent T-cell attack ("antibody-dependent cell-mediated cytotoxicity" -- generally classed as type II nowadays)


• dysfunction without destruction of cells
Disease caused by autoantibodies against circulating molecules such as clotting factors belong here.

Type III... Antigen-antibody complexes ("immune complexes") precipitate and cause the damage

Type IV... Havoc wrought by specifically-sensitized T-cells without involvement of antibodies. This includes...

CLASSIC DELAYED HYPERSENSITIVITY, in which the harm is done primarily by recruited macrophages and innocent bystander cells are also massacred. No antibody is involved.

ANTIBODY-INDEPENDENT CELL-MEDIATED CYTOTOXICITY, in which individual cells are assassinated ("apoptosis") by T-CTL lymphocytes, without harm to innocent bystanders. This term is still in some use.

This covers such things as metal jewelry allergy and poison ivy.

Exactly which illnesses generally believed to be T-cell initiated will end up in this category remains speculative.

No one uses the term for such illnesses as most viral hepatitis, in which most of the damage is done by T-cells removing infected cells.

* You may hear the term "Type V" hypersensitivity either for diseases in which autoantibodies stimulate a receptor, or when antibodies against a receptor trigger cell mediated immunity. I suggest you not use this term.

HAPTENS are atoms or small molecules that elicit an immune response when, and only when, they are bound to a larger carrier molecule, generally a protein. The body's rejection of the hapten-protein adduct does the damage. Some famous examples are:

• nickel binding to keratin on the skin ("nickel allergy" in those wearing jewelry)
• the wax from poison ivy binding to skin proteins
• penicillin binding to red blood cell surfaces, causing autoimmune hemolysis

Many (maybe most) really surprising, rare idiosyncratic drug reactions involve the drug acting as a hapten.

CELLS OF THE IMMUNE SYSTEM

{14252} lymphocytes {14720} lymphocyte {14716} lymphocyte, large (i.e., a little bit turned-on) {14718} lymphocyte, small (i.e., resting) {16197} lymphocyte, small {26001} lymphocytes in sputum {26226} lymphocyte and neutrophil {39919} lymphocytes (there's also a nice plasma cell right at the center)

Osmosis Jones

Overview of the immune system: Origins, molecular biology, basic components, with nice pictures and articles Sci. Am. Sept. 1993. Evolution of the vertebrate system: Proc. Nat. Acad. Sci. 91: 10769, 1994. Immunity in drosophila is quite different, and is just now being unravelled.

* Click here for a video-game in which you are the immune system fighting pseudomonas bacteria.

T-LYMPHOCYTES (T-cells):

A versatile family of cells that have passed through the thymus (and been acted on by the hormone thymosin) during early biological life.

T-cells are the center-piece of the immune system. T-cells of various sorts are predominant throughout the lymph nodes except in and around germinal centers. They also make up most of the white pulp of the spleen, and occupy the thymus gland. Around 80% of circulating lymphocytes are T-cells.

Young T-cells differentiate into many subtypes, which act as regulators and effectors.

Each T-cell acquires its specificity, which it transmits to its descendants, by recombination of its TCR gene before birth.

These rearrangements tell that a cell is a T-cell. When a group of cells all have the same rearrangement, it's clonal (i.e., neoplastic).
T-cell markers:

CD3 -- joins with the TCR surface molecule, but is not rearranged. General T-cell marker.
CD4 -- helper cell marker
CD8 -- killer cell marker (cytoyltic T's, natural killers)
CD28 -- TCR co-receptor, marker for T-cells


T-helper cells (T_H-cells) activate B- and other T-cells

Many subclasses exist to do different things. You'll learn about them in "Immunology".

Worth remembering: T_H1's produce IL-2 and INF-gamma and act on macrophages; T_H2's produce IL-4 and IL-5 and work on the eosinophils.

T-cytolytic (T-CTL-cells, T-killer cells) cells attach to and kill (apoptosis) cells bearing whatever antigen against which they are specifically programmed and sensitized. These cells may be T4+ or T8+.

After a T-cell has responded to a particular antigen and proliferated, some members of the clone survive and thus the response to the antigen is stronger next time it is encountered ("clonal expansion").

B-LYMPHOCYTES (B-cells):

Another class of lymphocytes, which when activated produce freely circulating immunoglobulins ("antibodies", "gamma globulins", "humoral immunity").

Antibodies coat harmful foreign particles, and bind to foreign molecules.

Sometimes this helps (pneumococcal pneumonia, measles, hepatitis B).

Sometimes it doesn't seem to help (AIDS, many other infections, cancer).

Sometimes it hurts (ragweed allergy, autoimmune hemolytic anemia, systemic lupus, pernicious anemia, and every other type I, type II, and type III hypersensitivity disease).

B-cells predominate in the follicles (germinal centers) of the lymph nodes and are more common than T-cells in the red pulp of the spleen and in the bone marrow.

In the germinal centers, antigen-antibody complexes are presented to baby B-cells by the dendritic follicular cells (seen 'em?); the ones that match the antigen best are caused to divide and mature (Nature 367: 425, 1994). These will be the ones that make IgG.

Around 15% of circulating lymphocytes in the peripheral blood are B-cells.

B-cells have surface immunoglobulin, which is how we usually spot them.

There are a host of other markers that recoginze B-cells in various stages of differentiation. Don't worry about these.

B-cell activation is partially understood.

Before birth, each B-cell gets its immunoglobulin gene rearranged to recognize a particular antigen. The antibody that the B-cell will make is displayed on its surface, with its business end pointing straight outward.

As with T-cells, rearrangement of these identity genes is a marker for B-cell lineage, and if all the cells have identical rearrangements, it indicates clonality (i.e., neoplasia).

If and when this antigen comes along, it triggers the B-cell, which starts dividing (under the modulation of T-cells, of course).

After assuming a variety of curious shapes (look at the cells within a germinal center), most of the original B-cell's progeny become a "selected clone" of plasma cells pumping out specific antibody.

{46429} plasma cell, electron micrograph

When the immune system wins, the plasma cells mostly die, but plenty of the original B-cell's clones survive and "remember". Next time the antigen comes along, the antibody response will be much greater ("anamnestic response", i.e., "we haven't forgotten").

Remember: you can't tell resting B-cells from resting T-cells by their morphology.

NATURAL KILLER LYMPHOCYTES:

"Natural killer lymphocytes" (NK-cells) are bigger than other lymphocytes, and have cytoplasmic granules (i.e., you can pick them out on a smear; they make up around 10% of the circulating cells).

They attack and cause apoptosis in cells with altered class I MCH antigens, without being "specially sensitized".

The cells trigger the fas ligand.

The granules, which are injected into the target cell, contain perforin and granzyme, along with other stuff (* TIA-1 etc.).

CD57 -- cytotoxic natural killers


MONONUCLEAR PHAGOCYTES

This is all of the "reticuloendothelial system", found throughout the body. Probably this is the oldest component of the immune system.

The familiar wandering macrophages and microglia are monocytes from the peripheral blood that have entered the tissues. (Same cell, different names.)

Fixed phagocytes (the rest of the "mononuclear phagocytic system") line the vascular channels of the body. They, too, were once circulating monocytes.

A special subclass of mononuclear phagocytes, the "dendritic" and "Langerhans'" cells (together, "the accessory cells", etc.), seem to be the best antigen processors and the poorest effector phagocytes. They have special surface antigens (Ia -- Immune activation antigens coded by HLA genes) and have other special features.

Mononuclear phagocytes are essential to immune responses.

The "accessory cells" ("dendritic" and "Langerhans'") apparently phagocytize antigens, process them (into "epitopes"), attach them to Ia antigens, and present them to lymphocytes to begin the immune response.

Busy macrophages modulate the activities of other cells by secreting soluble factors such as interleukin 1 and TNF-alpha (see above), as well as some complement components (supplementing the bulk, which come from the liver).

In addition, macrophages are effector cells when summoned by T-cells or activated complement. They devour and sometimes digest harmful things, and can become epithelioid cells of granulomas to wall off other bad things.

They have receptors for the F_c portion of IgG and for various complement components.

The milieu of sex hormones has a host of effects on immune function, and you will be completely mystified if you try to sort through even a few papers. If you are going to approach this subject at all, you may enjoy J. Leuk. Bio. 75: 1166, 2004 and J. Imm. 175: 5716, 2005, both first-authored by our own Chad Lambert '09.

We stain for common macrophages using CD68. We stain for antigen-presenters with CD1a.

{08230} macrophage containing leishmania (Baghdad boil)

MAST CELLS AND BASOPHILS

These cells are rich in vasoactive (and other) substances. In addition to the familiar histamine (right away) and leukotrienes (after a while), remember endothelium relaxing factor and neutrophil chemotactic factor.

When mast cells are activated (usually by something reacting with the IgE that covers their surfaces), the substances are released (histamine right away, leukotrienes over a few hours). These have a variety of effects on blood vessels, smooth muscle, gastric parietal cells, etc.

* In 1989, at a scientific meeting, the author got into it with French biochemist Jacques Benveniste, who claimed to have demonstrated an effect of homeopathic-type dilutions on basophil degranulation. Dr. Benveniste showed a phase contrast photo that the author believed was a neutrophil, and called it a degranulated basophil. Dr. Benveniste graciously acknowledged that making the distinction was difficult. I believe he is sincere, if perhaps wrong. For more on Dr. Benveniste, see Skeptical Inquirer 22(1): 19, Jan-Feb 1998.

{09205} mast cell granules (electron micrograph)
{13733} mast cells
{14539} mast cells (purple ones) and fibroblasts
{14542} mast cell degranulating
{15117} mast cell city!
{46472} mast cell, electron micrograph, intact
{46473} mast cell, electron micrograph, degranulating

NEUTROPHILS: You are already familiar with these important commando cells. They continue to surprise -- one recent review is Chest 134: 606, 2008.

Polys elaborate at least 50 distinct destructive substances. Remember that, while they fight infection, neutrophils also do tremendous damage to the body itself.

In the common (1/2000 people) "chronic granulomatous disease", the neutrophils cannot produce peroxide to kill staphylococci, so the epithelioid macrophages must take over (hence the name of the disease).

EOSINOPHILS: Review in J. Allerg. Clin. Immuno. 105: 651, 2000.

{09207} eosinophil granules
{14099} eosinophils
{14708} eosinophil

IMMUNOGLOBULINS and COMPLEMENT should be familiar to you. For a pathologist's perspective on complement today, see Am. J. Path. 171: 715, 2008.

IgM (our most important macroglobulin) molecules are large pentamers, tend to be cold-reactive, appear early during the humoral immune response, and can fix complement when just one molecule binds to something. IgG molecules are usually monomers, tend to be warm-reactive, appear later during humoral response, include some classes that can fix complement when two or more molecules find to something, and comes from B-cells clones with good memories. IgA molecules tend to be found on mucosal surfaces and in mothers' milk. IgD is a receptor on a B-cell, and its significance in the circulating blood remains obscure. IgE sticks by its F_c portion to basophils and mast cells, ready to tell them to degranulate.

Idiotypes are the specific recognition sequences that make a particular antibody unique. Watch for "anti-idiotype" molecules as an up-and-coming way of modulating the immune system (and evidence that it's one way in which we modulate our own system. Note that an anti-idiotype antibody is likely to resemble the antigen, since both bind to the same location.)

The complement cascade, when activated, increases vascular permeability, summons polys and monos, and punches holes in membranes. All chordates have complement.

CYTOKINES

Immune cells send messages by cytokines (formerly called "lymphokines"), and receive similar messages from other cells. Over a dozen of these "biologic response modifiers" are well-characterized, and several are now undergoing clinical trials.

INTERLEUKIN 1: two "monokines" produced in bulk by macrophages that are phagocytizing or hurting, this substance causes T-cells to multiply. It also causes the acute-phase reaction (* with interleukin 6 and TNF; you will learn about the acute phase reaction later), acts on the brain to cause fever and fatigue (etc., key paper Science 240: 321, 1988), causes catabolism of muscle in acute illness, recruits macrophages for granuloma formation, and is largely responsible for the increase in circulating neutrophils.

* Interleukin-1 receptor antagonist (IL-1RA; "anakinra" etc.) is yet another molecule in your internal milieu. For years these notes mentioned that this is a molecule in search of a disease for which it's the magic bullet. Today, the rare "neonatal-onset multisystem inflammatory disease", with a lack of cryopyrin (CIAS1 locus), is more mangeable with anakinra (NEJM 355: 581, 2006); it's also proved useful in refractory rheumatoid arthritis.

INTERLEUKIN 2 (IL-2, "T-cell growth factor"): a lymphokine from activated T4⁺ cells that promotes the division of other T-cells.

This -- with or without killer cells -- is a perennial experimental cancer therapy. It causes severe fatigue and insanity.... (horror stories Ann. Int. Med. 107: 293, 1987), and old reports that it was extremely elevated in the controversial "chronic fatigue syndrome" ("myalgic encephalomyelitis"; "Yuppie 'flu", Ann. Int. Med. 110: 321, 1989) have failed to find additional support; this claim (and others about cytokines, in chronic fatigue syndrome and in fibromyalgia) have failed by today's tests (J. Clin. Immuno. 19: 414, 1999; Clin. Exp. Imm. 132: 360, 2003). Whether there is some more subtle disturbance remains unknown -- I still suspect there is.

Its use in treating kidney cancer is still controversial: Science 255: 528, 1992. Possibly the archaic bacterially-derived "Coley's toxins" worked against cancer by making the body produce interleukins (Nature 357: 11, 1992).

IL-2 receptor levels, from breakdown of T cells, lets you know level of activity of immune disease.

* They are sometimes used to follow the therapy of various granulomatous diseases (Chest 99: 268, 1991).

The interleukin 2 receptor is now the target for a variety of therapeutic monoclonal antibodies, including daclizumab ("Zenapax", now in use for multiple sclerosis, psoriasis, ulcerative colitis, and other illnesses)

INTERLEUKIN 5 is the great mobilizer of eosinophils: NEJM 324: 1110, 1991 (still good). It is blocked by meprolizumab, which has shown great promise in managing eosinophil-related diseases such as severe asthma (NEJM 360: 973, 2009).

INTERLEUKIN 8 is chemotactic for neutrophils. We'll meet both of these throughout the "Pathology" lecture sequence.

INTERFERONS: a class of substances, some produced by T-cells, which "interfere with viruses" and have a huge variety of other activities.

ALPHA (alfa) INTERFERON (* many subtypes exist) is a good therapy for hairy-cell leukemia, chronic hepatitis B and C, essential thrombocythemia, laryngeal warts, chronic granulocytic leukemia (nobody knows how this works), and "chronic granulomatous disease" (i.e., weak polys). Successes against cancer have been less impressive, though it's helped some melanoma patients. Administration causes a 'flu-like syndrome; it also acts on the brain, causing severe fatigue and/or even insanity.

BETA INTERFERON is the old name for B-cell stimulating factor, which turns B-cells into plasma cells. Two forms are in use (IFBeta-1a and IFBeta-1b), an important part of the treatment of multiple sclerosis.

GAMMA INTERFERON seems to be the principal substance that makes macrophages angry and form granulomas, and the substance that causes macrophages to express Ia antigens. Clinical uses now include leprosy, leishmaniasis, atypical mycobacteria, and stubborn venereal warts. It can be administered by vein (the 'flu-like syndrome it produces is mild), or inhaled for lung disease.

Someday we may inhibit interferon-gamma in order to prevent intestinal adhesions after surgery (perhaps using hepatocyte growth factor: Nat. Med. 14: 437, 2008).

TUMOR NECROSIS FACTOR: a "monokine" ("tumor necrosis factor alpha", "cachectin", now usually called simply "tumor necrosis factor" or "TNF") and a closely-related "lymphokine" (tumor necrosis factor beta", now usually called simply "lymphotoxin"), tandem homologous gene products that mediate a wide range of tissue injuries.

* This was a hot topic especially in the 1990's. Everything from endotoxic shock and "the Schwartzman reaction" (an old experimentalist's disease model with two doses of endotoxin, the second proving fatal -- historic interst) to the Herxheimer response (sickness after syphilis treatment due to the dead spirochetes -- NEJM 335: 311, 1996) to Waterhouse-Friderichsen syndrome to extreme over-activation of arachidonate metabolite systems to cachexia of cancer and AIDS is attributed to these substances. Key review NEJM 316: 379, 1987; still good. TNF causes emaciation by blocking adipocyte lipoprotein lipase -- does anyone want to try it for dieters?

* It's been known for over a decade that TNF also participates in granuloma formation, probably acting as an autocrine factor (Cell 56: 731, 1989, Clin. Imm. Imm. 51: 419, 1989). TNF is able to generate granulomas in the absence of any lymphocytes (Nature 356: 604, 1992), contradicting classic assumptions ("All granulomas are held together by gamma interferon"), and explaining why AIDS patients can still make reasonable granulomas.

Thalidomide selectively inhibits alpha-TNF production (Proc. Nat. Acad. Sci. 90: 5974, 1993 was key) and is finding uses in clinical medicine (sarcoidosis, inflammatory bowel disease, ankylosing spondylitis, Behcet's, recalcitrant aphthae in AIDS, even congestive heart failure).

* In the mid-1990's, a group of clinicians tried to help septic shock patients by removing tumor necrosis factor using antibodies. This didn't help, and seems to have killed a bunch of people, probably by a type III immune mechanism: NEJM 334: 1697, 1996.

TNF receptors are a story in themselves, and include the apoptosis equipment (no surprise): NEJM 334: 1717, 1996. One of the great success stories of today's medicine is administration of recombinant TNF receptors to soak up TNF itself in various diseases.

* "TRAPS" (TNF-receptor-associated periodic syndrome) is an episodic fever syndrome caused by a mutation in the TNF receptor (Medicine 81: 349, 2002).

TRANSFORMING GROWTH FACTOR BETA exists as isoforms that apparently turn down most aspects of chronic inflammation. Mice born without the first isoform die young of widespread chronic inflammation (Proc. Nat. Acad. Sci. 90: 770, 1993).

The CHEMOKINES bring in and (sometimes) activate specific subsets of white cells, etc., etc. Lancet 349, 1997.

Simply injecting the DNA for a particular protein into muscle or dermis commonly results in B-cell and T-cell immunity to that protein (Proc. Nat. Acad. Sci. 91: 9519, 1994). This is now a BIG deal, especially for vaccines.

TYPE I IMMUNE INJURY IN HUMAN DISEASE

Type I hypersensitivity ("anaphylactic" or "immediate hypersensitivity") is the result of antigen binding to IgE on the surface of mast cells and basophils. These instantly degranulate and release active substances into the surrounding tissue.

The reaction begins within seconds to minutes following antigen exposure, and is over within a few hours.

IgE protects us against worms. (Almost everyone becomes allergic to ascaris worm once they meet it.) The idea that type I hypersensitivity was created to help protect us from worms has found good experimental support: Nature 349: 243, 1991.

* IgE production is of course orchestrated by T-helper and T-suppressor cells that specialize in just this.

* A few unusual types of IgG attached to mast cells can do exactly the same thing that IgE does.

Some people make IgE much more readily than others, and these are the people with allergies ("atopic disease").

"Atopy" means "strange". It's strange that some, but not all, people get asthma from something as trivial as cat dander.

Many "allergy freaks" (and therefore perhaps the author of these notes) express IgE receptor (Fc[epsilon]RI) on the antigen-presenting cells. Despite "Big Robbins", this does seem to be holding up (J. Clin. Inv. 111: 1047, 2003; J. Imm. 171: 6458, 2004). In asthmatics: J. Allerg. Clin. Immuno 112: 1132, 2003. A pathway to mucus metaplasia / asthma by this route after viral infection: J. Exp. Med. 204: 2759, 2007.

Once induced (by one or more encounters with the antigen, or "allergen"), IgE binds to the mast cells and basophils. The person is now allergic to the particular "allergen".

It will get worse every time the allergen is encountered, and if the allergen is carefully avoided, the allergy will become less severe.

The mast cell mediators cause a reaction that would help expel a worm (itching, sneezing, coughing, vomiting, diarrhea). Type I allergic responses to harmless allergens range from annoying to fatal.

Histamine from mast cells makes vessels leaky, causes bronchial smooth muscle to constrict, and causes the gastric parietal cells to churn out acid.

Thus, depending on the location of the degranulating mast cells, the patient gets irritation (itching), tissue edema (soft tissue swelling, sniffling, sneezing, maybe diarrhea, even pulmonary edema), starts wheezing, and gets "sick to the stomach" (histamine mediates acid secretion in the stomach).

Mast cells also release "eosinophil chemotactic factor of anaphylaxis" (which summons the eosinophils characteristic of allergy and worm infestation), and neutrophil chemotactic factor (perhaps to eat the suspected worm).

* And plenty of other stuff of uncertain significance is found in mast cell granules.

The acute phase is done in maybe an hour, and the LATE PHASE may then begin, with infiltration of the tissues by B and T cells and eosinophils.

LEUKOTRIENES (C₄, D₄, E₄) mediate much of this. They are arachidonic acid metabolites, the old "slow reacting substances of anaphylaxis". They are not released from mast cell granules, but synthesized for the occasion after the cell has degranulated. Leukotrienes (NEJM 357: 1841, 2007) are responsible for some of the allergic wheezing, etc., that does not respond to antihistamines. Today's avant-garde anti-allergy drugs target leukotrienes and their receptors.

* Prostaglandin D₂ and "platelet activating factor" are two other made-to-order mediators.

* Also watch mast cell tryptase. It's the most abundant substance in mast cell granules, and must be there for a reason.

Future pathologists: You can just barely distinguish mast cells in a standard H&E preparation, but you can see them easily if you use add bit of toluidine blue, which stains the granules a deep purple.

Local anaphylaxis: more often a nuisance than a real danger

Urticaria ("hives"): analogous to the wheal-and-flare effect of histamine in acute inflammation. Red, itchy swellings of the skin that blanch easily on pressure.

{09716} urticaria
{09719} urticaria
{09720} urticaria; this is a variant with pressure-sensitive mast cells ("dermographism")
{12238} urticaria
{12240} urticaria
{25474} urticaria

An itchy mosquito bite is an example of localized urticaria.

In COLD URTICARIA, lowering the temperature causes mast cells to degranulate. The mechanism is obscure. (No one knows exactly what the basis is; these people usually have other IgE-mediated allergies. These patients can die instantly when they jump into cold water.)

* There's a familial syndrome in which the cold produces not urticaria, but a maculopapular rash caused by lymphocyte and macrophage infiltration). Again, the locus is the cryopyrin / Muckle-Wells gene CIAS1 (Am. J. Hum. Genet. 71: 198, 2002). Treating the severe form with interleukin-1 receptor antagonist: NEJM 348: 2583, 2003.

Finding the allergen in CHRONIC URTICARIA may require an elimination diet. Today's thinking is that food is rarely a cause (Pediatrics 111: 1617, 2003 -- remember it's often a problem in atopic dermatitis). It is now clear that in around 40% of cases, chronic urticaria is an autoimmune disease caused by antibodies against the alpha subunit of the high-affinity IgE receptor and/or IgE (J. Allerg. Clin. Imm. 110: 492, 2002; J. Allerg. Clin. Imm. 117: 1430, 2006 and below).

* Especially in patients with chronic urticaria who also get sick from aspirin, the IgE receptor promotor is often mutated (J. Allerg. Clin. Imm. 119: 449, 2007).

* Autoimmune chronic urticaria responds to omalizumab (J. Alleg. Clin. Immuno. 122: 569, 2008).

* Sulfasalazine for chronic idiopathic urticaria: Arch. Derm. 142: 1337, 2006.

CHOLINERGIC URTICARIA is the little red heat-induced blotchies that some folks get in a hot shower or on exercising. They start on the chest and spread, and may be accompanied by parasympathetic stuff. Long a minor mystery of medicine, it's now clear that the real cause is obstruction of the outlet of the sweat ducts, especially when sweating occurs infrequently (Dermatology 204: 173, 2002).

Angioedema: similar to urticaria, but a whole organ is involved. (When it's the tongue or larynx, the patient is in serious trouble.) It often results from C1-esterase inhibitor deficiency. Review Am. J. Med. 119: 267, 2006.

* In patients with the classic hereditary disease, C4 will be low (why?); when acquired due to an autoantibody against C1-INH, C1q will be low (Mayo Clin. Proc. 81: 958, 2006).

* Injectible C1-INH is available for crises. You remember that C1-esterase inhibitor is the principal brakes on the kallikrein-kinin pathway. An synthetic kallikrein inhibitor is now available and seems to help (J. Allerg. Clin. Imm. 120: 416, 2007).

* You'll learn other causes of angioedema on rotations. When there's no concurrent urticaria, think of a reaction to ACE-inhibitors, autoimmunity, or allergy to food or drugs (CMAJ 175: 1065, 2006).

Allergic rhinitis ("hay fever"): sneezing and itchy conjunctiva due to exposure to airborne allergens (pollens, mold spores, house dust, mites, animal dander)

Allergic ("extrinsic") bronchial asthma: bronchoconstriction following inhalation of an allergen.

Generalized ("systemic") anaphylaxis: a life-threatening emergency in which seconds count. Review: Am. Fam. Phys. 68: 1325, 2003.

The commonest clinical settings are penicillin injection, insect stings, and certain "notorious" food allergies.

Three out of every 10,000 patients that get a penicillin injection have anaphylaxis, 10% of these people die from it. You have been warned.

Laryngeal edema
Anaphylaxis
WebPath photo


One of the situations in which allergy shots work is for allergy to insect stings (NEJM 351: 668, 2004). Today, asthma and hay fever are being treated by sublingual allergens (Chest 133: 589, 2008; NEJM 358: 2259, 2008; Chest 133: 599, 2008; the first extract licensed in the US is for grasses but the Europeans have been using a wide variety for some time).

Some anaphylaxis is "idiopathic" and recurrent. This can kill you.

The entire vascular bed opens and leaks, causing blood pressure to drop catastrophically ("anaphylactic shock").

If the patient survives this, all the small airways clamp shut ("bronchospasm", hard to treat effectively).

The mainstay of treatment is epinephrine. Follow-up is a warning bracelet and an anaphylaxis kit!

Food allergies really exist and can cause any form of localized or generalized type I hypersensitivity.

Really severe reactions are known to occur to tiny doses of eggs (my late mother was like that), various nuts (Br. Med. J. 300: 1377 & 1378, 1990; Br. Med. J. 312: 1050, 1996), sesame seeds, shellfish, and fish. Yes, people do die of these (NEJM 327: 374, 380 & 424, 1992) -- an update finds in the USA alone, there are 30,000 anaphylactic reactions, 2000 hospital admissions, and 200 deaths yearly (Lancet 371: 1538, 2008).

* Will it hold up? Having had a peanut-oil-based salve applied to a baby's rash increases risk of subsequent peanut allergy about sevenfold (NEJM 348: 977, 2003). Stay tuned.

Common allergies to wheat and cow's milk are less severe and unlikely to kill.

Food allergy review: JAMA 278: 1888, 1997. The "green" claim that genetically altered foods will be allergenic is an obvious disinformation campaign (common sense, and J. Allerg. Clin. Imm. 107: 765, 2001).

* Do not confuse IgE-mediated hypersensitivity to wheat or milk with gluten enteropathy, galactosemia, or lactose intolerance.

Chocolate, strawberries (* Shakespeare's Richard III), and codeine release histamine non-immunologically in everyone. (Some get it worse than others, and are "allergic").

* In the 1980's, cow's milk was blamed by some people for most diseases and behavior problems of young children. This goofy fad has pretty much died down.

* Conversely, many inexperienced physicians do not believe in food allergy. (Many food allergies are imaginary, and adults usually have enough sense to avoid foods that make them sick.)

A claim that pertussis immunization in infancy exacerbates allergy later simply isn't true (anti-immunization militants forced a huge, long study: Br. Med. J. 328: 925, 2004).

Since nobody really knows how to diagnose food allergy (i.e., it's based on history; skin testing and food-specific Ig# are so-so), and nobody knows how to treat it (i.e., nobody complies with an elimination diet), food allergy remains mosr of a mystery that other illnesses (JAMA 303: 1848, 2010).

Hypersensitivity as a cause of "functional" or "idiopathic" illness:

Atopic dermatitis ("eczema"), is a common skin disease that occurs in people who have other allergies. The current literature will leave you wondering whether food allergy is usually the underlying cause, or whether it's essentially a genetic disease, with out-of-synch mediators. And it's hard to decide, since there's no obvious link, and nobody's going to comply with an elimination diet because the disease usually responds nicely to today's topical glucocorticoids.

Thinking about atopic dermatitis has been revolutionized during the past few years by the discovery that in these patients, the dendritic macrophages express IgE receptor (Fc[epsilon]RI) on their surfaces (J. Allerg. Clin. Imm. 112: 411, 2003).