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Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at myphysicians.com, and another at www.afraidtoask.com.

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I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.

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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 linked below. 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.

I cannot examine every claim that my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority that seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

This site is my hobby, and I presently have no sponsor.

This page was last updated February 6, 2006.

During the ten years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

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Describe the principal cells of the immune system, where they are found, and what we think they do. Identify CD4, CD8, CD6. Explain the CD4+/CD8+ ratio, especially as it applies to the historic test for AIDS. Identify interleukin 1, interleukin 2, tumor necrosis factor, lymphotoxin, and interferons.

Identify the five classes of antibodies, and tell what we know they do. List some helpful, some useless, and some harmful antibodies that our immune systems can make. Tell what complement is and what we know it does. Tell 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)

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

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

Autoimmune gastritis
Hashimoto's thyroiditis


Antibody-mediated dysfunction ("Type V immune injury")

circulating anticoagulants
classic pernicious anemia
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)
polyarteritis nodosa secondary to hepatitis B infection

Type IV (delayed hypersensitivity, + non-antibody-mediated)

tuberculin skin test
nickel skin allergy
multiple sclerosis
juvenile-onset diabetes mellitus
"anergy"

Recognize each of the following using the microscope:

eosinophils, plasma cells, basophils, lymphocytes
vasculitis (with and without fibrinoid)
granulomas and their epithelioid cells

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."

QUIZBANK

Immunopathology (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")


• 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.

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)

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.

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
CD4 -- marker for cells such as helpers, which recognize class II MHC antigens
CD8 -- marker for cells such as killers, which recognize class I MHC antigens.
CD28 -- co-receptor that must be stimulated when the TCR is stimulated, or else the T-cell becomes anergic or apoptotic

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.

* Misleading statement in Big Robbins -- we often do not see germinal centers in the spleen, especially in older folks.

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

B-cells have surface immunoglobulin, F_c receptors, C3b receptors, and * CD40 (which we'll meet again).

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. (* Special stains are available that use the OKT system of monoclonal antibodies.)

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.).

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), express CD6 (OKT1), 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.

{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.

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.

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. (* There are lymphokine reviews by the dozens. How B-cells and T-cells communicate with each other: Nature 367: 425, 1994, still good; lots more.)

Interleukin 1: a "monokine" 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. IL-1 reviews: Blood 87: 2095, 1996; Blood 88: 2465, 1996.

* Interleukin-1 receptor antagonist (IL-1RA) is yet another molecule in your internal milieu. It is still search of a disease for which it's the magic bullet (Postgrad. Med. 106: 82, 1999).

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" ("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 presently 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). 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 currently standard 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., bad 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. It is now 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.

Tumor necrosis factors: 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 -- "the Schwartzman reaction" -- to the Herxheimer response (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 is three 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.

Lately we've discovered that 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 (* ahh--CHOO!)

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 gets allergic to ascaris worm once they have met 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.

"Allergy freaks" (like 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).

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 dubious significance is found in mast cell granules.

The acute phase is done in 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 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 a bit of toluidine blue.

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). The locus is the cryopyrin / Muckle-Wells gene CIAS1 (Am. J. Hum. Genet. 71: 198, 2002). Treating the severe form with interluekin-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). Very often, it's an autoimmune disease caused by antibodies against Fc episilon RI and/or IgE (J. Allerg. Clin. Imm. 110: 492, 2002 and below)

Cholinergic urticaria is the little red 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.

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 setting is 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).

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).

* A new study finds that 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 "pop" claim that pertussis immunization in infancy exacerbates allergy later simply isn't true (forced huge, long study: Br. Med. J. 328: 925, 2004).

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 receiptor (Fc[epsilon]RI) on their surfaces (J. Allerg. Clin. Imm. 112: 411, 2003).