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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.

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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.

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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.

Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!

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Describe some theoretical mechanisms of autoimmune disease. Give examples of known or suspected triggers for autoimmune disease.

List the common autoimmune diseases -- both those included in this lecture, and related disorders.

Give the predisposing factors, typical symptoms, signs, laboratory findings (especially autoantibodies), and pathologic anatomy for each of the following:

systemic lupus
discoid lupus
drug induced lupus
Sjogren's syndrome
progressive systemic sclerosis (scleroderma)
polymyositis-dermatomyositis
fibromyalgia syndrome ("fibrositis" -- not an autoimmune disease)
graft vs. host disease

Give the distinguishing features for each of the following:

CREST syndrome (anti-centromere disease)
mixed connective tissue disease (anti-ribonucleoprotein disease)

Recognize the following using the microscope:

acanthosis
parakeratosis
keratin plugs
hydropic change of basal cells
lupus dermal inflammatory infiltrate
Sjogren's changes in salivary gland
scleroderma skin changes
intimal proliferation ("onion-skinning") in the renal arteries
rheumatoid nodule (characteristic features)
polymyositis

Recognize lupus as today's "great imposter", and keep a high index of suspicion for all the common autoimmune diseases.

Autoimmunity From Chile In Spanish

Immune System Mark W. Braun, M.D. Photomicrographs

Immunopathology Great pathology images Indiana Med School

INTRODUCTION TO AUTOIMMUNE DISEASE

Autoimmune disease in humans can involve any of the types of "immunologic injury". (Type I injury is rare.)

The mechanisms of autoimmunity remain speculative, despite the elaborate discussion in "Big Robbins". Review: Nat. Med. 7: 899, 2001. Yet another: Nat. Med. 8: 899, 2002. To begin with, nobody really understands why our immune system doesn't attack ourselves more often. You'll hear about clonal deletion, clonal anergy, and suppression of autoreactive clones (by such things as anti-idiotype networks, etc.)

Whatever the "cause" of autoimmunity, infectious agents may be involved as triggers. For example:

Coxsackie B virus apparently shares an antigen with myocardium, and infection with this virus can trigger a lethal myocarditis ("Barney Clark's disease", etc.)

Measles virus shares an antigen with T-cells, and people with measles have greatly diminished T-cell function (anergy).

The Lyme bacillus flagellum protein ("flagellin") is a mimic for axon protein, and one of the most dread effects of Lyme infection is toxicity to the nerves; despite a decade of discussion, whether this is clinically important remains unsettled (Infect. Immun. 65: 1722, 1997). An outer surface protein is a mimic for one of the HLA types that, when present, results in Lyme patients developing an arthritis that does not resolve after the micro-organisms are killed (J. Immuno. 166: 5286, 2001).

Beta-hemolytic streptococci share an antigen with myocardium (causes the myocarditis of rheumatic fever) and basal ganglia ("St. Vitus Dance", "Sydenham's chorea", PANDAS -- "pediatric acquired neurotic disorder after strep").

* During the 1990's, several gram-negative bacilli were "usual suspects" in autoimmune disease. Again, the area's hard to study; the one link that seems to be holding up is klebsiella and ankylosing spondylitis. The molecular biology of gram-negative bacterial-induced molecular mimicry: Nat. Med. 6: 215, 2000.

* Molecular mimicry probably causes the production of the autoantibodies that cause Guillain-Barre syndrome (Neurology 54: 1453, 2000; Lancet 352: 635, 1998; Neurology 57: 736, 2001).

* Molecular mimicry is the cause of post-herpes corneal interstitial inflammation in mice (Science 279: 1344, 1998).

* Beçet's (aphthous-style ulcers in the mouth, maybe genitals, elsewhere, plus maybe vasculitis-thrombosis, plus maybe iridocyclitis) seems to be caused by T-cell autoimmunity / molecular mimicry against the heat-shock proteins (Lancet 347: 789, 1996; Lancet 350: 28, 1997).

AIDS virus infection can simulate (trigger?) lupus, rheumatoid arthritis, Sjogren's, or polymyositis-dermatomyositis.

Other triggers are also becoming apparent.

Thymomas express something very much like acetyl choline receptor, thereby triggering myasthenia gravis (Lancet 339: 707, 1992). Oat cell carcinoma (a lung cancer that simulates nerve cells in several respects) is notorious for exciting autoantibodies against cerebellum, retina, synapse, and/or amygdala. Stay tuned for more of these.

Foreign materials may alter the body enough that it begins attacking itself. Decide for yourself whether breast implants ever cause lupus and scleroderma (I'm unimpressed). But it's generally accepted that there's a link between coal and rock dust exposure and several autoimmune diseases ("Caplan's").

More generally, since the autoimmune diseases exacerbate and remit (until fibrosis / gliosis dominate the picture, of course), it's easy to believe that they result from modulation problems within complex feedback networks.

In Sjogren's, insulin-dependent diabetes, and some other autoimmune diseases of glands, part of the pathogenesis seems to be inappropriate expression of HLA-D (i.e., class II) proteins on the target organ's cells. More about this later. Apoptosis in peripheral lymphocytes is faulty in human lupus, and the mysteries are being unravelled. Br. J. Rheum. 36:158, 1997.

Even more curious, the T-cells of lupus patients evidently attack monocytes and cause them to undergo apoptosis, both providing more antigen and failing to clear apoptotic debris (J. Immunol. 167: 5963, 2001; J. Immunol. 169: 6020, 2002; Arth. Rheum. 46: 191, 2002).

It's hard to study, but I've been able to find nothing at all published recently to support the "pop" notion that emotional stress precipitates autoimmune disease.

* If you are very interested in the molecular basis of the immunogen-toleragen seesaw, check out Lancet 357: 2115, 2001.

Rules that almost always work:

Autoimmune diseases typically are linked to particular Class I (A, B, or C) or Class II (D) HLA antigens, but not both. Those linked to particular class I antigens (i.e., ankylosing spondylitis, Reiter's syndrome, common psoriasis) are more common in men, while those linked to class II antigens (the rest of the autoimmune diseases) show a slight to striking female preponderance. (Type I diabetes favors neither males nor females.) Patients inherit the same HLA antigens as many of their healthy counterparts.

"Because they reflect deviations in complex control networks", the autoimmune diseases are diseases of exacerbations and remissions.

Monozygotic twins of patients are at increased risk, but it is never >30% (i.e., the risk is greatest with juvenile onset diabetes).

Selection of T-cells after antigenic stimulation has been studied in identical twins; if both are sick with a particular T-cell mediated disease, the clones they select tend to be identical; if only one is sick, responses tend to be different. (See Nature 364: 243, 1993.)

Siblings not inheriting the same HLA's that are linked to the immune disease are still at slightly increased risk.

The systemic autoimmune diseases are a family of chronic illnesses of generally unknown etiology. Their older name, "the collagen vascular diseases", is meaningless today. Except for DM-PM and the enthesopathies, all are more common in women.

They include systemic lupus, rheumatoid arthritis, juvenile rheumatoid arthritis, the enthesopathies (probably), scleroderma, DM-PM, Sjogren's syndrome, rheumatic fever, variants of all these, and overlap syndromes. (* We will save some of them for later.)

Each shows some familial tendency but no clear-cut pattern of inheritance.

There is a link between HLA antigens and various autoimmune diseases. The strongest link is between HLA-B27 and spondylitis. * For USMLE I and clerkships, remember B8 (autoimmune diseases of various glands), D2/D3 (lupus), and D4 (rheumatoid arthritis).

Remember that all these diseases are likely to overlap, and that each is probably a syndrome with several possible causes.

"Lupoid chronic-active hepatitis" (several types) and "primary biliary cirrhosis" overlap with this family also, and may be seen with any "systemic autoimmune disease".

The autoimmune diseases all involve abnormal cellular proliferations (lymphocytes in systemic lupus, synovial lining cells in rheumatoid arthritis, fibroblasts in scleroderma and primary biliary cirrhosis, etc.)

Remember also that many apparently healthy people, especially older people, have autoantibodies in relatively high titers.

The most curious new approach to treating autoimmune disease is by feeding the autoantigen.

I am not making this up. The First Americans fed poison ivy to their babies, imparting a tolerance to the rhus hapten. The mechanisms (then and now) include suppression of immunity by TH2 cells, and depletion/anergy of TH1 cells.

Feeding a peptide that mimics myelin basic protein is now a mainstay of the management of multiple sclerosis. Stay tuned for more amazing successes.

In the future, watch for autologous hemopoietic stem-cell transplantation as therapy for refractory autoimmune disease (Lancet 353: 550, 1999).

* Here are the famous HLA linkages for diseases. This information is not very useful clinically, but has a way of popping up on exams (though not mine).

B8 & DR3

autoimmune Addisonism myasthenia gravis Sjogren's

B27

ankylosing spondylitis Reiter's syndrome enteropathic arthropathy autoimmune uveitis

B35

DeQuervain's

B38

psoriatic arthritis

B51

Beçet's

B47

21-hydroxylase deficiency (gene is in the allele)

Cw6

common psoriasis

DR2

Goodpasture's multiple sclerosis

DR3

celiac sprue / dermatitis herpetiformis lupoid hepatitis lupus (weak)

DR3, DR4

autoimmune diabetes

DR4

pemphigus rheumatoid arthritis

DR5

autoimmune pernicious anemia Hashimoto's autoimmune thyroiditis

THE AUTOANTIBODIES (Am. J. Med. 100(2A): 16S, 1996)

When you order an "ANA" ("anti-nuclear antibodies") screen, the patient's serum will be placed on some mammalian cells and counterstained to stain green any patient antibodies that may have stuck.

The pattern may give you a hint of which antibody is present! (With today's newer tests, these don't work so well as they once did.)

RIM PATTERN

Probably anti-dsDNA. Your patient probably has systemic lupus.

HOMOGENEOUS PATTERN

Probably anti-histones. Your patient probably has drug-induced lupus.

SPECKLED PATTERN

Could be anti-Sm and/or anti-Ro/SSA and/or anti-La/SSB and/or anti-U1RNP and/or any of several others. You'll certainly want to continue your workup!

CENTROMERE PATTERN

An especially fine speckling with little background staining. This is anti-centromere, the marker for CREST / pulmonary hypertension.

NUCLEOLAR PATTERN

anti-Th or anti-fibrillarin / anti-U3RNP or anti-U17RNP. Think of scleroderma, though most scleroderma patients don't show the nucleolar pattern.

Notice the titer. If it's 1:40 or less, it probably means nothing. If it's 1:160 or more, your patient probably has something going on.

You can also order these tests for individual autoantibodies.

anti-dsDNA

Anti-double stranded DNA. A misnomer, of course. Your patient has systemic lupus. About half of lupus patients have these antibodies.

anti-ssDNA

Anti-single stranded DNA. Think of drug-induced lupus.

anti-histone

Think of drug-induced lupus.

anti-Sm

Anti-Smith. Your patient has systemic lupus. About a third of lupus patients have these antibodies.

anti-Ro/SSA

Lupus, Sjogren's, neonatal lupus, or some mix of these.

anti-La/SSB

Lupus, Sjogren's, or some mix of these

anti-U1RNP

Anti-ribonucleoprotein. When this is the main autoantibody, your patient has mixed connective tissue disease.

Anti-Scl70

Anti-topoisomerase. Your patient has the bad kind of scleroderma. A large minority of people with the bad kind of scleroderma have this autoantibody.

Anti-centromere

Very sensitive and very specific for CREST, the limited scleroderma variant.

Anti-Jo

Antibody against transfer-RNA synthetase. Your patient probably has polymyositis / dermatomyositis. About half of PMDM patients have this autoantibody.

In the future, watch for cheap autoantibody assays to screen for impending (a few years) disease. Anti-citrulline to predict who's going to get rheumatoid arthritis: Lancet 363: 1544, 2004. Autoantibodies in lupus are there years before symptoms: NEJM 349: 1499 & 1526, 2003.

You probably realize that the immune system is a chaotic system, with tiny tweaks able to cause large changes. For example, in lupus there are antibodies that bind antibodies that bind antibodies ("idiotype network": Nat. Med. 10: 17, 2004).

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE, "the red wolf"; NIH review Ann. Int. Med. 123: 42, 1995; Med. Clin. N.A. 81: 113, 1997).

Lupus From Chile In Spanish

Lupus Text and pictures From "Big Robbins"

Pathology of Lupus WebPath Tutorial

{08403} lupus immune complexes (green) trapped in the glomerulus
{28142} discoid lupus on the face (what features do you see?)

Lupus is a common, dread, remitting and relapsing illness defined by clinical criteria that you will learn on Internal Medicine. (You can find them in Arthr. Rheumatol. 25: 1271, 1982 or in "Big Robbins".)

Lupus usually manifests as arthritis, skin changes, kidney damage, inflamed serosal membranes, fever, and mental changes. Most lupus victims look healthy, but they are very sick.

Lupus is mostly a disease of young women, though no one is immune; it is slightly more common in blacks. At least one woman in 1000 in the US and worldwide has overt lupus. (* The pediatric disease is essentially the same as the adult form: Pediatrics 83: 325, 1989).

* The biopsychosocial impact of lupus: Arthr. Rheumatol. 27: 13, 1984; J. Rheumatol. 13: 570, 1986. Probably little has changed.

Lupus is a disease of many curious autoantibodies directed against antigens that are common to most or all cells.

The etiology is unknown and surely differs from case to case.

* There is much discussion nowadays, but little hard evidence, of defective clearance of apoptotic cells as "the cause of lupus" (Rheum. Dis. Clin. N.A. 26: 215, 2000; Arth. Rheum. 46: 191, 2002; Arth. Rheum. 48: 2888, 2003). This fits with the photosensitivity (why?), and might explain the lupus-like syndrome in complement component deficiencies (uh, maybe these are required to clear apoptotic bodies). However, excessive numbers or appearances of apoptotic bodies themselves is not seen in lupus under the microscope.

* Alfalfa, which contains L-canavanine, a bizarre amino acid, causes lupus in monkeys and sometimes in humans.

* For the molecular biology of the principal lupus autoantigens, see Arthr. Rheumatol. 29: 457, 1986. These include nucleosomes (by far the most important -- J. Immuno 174: 3326, 2005) and the cytoplasmic Ro antigens; the mechanisms of immune activation appear to be novel for lupus (J. Clin. Invest. 115: 407, 2005).

An environmental agent may contribute. One group claims that dogs belonging to lupus patients are more likely than others to have autoantibodies (Lancet 339: 1378, 1992).

Which autoantibodies are harmful, and how they do their damage, is not always clear.

Most lupus patients make antibodies against their own DNA (mega-review NEJM 338: 1359, 1998). Double-stranded DNA ("native-DNA", * "peripheral" or "rim pattern antibodies") gets trapped in the glomeruli, where it complexes with anti-nDNA (see J. Rheumatol. 13: 512, 1986). The complexes cause damage by a Type III mechanism. (Of course, anti-nuclear antibodies of any sort should be harmless to living cells.)

Other anti-nuclear antibodies are responsible for the "hematoxylin bodies" seen occasionally in tissues, and for the "LE cell phenomenon".

Hematoxylin bodies, pathognomonic of lupus, are altered remnants of nuclei. (* You will not be expected to recognize hematoxylin bodies.)

The LE body is a white blood cell nucleus that has been stripped of its cytoplasm during the phlebotomy, homogenized and opsonized by anti-nuclear antibodies (* typically anti-histone H1: Arth. Rheum. 41: 1446, 1998), and then eaten by a poly or mono. The cell that has eaten the LE body is then called the "LE cell".

LE cell
WebPath photo