CLASS: 10:00 – 11:00
Scribe: Allison O’Brien
DATE: November 19, 2010
Proof:
PROFESSOR: R. Pat Bucy
Immunopathology II
Page 1 of 6
I.
Introduction [S1]
a. Today we are going to talk about autoimmune diseases. (Yesterday was the way that immune system causes
damage from an exogenous antigen or infection)
b. We think these diseases are due to a response to an auto-antigen (Remember that this is the definition of an
autoimmune disease-that the Antigen is an auto-antigen). However, a lot of times we don’t know what the
antigen is. How do we know its an auto-antigen? There is Circularity in the definition.
c. Best we can say is that in an autoimmune disease its the effector parts of the immune system causing the
tissue damage and that an antigen has not been identified as an infectious agent.
II. Organ Specific and Non-Organ Specific Autoimmune Diseases [S2]
a. Autoimmune diseases are divided into two categories: Organ specific and non-organ specific.
b. Lesions are either specific to one organ or found throughout.
c. Non-organ specific: Immune Complexes (Type III Hypersensitivity)-skin, joint, and kidney (particularly
glomerular nephritis) are the primary targets. Damage is done by the immune complexes. Antigen specificity
in immune complex are not particular to organs but to antigens that can be anywhere and cause immune
complexes to deposit anywhere.
d. Organ specific-a particular antigen localized to tissue type/organ. The Target of immune attack is against Ag
so the lesion is in the organ where the Antigen is.
e. Can have an overlap situation and start in the organ (specific) and then stimulate immune complex to get
whole non-specific reaction and the two happen together basically (co-incidental).
III. Breaking Tolerance [S3]
a. Tolerance is the normal mechanisms to maintain the lack of any self responses.
b. One of these is to covalently link self epitopes to immunogenic epitopes (if you modify protein with external
chemical) OR
c. Another Classical example-in thyroid disease you can immunize another species thyroid (thyroglobulin) to get
an immune response to that epitope. This occurs because of the differences in species. Because its also
linked with shared sequences (thyroglobulin has homology), you get an autoimmune response to animal’s
own thyroglobulin, but the target is the animal’s own thyroid gland. We haven’t manipulated the thyroid gland,
but Induction of an active immune response to a linked epitope causes cross-over and development of
reaction to self Ag.
d. Another principle is the Localization of a self Ag together with an immune response with strong adjuvant.
Immunization with adjuvant that has heat-killed mycobacteria in a viscous oil that holds Ag tightly in one
injection site, causes inflammatory response. Inflammatory microenvironment response to self Ag is
lessened, and you develop immune responses to self Ag, which alone wouldn’t cause autoimmune response.
Inflammatory microenvironment-you can overcome normal mechanisms that maintain unresponsiveness to
self antigens.
e. Some body compartments-eye-don’t normally have lymphocytes recirculating-like the cornea, because don’t
want blood vessels circulating because you need it to be clear. Uvea also protected. If you get injury to one
eye, autoimmune uveitis attacks injured eye and the other eye. Tolerance maintained by unavailability of self
antigen in re-sequestered compartment, release Ag that normally wasn’t present, this is enough to activate an
autoimmune response.
f. Multiple Genetic patterns of responsiveness-linked to major histocompatibiltiy complex, HLA. Control
structure, T cells control peptide Ags, causes T cell repertoire to have different structure, have a different kind
of both positive and negative selection, difference in pattern translates into some individuals might have
ankylosing spondylitis than if you don’t have HLA B 27 -100% more likely to get it. Among HLA B27+ people,
much higher incidence rate of AS, not complete penetrance of gene but they are clearly related.
g. Another example of genetic pattern=Promoter polymorphism makes macrophages 30% more responsive
given the same level of stimulus. Add different doses of LPS, bacterial endotoxin that activates TLR4, MQs
produced TNF alpha. 30% higher at the same doses for people caring particular allele of that polymorphism
at same doses. Gain is higher for pro-inflammatory cytokine, and given a stimulus more likely to develop
rheumatoid arthritis that have excess TNF alpha production. You can treat RA with TNF alpha blockers. Our
genomes are littered with different genetically polymorphisms. This is a really complex pattern of immune
regulation and modifications in any one of those different molecules might alter immune sensitivity to immune
diseases.
IV. General Scheme [S4]
a. Induction of a local immune response (might be infectious agent, drug, hypersensitivity, trauma- a number of
different things it could be) if you break mucosal barrier-infection that’s persistent, periodontal disease. Think
there might be some component of auto-antigen response as well as hypersensitivity and damage by
infectious organisms themselves. Then, based on genetic predisposition, normal immune response is
CLASS: 10:00 – 11:00
Scribe: Allison O’Brien
DATE: November 19, 2010
Proof:
PROFESSOR: R. Pat Bucy
Immunopathology II
Page 2 of 6
somehow altered, many different alteration of mechanism can take place-two factors combined can lead to
progressive immune response to an antigen.
b. Have to have genetic susceptibility as well as environmental insult not dictated by gene. Gene doesn’t directly
cause disease.
c. People can get insult or have gene but must have right combination of both to get a progressive immune
response.
d. You can get epitope spreading, both B and T cells can respond to Ags present in local environment.
e. Tissue destruction in Bile ducts caused initially by T cell infection, can get Abs to intracellular Ag that you
wouldn’t have normally and cause further destruction of bile ducts and can get new T cell responses.
f. Rumbling type of infection/hypersensitivity/overexposure of auto-ags leads to progressive tissue destruction,
loss of function of whatever target involved.
g. What this looks like is widely variable and depends on the particular organ physiology.
V. Organ Specific Autoimmune diseases [S5]
a. This slide indicates there are many organ specific autoimmune diseases that have similar characteristics.
Infection might start it and get autoimmune responses but might wax and wane periods of episodes and
recovery.
b. Some are relatively common like Type 1 insulin dependent diabetes, others are not so common like idiopathic
hypophysitis has many of same characteristics in terms of physiology.
c. Outcome of loss of function is completely different for the different target tissues.
VI. Multiple Sclerosis [S6]
a. Immune mediated destruction of myelin in the CNS.
b. Histopathology of lesion depends on stage of the lesion.
c. Acute phase can last only a month, 6 weeks, In local microenvironment the lesion resolves and results in a
scar.
d. Later on, Person might have another attack in a local spot in the brain and then it resolves.
e. Over time the person develops multiple different scars In the central nervous system that are the end result of
local inflammatory type response.
f. Evidence that Viral infections that are tropic for CNS oligodendrocytes might initiate that lesion-Some
investigators believe that it is a result of an infection not an immune defect, Simply Collateral damage (like in
leprosy) tissue damage as secondary consequence.
g. Animal model-EAE, talk about it later.
VII. Cross Sections of Spinal Cord [S7]
a. Gross photographs of spinal cord from cervical to lumbar to caudal region
b. Myelin is stained dark blue color
c. See lesion where myelin is gone, the lesion gets smaller in successive sections and then disappears
VIII. [S9]
a. This also occurs in the brain-MS plaque, name for acute lesion in brain
b. T cell infiltrate and Destruction of oligodendrocytes (make myelin to insulate nerves in CNS)
c. Lesion in different spots cause problems in different parts of body (arm numbness, bladder control loss)
d. This is by chance where it will be
IX. [S10]
a. MRI of a person with MS looks like this
b. Lesions pop up and go back down if you take them over time
c. Get more lesions than you actually have individual symptoms
d. Immune response has normal inhibitory mechanisms, also get rid of myelin in lesion area (taking away the
Ag, so immune response will also go down because of this)
X. Experimental autoimmune encephalomyelitis (EAE) [S11]
a. Occurs when you inject myelin protein and rat develops hindlimb paralysis
b. Haven’t done anything to CNS (relatively protected), if you get a strong response in lymph nodes, Tcells find
myelin in CNS
c. We don’t know the mechanism of how the Tcells find the Ag in CNS
d. Take T cells out in vitro and stimulate
e. Inject into normal animal can directly cause EAE
f. Don’t have to transfer Abs/T cells to cause exact same disease
g. Another case can transfer Abs to cause disease (passive transfer experiment)
h. Can’t do direct transfer of T cells in humans obviously
i. Pasteur used rabbit SC to do rabies vaccine, this contained a lot of myelin, people developed syndrome
similar to EAE, so not just a mouse/rat phenomenon, however not clear that this model is what MS is
XI. Mouse pic [S12]
CLASS: 10:00 – 11:00
Scribe: Allison O’Brien
DATE: November 19, 2010
Proof:
PROFESSOR: R. Pat Bucy
Immunopathology II
Page 3 of 6
a. Picture of a mouse with hindlimbs dragging because has been injected with EAE
XII. Type 1 Diabetes [S13]
a. Autoimmune disease, destruction of Beta islet cells
b. Not much islet cell mass, possible for immune response to wipe out all islets, so people could have no insulin
producing cells
c. Now we can inject insulin, but it is still hard to control the levels so people still have the disease, this still
works much better than before=death in two weeks
XIII. Islet of Langerhans [S14]
a. Pathology of pancreas of someone who has had diabetes for 20 years-no evidence of diabetes just a Lack of
islets, a little bit of fibrosis. This is because once you get rid of Ag, all that’s left is deficient function of target
tissue
b. Also evidence for tropic viral infection growing specifically in beta islet cells might initiate immune response
c. Predisposition of genetics also-MHC linkages.
d. Animal models-non-obese diabetic mouse (NOD). 10 different genes present in NOD mice separated by
breeding experiments, about 80% of animals develop lesion (insulitis) at about 12-20 weeks old and get
diabetic, hyperglycemia all the time these mice are not treated with insulin and not all islets killed but high
blood sugar levels. We think human Type 1 diabetes same process (T cells mediate islet destruction)
XIV.
Autoimmune Thyroiditis [S15]
a. Has two forms Lymphocytic thyroiditis-chronic inflammatory lesion that ends up destroying the thyroid,
difference is that thyroid follicles can regenerate and replace the function making thyroglobulin
b. Beta cells are the opposite, if they are gone=no insulin (can occur ~ 6months)
c. Thyroid gland can regenerate, so takes a long time to deplete them all to get hypothyroidism (20 years, 10
years)
d. Sometimes people get Specific Ab to TSH receptor, which is a molecule on follicle cells that makes them
respond and that controls level of growth and activity of thyroid follicular cells. When you get this Ab, turn to
be hyperthyroid. Normal mechanism TSH receptor stimulates thyroid hormone production. Unlike normal
system that has a control-Here, excess thyroid hormone feedbacks to drive thyroid to excess. Therapy is to
surgically remove thyroid.
XV. Graves’ Disease [S16]
a. Sometimes people have extraoccular eye muscle associated with Graves’ disease.
b. If you get rid of Ag can cure disease (take out thyroid, give radioactive iodine)
c. Can’t just cut out the brain in MS—but both autoimmune
XVI.
[S17]
a. photomicrograph of thyroid gland with active follicular epithelium, involutions, inflammatory infiltrate inside
XVII.
[S18]
a. Hashimoto’s disease don’t really see follicular hyperplasia
b. Struggling Follicular cells killed by inflammatory infiltrate, sometimes get germinal centers
c. All lymphocytes, looks like a lymph node, some efforts at regeneration, can result in complete destruction of
all thyroid cells
XVIII. [S19]
XIX.
[S20]
a. surgical specimen shows little lymph nodes in thyroid gland completely replacing follicle areas remaining red
meaty tissue has thyroid follicular cells still there
XX. Myasthenia Gravis [S21]
a. Neurologic disease in which there is muscle weakness, blurred vision is a symptom
b. Have to be extremely controlled nerves to muscles, can’t coordinate two eyes
c. Also get slurring of speech because tongue is also amazingly connected to your brain
d. Both require tight muscular control, don’t get muscle weakness in big muscles like hips, delicate muscles first
to go
XXI.
Myasthenia Gravis [S22]
a. Caused by Antibody developing to ACH receptor, causes it to be internalized and digested, a little bit of
receptor is put back on cell surface but have only about 10% receptors put back on and the NMJ is not
working correctly. Not complete connection between nervous impulse and muscle.
XXII. Inflammatory Bowel Disease [S23]
a. comes in two types-Crohn’s (regional enteritis)=trans mural inflammation of any part of GI tract, tends to
focus in ileum but can go in colon or esophageal lesions
b. there are so called skip lesions-inflammation in one part of SI and another part of colon but in between can
have no tissue damage at all, similar to MS lesions popping up at different places and resolve
CLASS: 10:00 – 11:00
Scribe: Allison O’Brien
DATE: November 19, 2010
Proof:
PROFESSOR: R. Pat Bucy
Immunopathology II
Page 4 of 6
c. in Crohn’s there are lesions that go through to muscle, mucosa, and serosa. You can get erosion and fistulas
that can cause problems like a fistula between intestine and bladder can occur, spillage can occur.
d. inflammation causes bloody diarrhea, lose weight etc
e. animal models of Crohn’s=IL-10 is a cytokine that inhibits MQ activation
f. counter regulatory molecule to gamma interferon, if IL-10 is knocked out, get IBS so suggests that normally
its an inhibited immune response because of normal intestinal contents
g. Ulcerative colitis is a little different-inflammation restricted to mucosa (the superficial layer=usually in colon
but involves contiguous areas of the colon, essentially one big ulcer that grows and is all connected
XXIII. [S24]
a. this is an Ulcer in crohn’s disease in a small bowel section
XXIV. [S25]
i. epithelium is completely eroded, fibrin clots, cells, fluids
ii. involves inflammation in muscle layer and serosa leads to fistula formation-treatment is to cut out those
sections of the intestine, can give immunosuppressive drugs but doesn’t prevent new lesions
XXV.
[S26]
giant cells form from lesions
XXVI. [S27]
a. linear ulcers-bear claw lesions, all parts of ulcer are topographically connected to one another
XXVII. [S28]
a. pseudopolyps-when it gets really severe
b. bumps are remaining normal intestines, shiny flat stuff is ulcer bed with fibrin coating but bacteria and
intestinal contents are leaking into tissue and a lot of inflammation associated with big ulcer
c. no Ag has been identified in either of these diseases but it has been suggested that it could be luminal
bacteria, makes an ulcer a little better but no Antibiotic treatment for Crohn’s (autoimmune)
XXVIII. [S29]
ulcerative colitis-granulocytes as opposed to lymphocytes, nothing in submucosa or muscularis
XXIX. [S30]
a. granulocytes
XXX. Rheumatoid Arthritis [S31]
a. Another autoimmune disease, chronic lesion of joints synovium
b. IgM Ab that binds to Fc region of IgG, forms in most patients but not all
c. No one has a clear idea of what Rheumatoid factor is doing
d. Never get glomerular nephritis which you expect to see
e. Immune complexes all over the place with rheumatoid factor, if you have the factor indicator, but its not clear
if this is the Ab involved in RA
f. Lesions itself is erosive lesion of cartilage and bone called pannus
g. Associated with other kinds of syndromes
XXXI. [S32]
a. Think that CD4 Tcells are involved with genetic susceptibly, mark genetically
b. Synovial lesion-not many T cells in there, anti T cell therapy doesn’t really help RA
XXXII. Rheumatoid Arthritis [S33]
a. Villus frawns; microscopically-lymphocytes and plasma cells producing rheumatoid factor and synovial lesions,
joints swell up and have to drain off the fluid, drained in order for joint to function
XXXIII. Rheumatoid Nodule [S34]
a. get necrotic center and granuloma, MQs lined up along necrotic centers. Occur around constantly traumatized
joints, elbow hip wrist-pressure points.
XXXIV. Plasma cells in Rheumatoid synovitis [S35]
a. pannus tissue -plasma cells producing Abs. Multiple myelomas with sheets of plasma cells producing Abs with
specificities we don’t know and don’t know how they relate to synovitis
XXXV. [S36]
XXXVI. Rheumatoid Arthritis [S37]
synovial layer is usually just one cell layer thick and no basement membrane merges to inflammatory tissue beneath,
severe RA-joint has been eroded and deformed, person has no good movement of their fingers-radiographs of fingers can
see little lesions and tissue is being eroded by pannus (inflammatory mass of tissue) which destroys cartilage and bone
=get trauma and leads to further inflammation and cycles on itself for years and years
XXXVII. Rheumatoid Arthritis [S38]
CLASS: 10:00 – 11:00
Scribe: Allison O’Brien
DATE: November 19, 2010
Proof:
PROFESSOR: R. Pat Bucy
Immunopathology II
Page 5 of 6
picture of where bone has been eroded by pannus tissue, now actually pretty fibrotic and not active- bone cant grow
back correctly
XXXVIII.
[39]
XXXIX. Systemic Lupus Erythematosis [S40]
a. classic systemic autoimmune disease
b. mediated by immune complex injury, DNA/anti DNA complexes are often implicated in tissue destruction
c. measure anti-DNA Abs in serum, high titer of Abs almost diagnostic of lupus
d. lesions in lupus can be many things
e. animal models where certain strains are susceptible, by genome mapping studies-there are 10-20 different
genes associated with development of lupus, and in addition genetic alleles predispose people, many have to
do with Fc receptors that control how immune complexes are handled, a mutation where Fc receptor doesn’t
cycle fast enough leads to more immune complex injury
XL. Lupus Nephritis [S41]
a. renal injury is by far the most serious of lupus injuries
b. focal proliferative glomerular nephritis, diffuse proliferative (see a lot more cells-mesangial cells proliferate),
membranous lesions
XLI.
Lupus skin lesion [S42]
a. Subendothelial immune deposits-dark stuff is immune complexes, lighter band is basement membrane,these
objects are foot process of podocyte, blood filtered across junction but if junction is destroyed have renal
failure. Treatment dialysis or transplant. granular pattern appears as lumpy immunofluroscence
XLII. Butterfly rash [S43] Ab appears to bind to BM in epithelial cells. appearance over bridge of nose and face.
Speculated because sunlight damages tissue initiates skin rash immune complex disease in this area more exposed to
irradiation.
XLII.
Overview of Immunopathology [S44]
a. organ specific-induction of local immune response coupled with malfunction regulation of immune response
and associated epitope spreading, can resolve in a lesion that burns out in that spot
b. over time, depending on how regenerative organ is tissue damage or loss of function
XLIII. Cartoon (not in slides)
Imagine a tissue that gets a viral infection. Immune response grows until it is Killing the virus faster than virus can
infect new cells. Viral infection goes down, immune response overshoots a little bit and lose Ag and then immune
response comes down. Left with more lymphocytes and more active set of lymphocytes to that Ag, that difference is
immunologic memory. Associated with this you have tissue injury both from virus and also immune system killing
those cells. Tissue injury releases auto-antigens. These auto-antigens might stimulate auto-antigen specific T cells.
Tissue injury and induction of auto-ag specific cells we have Potential for hypersensitivity-immune response directed
at. Autoimmune disease can develop as well. Normal mechanism is that tissue destruction wanes as viral wanes,
auto reactive t cells fall off so don’t cause further injury and regulatory cells inhibit response so lesion comes back to
normal. If that doesn’t induce auto reactive t cells, Acute viral infection, can all go away and is normal event. If critical
juncture could get auto reactive T cells that get new round of tissue injury, eventually this and immune response goes
down due to regulation, auto-antigens go down. Immune response comes back, tissue injury occurs, immune
response down, tissue injury down. Cycles of activity that can move around in space and time.
Another outcome, Virus can also develop a chronic infection doesn’t completely go away, immune response hovers
and damages tissues and Get auto-reactive t cells, driven by cycles of chronic low levels of infection. Happens in
hepatitis B, Get an effective immune response but can get hepatitis because your immune system kills off too many of
your liver cells-cirrhosis. Scarring locks up anatomy of liver Because of this chronic infection and the immune
response to that infection. So that process depends on biology of virus.
What controls this process? All the things we learned in immunology. Dynamics of infectious organisms matter.
Influenza grows like crazy but then can be resolved and when resolved all infection is gone. Each infection is a
complete ending episode. On the other hand, Hepatitis B almost always cause chronic infection. People with
exuberant immune response get way more damage than people with weaker immune response and letting virus just
infect the hepatocytes.
Frequency in function of autoreactive cells. Are they regulatory or destructive? All these controlled by MHC Ags that
leads to genetic predisposition of autoimmune diseases.
Also have cytokines, TNF B and IL-10 tend to lead to development of regulatory cells and inhibition of tissue injury,
fibrosis response where lesion cools down and scars up and don’t get more active inflammation.
IL-6, TNF alpha, gamma INF,IL-17 drive destruction kinds of immune response. higher or lower response of one of
these cytokines. IL-10 can be produced by many cells. How much given how much tissue injury variable. Overall
cytokine milieu cytokines control overall outcome.
CLASS: 10:00 – 11:00
Scribe: Allison O’Brien
DATE: November 19, 2010
Proof:
PROFESSOR: R. Pat Bucy
Immunopathology II
Page 6 of 6
Finally, Amount and kinetic course of auto-antigen, burn it out you can resolve the lesion. If its big say Iike in the liver,
immune system can’t kill liver all at once, the kinetic course of auto Ag may be coupled with viral antigen has
determining control feature over immune response.
Overview-immunopathology are diseases in which immune mechanisms result in tissue injury. classification can be
done based on mechanism=4 types hypersensitivity or the thinking about ag source types of antigen involved
)exogenous, infectious agents, solid organ transplants, bone marrow transplants, neoplastic cells that may have new
Ags that can cause destruction, in this case we’d rather have a stronger immune response than inhibiting. Auto-Ags
are situations where you have an immune response but you wish you could turn it off. Typically Give
immunosuppressive drugs to control that kind of response.
[End 59:19 Mins]