Fundamentals 2: 11:00 - 12:00 Scribe: Molly Clark

Fundamentals 2: 11:00 - 12:00 Scribe: Molly Clark

Monday, October 19, 2009 Proof: Melissa Precise

Dr. Bucy ImmunoPathology I Page 8 of 8

I.  ImmunoPathology I [S1]:

a.  I’m going to talk about immunopathology or how the immune system, which you’ve already heard about, can cause disease. And I’ll talk to you this morning and then again tomorrow morning about that.

II.  No Title – Summary Chart [S2]

a.  One of the ways to organize this very large body information is to focus on the immune mechanism involved, and there are classically four different types of so-called “hypersensitivity.”

b.  And this kind of material is sort of an ideal test or board question kind of thing, in which different characteristics of these four different types of immune response would be matched and other kinds of things with the diseases or the mechanism or other features. So this is just a summary. You have it on your computers, and I’m going to move on and sort of go through each one of those different features.

III.  Type I Hypersensitivity [S3]

a.  Type I hypersensitivity is also called immediate type or anaphylactic type hypersensitivity. And the reason they’re called immediate is, if one puts an antigen in the skin, you get a dermal response that in type I is called a wheel and flare, and that develops in about ten minutes. So that’s immediately after you put the antigen on.

b.  The mechanism of type I hypersensitivity is due to the properties of IgE antibody, a special class of immunoglobulin. And briefly the mechanism is that IgE is formed, attaches to an Fc receptor on a mast cell, and if the antigen comes along, the Fc receptors are cross-linked, and you get release of the mast cell contents which causes a syndrome called anaphylaxis, which can either occur locally or systemically if it occurs in a broad enough distribution.

IV.  Immediate Hypersensitivity (Type I) [S4]

a.  So the formation of IgE is still not completely clear. It’s a different kind of response both from the T cell and the B cell standpoint.

b.  Mice that lack the ability or have a knockout of IL4 can’t make any IgE, and therefore that TH2 type response is thought to be important in the switching of the B cell that would normally be making IgG into one that makes IgE.

c.  Once a plasma cell or an antibody-producing cell that makes an allergen specific antibody is formed, then it circulates and binds to mast cells. When the allergen or antigen binds to the mast cell, it cross-links the Fc receptor that the Ig is bound to and you get effects on a number of other tissues via the soluble small molecules that are in the granules.

V.  No Title - Diagram of Immediate and Late Phase Responses [S5]

a.  Chief among these small molecules is histamine, which you’ve all heard of because of the drugs antihistamines that block the effect of histamine. For instance of the nose, if you take medicine that blocks histamine, that’s blocking the final stage in the pathway which IgE cross linking produces symptoms. It doesn’t however do anything about the production of IgE or the presence of the antigen that causes the cross-links.

b.  There are a number of other mediators in the mast cell including proteases and chemotractic factors. And you can get inflammation if that occurs over a long period of time, and you can get late phase responses including leukocyte infiltration, epithelial damage, and importantly, in a disease called asthma you can have broncho-spasms that are due to the production of these kind of mediators.

VI.  No Title – Graph of Immediate and Late Phase Responses [S6]

a.  So as I mentioned, the peak of the immediate type hypersensitivity is in ten minutes or so, and histologically that’s characterized by mast cell degranulation.

b.  The mast cells normally sit around small vessels and therefore are ideally placed to mediate changes, particularly edema because the endothelial cells separate, and fluid can get into the interstitial space.

VII.  No Title – Picture of Dust Mite [S7]

a.  This is a picture of the dust mite, and the feces of the dust mite are a common allergen that people in places in inner cities and a lot of children that come in the hospital chronically are allergic to a protein in the feces of dust mites.

b.  Trying to get rid of dust to prevent allergies is a difficult task, but it works if you can do it and is much better than chronic drug treatment for things like asthma.

i.  So the quick lesson that that ended is that, if you can get rid of the antigen, that’s sort of the preferred way to inhibit an immune response different from a response to inhibit immune responses that are causing symptoms are much more problematic.

I.  Type II Hypersensitivity [S8]

a.  Type II Hypersensitivity is also called antibody mediated cytotoxic type, and it basically involves two different kinds of mechanisms.

i.  One is that antibodies can coat cells, or if the cell is a bacteria that would be called opsonization that you’ve probably heard about in your microbiology classes. And then other effector cells, the myeloid lineage particularly, can engulf and phagocytose the antibody-coated cells. And phagocytosis is much more efficient if there are Fc receptors of antibodies decorating around the cell. And also NK cells and other T cells can mediate a process called antibody dependent cellular cytotoxicity (ADCC) in which the antibody causes cross-linking of receptors on the surface of the cell, and that delivers a cytotoxic signal to the target cell.

ii.  In addition you can have antibody and complement mediated lysis of cells, which generally does not occur that much in solid tissues, but for things like red blood cells, where antibodies might coat a red cell, that kind of complement mediated lysis can be an important contributor to the destruction of red cells in anemia.

iii.  You can also have antibodies that interact with the cell surface receptor. And although they don’t cause cytotoxicity, they can either activate or inhibit bioactivities.

II.  No Title – Diagram showing phagocytosis, inflammation, and dysfunction [S9]

a.  So this is a little cartoon of that in which the formation of the antibody primarily targets the phagocytic cell to the target cell. You get, engulf and then adapt to the target cell.

b.  Antibody and complement. Six complement at the terminal parts of that protein cascade drill little holes in the cell surface, and the cell dies by necrosis as opposed to apoptosis, which occurs in CTL activity or ADCC.

c.  And then finally this is a picture of a situation in Graves’ disease, or in myasthenia gravis, which I’ll talk about tomorrow.

III.  Examples of Antibody-Mediated Diseases (Type II Hypersensitivity) [S10]

a.  So these are some of the diseases that have been associated with type II hypersensitivity, and I won’t go through these in further detail. But you can look in your notes and on the transcript to have an idea that these kinds of diseases can be mediated by antibodies targeting different sites.

IV.  Type III Hypersensitivity [S11]

a.  Type III hypersensitivity is basically mediated by immune complexes. And the key point is that the antibody in an immune complex does not target tissues based on the specificity of the antibody.

i.  In type II hypersensitivity, if it were a red cell, then red cells would be targeted. If you have a thyroid cell, then the thyroid cell would be targeted.

ii.  In type III hypersensitivity you get a complex that can be soluble between an antigen and an antibody, and you get a large aggregate of those complexes. And then it’s the physical chemistry of those complexes where they deposit essentially a sort of precipitate out of solution in the interstitial fluid and the blood. And it’s where those complexes deposit, which may have no relationship to the production of antigen or the production of antibody, its just those soluble complexes deposit there, and that is particularly frequent in the vessel walls in the glomeruli of the kidney. Once they deposit, the phagocytic and inflammatory cells essentially see the Fc receptor portions of those complexes, think that that’s a bacterium that’s coated with antibodies, and then release mediators, attempt to phagocytose that material and otherwise cause inflammation in that site, and that produces symptoms and tissue damage.

V.  No Title – Diagram of 3 Phases of Type III Hypersensitivity [S12]

a.  The skin test for type III hypersensitivity is call the Arthus reaction, and it occurs in about ten hours.

b.  So in this case you get antibody production that happens by sort of an independent set of mechanisms. You have the presence of free antigen in the circulation, and that happens by a number of different mechanisms.

i.  The classic one for and a way in which this type of hypersensitivity worked out was that they used to give horse antibodies to people that got a tetanus infection. And they would develop an antibody to the horse antibody after a week or ten days, and some patients had an acute so called serum sickness syndrome. Serum being the horse antibody. And that was caused by immune complexes between the patient’s antibody or the host antibody and the injected foreign protein. So once that clears, if you don’t have a source of the foreign protein continuing then the symptoms go away in this kind of situation.

ii.  On the other hand if you have an antigen like hepatitis B surface antigen, which is continually produced in the liver by people that are infected with that virus, then you can have ongoing low levels and immune complex deposition, and you get a disease called glomerulonephritis.

iii.  In other situations cells might be continually dying and release DNA, and you can have DNA and immune complexes formed, and that causes deposition.

c.  So these immune complexes can deposit in vessel walls or in the glomerulus, and then those in the complexes activate a number of different effector mechanisms that cause injury to the site of deposition, and then a wound healing kind of process is scarring and proliferation of fibroblasts and so forth.

VI.  Immune Complex Deposition in the Kidney [S13]

a.  When they deposit in the glomerulus, the structure of the glomerulus determines basically where different size deposits go.

i.  Large complexes deposit on the endothelial or blood side of the glomerulus.

ii.  Intermediates ones can deposit right on the basement membrane

iii.  Smaller ones can sort of sieve through the basement membrane, but still deposit on the epithelial side of the glomerulus.

b.  This space (middle area at bottom of diagram) would be going down the nephron, ultimately producing the urine from the kidney. So this is sort of like the filter for large molecules that are in the blood. If you have inflammatory debris essentially in the blood then the filter is where that debris collects if you look at it simplistically.

VII.  The Arthus Reaction [S14]

a.  This is a diagram that shows the Arthus reaction. In this case, rather than a virus producing it or something, this is a test situation that injects the antigen in the skin. If you already have the right titer of antibody, then you can get the activation of complement and chemotactic factors that can activate mast cell degranulation and cause the other downstream effects.

VIII. No Title – Picture of the Arthus Reaction [S15]

a.  This is a picture of what the Arthus reaction looks like in a person’s arm where you injected a small amount of antigen in the dermis. It gets red, swells up, is painful depending on how much antigen or how much antibody, and it resolves over a period in another set of hours.

IX.  No Title – Histology Picture of Arthus Reaction [S16]

a.  Histologically, the key thing about an Arthus reaction is that the cells that infiltrate the site are acute inflammatory cells, granulocytes primarily.

b.  So that’s in contrast to type IV that I’ll mention in a second. But if you get a question or see polymorphonuclear cells in the lesion of an antigen test on the skin, that’s the tipoff that this is a type III process.

X.  Examples of Immune Complex-Mediated Diseases [S17]

a.  So there are a number of diseases.

i.  Systemic lupus is when you have nuclear antigens or other autoantigens that form, and you get immune complexes.

ii.  Poststreptococcal glomerulonephritis is an infection that the antibodies to the infectious agent are what form and deposit in the kidney.

iii.  You can have a disease called polyarteritis nodosa that causes systemic vasculitis. One of the antigens that have been associated with polyarteritis is Hepatitis B viral antigen, but there are also others.

XI.  Type IV Hypersensitivity [S18]

a.  So type IV hypersensitivity is also called cell-mediated hypersensitivity. And it basically is in distinction to the first 3 types that are mediated by antibodies. And one can distinguish various mechanisms of antibody formation or antibody effector activity into those three types.

b.  Type IV basically just lumps all the other kinds of effector activities into one category, however there are further subdivisions.