CLASS: 11:00 – 12:00 Scribe: Adam Baird
DATE: November 18, 2010 Proof:
PROFESSOR: Bucy IMMUNOPATHOLOGY I Page 7 of 7
I. IMMUNOPATHOLOGY I [S1]
a. Immunopathology encompasses the mechanisms by which an immune response causes tissue injury and how that tissue injury can then lead to disease. There are many different pathways by which this can occur.
b. Terminology and definitions:
1. “Immuno” refers to the adaptive immune system (T-cells, B-cells, etc.).
2. “Inflammation” refers to a non-antigen specific (innate) inflammatory mechanism.
c. There are three classifications that the different adaptive immune response mechanisms are categorized into. We will discuss these groups in more detail later.
II. NO TITLE [S2]
a. Prime test questions:
1. Matching up these features (namely the name of the process, how fast the response occurs, what the immune mechanism is, disease that result from these mechanisms). You need to know how everything fits together. This may show up on the test in the form of a matching question or a multiple-choice question.
III. TYPE I HYPERSENSITIVITY [S3]
a. The first category is called Type I, also known as the “anaphylactic type” or “immediate hypersensitivity”. It is immediate because a skin test response (a way to distinguish between these processes) is accomplished by putting an antigen into the skin, usually as in intradermal injection. In Type I hypersensitivity, this occurs in approximately 10 minutes. It’s considered immediate.
b. Type I hypersensitivity is understood to be synonymous with the activity of the special class of immunoglobulin, IgE (which behaves differently than the other classes of immunoglobulin).
c. IgE is cross-linked (bound) to special cell-surface receptors, called the FCε receptor, which is primarily on mast cells that surround small blood vessels.
d. The normal role of IgE is thought to be the immune defense against large parasites (like worms, for example). Many of these parasites are water-borne. The US doesn’t have many of these (because of our clean water supply), but other countries do. The normal function of IgE is not very relevant in modern medicine in the US, but it can be a nuisance.
e. The best therapy for Type I hypersensitivity is to get rid of the antigen. Symptoms can be treated, but that only have marginal effects. The antigen itself is what is causing the problem.
IV. IMMEDIATE HYPERSENSITIVITY (TYPE I) [S4]
a. When the IgE-specific antigen binds to the mast cells, it cross-links at 2 or more molecules of the IgE, which therefore drag the FCε receptors closer together on the cell surface. This interaction, then, initiates a signal cascade resulting in degranulation of the contents of the mast cells. The degranulation, in turn, results in a number of different pharmacologic activities. Very little IgE is present in the plasma or blood circulation though; all of the IgE is bound to tissue cells.
b. Like other types of immunoglobulin, IgE comes from B-cells that are induced with specific antigens and CD4 T-Cell help. IL4, in particular, is critical in this process. For example: As mice that are knocked out will have a genetically-induced mutation of IL4 genes, meaning that they can not produce any other IL4 genes, nor can they produce any more IgE.
c. The reason why certain antigens cause IgE formation (whereas other antigens don’t) is still unknown. It may have to do with the fact that some mast cells can actually produce Aisle 4, therefore driving an inflammatory response that initiates a positive feedback loop.
V. NO TITLE [S5]
a. The interaction between the IgE and mast cells primarily releases vasoactive amines (amines that affect the diameter of blood vessels, and thus blood pressure). This interaction also releases histamine as the chief pharmacological mediator in the granules of mast cells. There are many different granule contents though (like proteases, chemotactic factors, and arachidonic acids, which then give rise to leukotrienes and prostaglandins).
b. Non-steroidal anti-inflammatory agents tend to block this process. Antihistamines (like Benadryl, for example) block the action of histamine, not at the degranulation of a mast cell, but at the level that histamine interacts with its target cells.
c. Antihistamines are “less useful” though, because they also affect the CNS (causing drowsiness, for example). It cannot, therefore, be used a sufficient dose to completely overcome potentially serious Type I hypersensitivity.
VI. NO TITLE [S6]
a. If the antigen is injected into the skin (via intradermal injection), an immediate response occurs, which involves degranulation of mast cells. This, in turn, causes vascular congestion via chemoattraction of eosinophils and fluid leakage into the interstitial space (because the endothelial cells of small blood vessels open up and mucous production is stimulated).
b. This is why, if a patient has Hay Fever (which is an example of Type I hypersensitivity), their nose will clog up, they will have stimulated mucus production, and their sinuses will be swollen.
VII. NO TITLE [S7]
a. This is a dust mite.
b. The feces of the dust mite have a protein that is particularly antigenic and stimulates IgE responses.
c. Many people are “allergic to dust”, so they say, but they are actually allergic to the dust mite. It’s difficult to get rid of dust though, because dust is everywhere (carpets, pets, furniture, etc.). Ragweed antigen can set off IgE production too.
d. Antigens can be injected into the skin to observe what the patient might be sensitive to, all in hopes to inhibit the IgE response.
VIII. TYPE II HYPERSENSITIVITY [S8]
a. Type II hypersensitivity is also called the “antibody mediated cytotoxic type”. It involves two distinct mechanisms (and a third mechanism that is sometimes included in this group).
1. Ab coating of cells:
a. The antibody coats macrophages, granulocytes, and other kinds of inflammatory cells via specific FC receptors (similar to how mast cells bind to IgE). The antibody mediates phagocytosis of bacteria. So if the antibody covers the bacteria, for example, then the inflammatory cells can engulf the bacteria and digest it much more avidly than they can normally.
b. ADCC is when a coated macrophage kills a target cell based on the presence of the antibody. The antibody delivers the specificity component of the killing, but the cell mediates the actual lysis by secreting granules that destroy the target cell.
2. Ab plus complement:
a. This results in the direct lysis of cells. It is thought to occur with RBC and other similar targets.
3. Ab interaction with cell surface receptor:
a. This results in the stimulation or inhibition of the bioactivity mediated by the cell’s surface receptor.
b. It is an antibody-mediated mechanism (not of the IgE class and not of the immune complexes though) that can cause disease or other abnormalities.
IX. NO TITLE [S9]
a. The previous mechanisms are illustrated in this figure.
1. Opsonization and engulfment of a target cell based on the presence of antibody complement mediated lysis. Which involves a series of proteins that results in the lysis of the target cell as well as the activation of neutrophils and the release of their mediators.
2. Antibody-mediated cellular dysfunction is observed in two contexts:
a. Thyroid: TSH receptors
b. Grave’s Disease: Antibodies to the acetylcholine receptors (which mediates a disease called myasthenia gravis).
X. EXAMPLES OF ANTIBODY-MEDIATED DISEASES (TYPE II HYPERSENSITIVITY) [S10]
a. We won’t talk about everything on this chart, but it’s an important chart to review.
XI. TYPE III HYPERSENSITIVITY [S11]
a. Type III hypersensitivity, also known as the “immune complex type”.
b. The main idea here: antibodies interact with an antigen that is soluble.
1. The antibody-antigen complexes form and obtain a particular size and overall charge (usually multiple molecules of the antibody + multiple molecules of the antigen). The availability of the antigen and antibody determines the size of the complex. If there are more antibodies than antigens, the particles get coated with one antibody molecule per target and a complex isn’t formed (a complex wouldn’t be formed if there was more antigens than antibodies either). It’s dependent upon the correctly balanced physical ratio of the antigen and antibody. If the antibodies stick very tightly, there will likely be large complexes. If the antibodies are loose, however, the complex will likely fall apart. The disease course and characteristics, then, depends on the physical chemistry of the aggregates. Sometimes, the antibodies deposit in a particular anatomical site and the antibodies deposit in that site, causing immune complex disease (not because there are immune complexes in the blood stream or plasma, but are strictly localized in the tissue).
2. The immune complex deposition is in vessel walls and glomeruli (kidney). They can involve complement deposition and neutrophil activation.
3. A skin test of antigen peaks at about 10 hours. This particular skin test is called the Arthus reaction.
XII. NO TITLE [S12]
a. This is a picture showing the processes.
b. The antibodies and antigens are in the circulation. An antigen that is typically invoked is Hepatitis B core antigen (a chronic viral infection of the liver that doesn’t totally destroy the liver, but produced chronic levels of antigen in the blood stream). The antibodies, then, cannot clear the antigens because the liver is producing the antibodies – so the correct ratio can be maintained over an extended period of time, resulting in the accumulation of an immune complex injury.
c. The complexes will eventually precipitate into the blood vessel wall, activating complement and cells that have FC receptors. Granulocytes, then, are tricked: they think they are recognizing bacteria that are covered with antibody, but it is instead an immune complex that is deposited to another antigen.
d. Some of the cleave complement components are chemotactic (meaning that they recruit other inflammatory cells to the local site). This process continues, and hopefully the antigen goes away. However, persistent antigen concentration can lead to significant vasculitis.
XIII. IMMUNE COMPLEX DEPOSITION IN THE KIDNEY [S13]
a. They also deposit in the kidney.
b. Exactly what kind of glomerulonephritis (inflammation) is present depends on the size of the complexes. If the complexes are small, they deposit on the endothelial surface (notice the blood on the inside, urine on the outside), which will cause a specific kind of nephritis of the glomeruli (called membranous glomerulonephritis).
c. They can also deposit inside the basement membrane or on the epithelial surface.
d. Sometimes, diseases like systemic lupus (autoimmune disease where the regulation of antibody production is not functioning properly) result in antibodies multiply tissue antigens. This can lead to deposits in multiple places depending on the type of antibody involved.
f.
XIV. THE ARTHUS REACTION [S14]
a. The Arthus reactions works by the artificial injection of an antigen.
b. It takes a while for antibodies in the circulation to bind to the antigen. Once they are bound, though, it activates complement and polymorphonuclear cells, which releases chemoattractant molecules, potentially causing degranulation of mast cells and ensuing inflammatory response.
XV. NO TITLE [S15]
a. This is a picture of the Arthus reaction.
b. The skin is red because blood flow has increased.
c. There is a bump because fluid is leaking out of small vessels, leading to inflammation.
d. The complement factors (that are released by inflammatory factors) stimulate nerve ending that cause pain.
XVI. NO TITLE [S16]
a. This is a histological picture of what the Arthus reaction looks like.
b. Notice the granulocytes in the lesion (as opposed to lymphocytes and macrophages, which would be considered Type IV hypersensitivity).
c. Notice cell wall of the blood vessels. Notice that it also is filled with granulocytes.
d. Notice the muscle throughout.
e. Notice that the inflammatory lesion goes through the dermis and into the muscle.
XVII. EXAMPLES OF IMMUNE COMPLEX-MEDIATED DISEASES [S17]
a. Theses are examples of diseases that are associated with particular antigens.
XVIII. TYPE IV HYPERSENSITIVITY [S18]
a. Type IV hypersensitivity, also known as the “cell-mediated type”, is classically involved in “delayed type hypersensitivity”, which got its name from a delayed skin test, usually peaking from 24-48 hours (as opposed to 10 hours with the Arthus reaction Type III hypersensitivity or opposed to 10 minutes with Type I hypersensitivity or opposed to Type II hypersensitivity, where there isn’t a skin test involved). This delayed type hypersensitivity is now known as a response driven by CD4 T-cells as they recognize the specific antigen releasing cytokines (particularly γ-interferon and TNFα).
b. These cytokines activate endothelial cells to make them more leaky and to increase expression of adhesion molecules, so that other leukoctyes stick to the spot in the endothelium and migrate out into the tissue.
c. These cytokines also activate macrophages that come into that location. These macrophages release more cytokines and chemokines that auto-propel that lesion.
d. A pathologically distinct form of Type IV hypersensitivity is called granulomatous inflammation, in which the antigen doesn’t go away. Typically, delayed hypersensitivity goes away after 24 hours, for example, and last maybe 72 hours. The hypersensitivity stops once the antigen that has been injected gets cleared (once the macrophages digest it and make it into amino acids that are no longer stimulatory for the T-cell, then the whole response comes down). If the antigen is hard for the macrophages to digest (like fungal cell walls, for example), then the macrophages can’t completely clear the material, the T-cells continue to get stimulated though, and the process develops a particular type of morphology of a granuloma formation (which is basically an organized collection of macrophages)
e. Cytotoxic T-lymphocytes (CTL) delivers a distinct type of cell-mediated immunity, which is typically of the CD8 cell class (as opposed to CD4 cell class that is primarily responsible for DTH). The CTLs directly kill target cells that involve the T-cell antigen receptor mediated lysis at the final stage of delivering the “lethal hit”.
f. Examples: skin lesions of contact sensitivity, where T-cells mediate the lysis of individual epithelia cells that have an antigen on them.
g. NK cells activity is usually included in cell-mediated immunity. NK cells do not have a T-cell receptor or B-cell receptor immunoglobulin, but are driven by IL2 production (which is usually at a low supply in vivo. In certain types of viral responses though, NK cells may dominate in the response.