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218 Cards in this Set
- Front
- Back
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What is a hypersensitivity disease?
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When normal immune mechanisms are directed against inocuous agents
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What are some possible consequences of hypersensitivty disease?
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Tissue injury and serious disease
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What is type I hypersensitivity characterized by?
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Sensitization and IgE production
-It is immediate and associated with allergic responses |
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What is type II hypersensitivity?
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Antibody Dependent Cell dependent Cytotoxicity
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What is type II hypersensitivity mediated by?
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IgM and IgG
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What are type II hypersensitivity reactions responsive to?
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Cytoplasmic or cell surface antigens
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What is type III hypersensitivity?
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Immune complex mediated
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What is type III hypersensitivity mediated by?
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Soluble antigen
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What is type IV hypersensitivity?
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Delayed type
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What is type IV, delayed type hypersensitvity mediated by?
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T-Cells
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What is the most common type of misdirected response of the immune system?
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Type I hypersensivity (allergic reactions)
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When would someone exhibit an allergic response?
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Only after re-exposure to the antigen causing the hypersensitive response
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Where are the IgE antibodies found that mediate the type I hypersensitivity reaction?
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Tissue mast cells
Circulating basophils |
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What happens upon binding of IgE to allergen?
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-Cross-linking of Abs and a change in conformation of the receptor, resulting in the release of inflammatory mediators
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What types of effects can these inflammatory mediators have?
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Local or systemic
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What are some examples of mediators released in a type I hypersensitvity response?
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LTC4, PGD2, LTB4, PAF, IL3/4/5/6, GM-CSF, Eotaxin, Histamine, Serotonin
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What is systemic anaphylaxis?
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Allergic reaction to medication
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What is acute urticaria?
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Hives- caused by allergic reaction to animals
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What is allergic rhinitis?
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Hayfever- allergic to pollen
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What can stimulate asthma?
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allergies to pets/pollen
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What types of antigens cause IgM or IgG production in type II ADCC hypersensitivity?
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-Intrinsic
-Extrinsic |
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What are the intrinsic antigens that cause ADCC?
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Normal self antigens, due to a failure in immune tolerance
or due to cross reactivity of a foreign antigen with a cell surface self molecule on the surface of the host cell |
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What are the extrinsic antigens that cause ADCC?
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They are absorbed at the host's cell surfaces, for instance penicillin at the surface of RBCs
-The drug serves as a target for anti-drug antibodies, that in turn causes destruction of the cell |
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In both cases what happens once the antibodies bind to the surface of cells?
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-Opsonization
-Complement activation -ADCC (NK cells) -Activation or blockage of important cell receptors |
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How would hemolytic anemia result in type II hypersensitvity?
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Macrophages will phagocytose the RBCs that have antibodies on their cell surface
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How does ADCC via NK cells work in type II hypersensitvity?
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-NK cells attach to the Fc portion of the Abs, and it releases perforins and granzymes leading to apoptosis
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What is Myastenia Gravis?
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Antibodies against acetyl choline receptors are produced at the neuromuscular junction, resulting in a disease where you have progressive muscular weakness
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What are some diseases mediated by ADCC?
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ABO and Rb group incompatibilities and autoimmune disorders such as:
-Idiopathic thrombocytopenic purpura -Myasthenia gravis -Goodpasture's -Graves |
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What is Goodpasture's disease?
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Kidneys are attacked by the immune system
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What is Graves disease?
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Thyroid is attacked by the immune system
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How do immune complexes form in Type III hypersensitvity?
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An immune complex forms when antigen-antibody complexes form due to antigen excess
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How does immune complex formation differ in normal physiological situations and in type III hypersensitivity?
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In type III hypersensivity, the body has trouble clearing away the immune complexes and they deposit in various regions
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What are some areas in the body that are susceptible to immune complex deposition?
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Skin, Kidney, Joints
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How do immune complexes cause problems?
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They lodge into capillaries resulting in activation of complement
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What are some possible consequences of this activation of complement in type III hypersensitvity?
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-MAC lysis
-Aggregation of platelets -Recruitment of neutrophils -Massive inflammation (depending on where complexes deposit) |
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What is the Arthus reaction?
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A local reaction in which a soluble antigen is injected subcutaneously and for which the host has significant antibody titre
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What is serum sickness?
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When horse Abs were used for immunization, the host developed antibodies againt these horse Abs. Then, when the person was given more horse Abs, this "antigen" caused immune complex deposition
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What can serum sickness lead to?
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Chills, fever, rash, arthritis, and sometimes glomerulonephritis
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What are some other diseases that can result from immune complex deposition?
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-Immune complex glomerulonephritis
-Extrinsic allergic alveolitis |
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What is a classical type IV reaction?
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Tuberculin test to determine previous exposure to M. tuberculosis
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What is the name of this Tuberculin test?
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Purified protein derivative (PDD) test
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What happens during this Tuberculin test?
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WHen you inject the patient with the tuberculin, the APCs near the injection site will present this antigen. Th1 cells that are near that are specific to this antigen (from previous exposure) will release IFN gamma and TNF-beta
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What happens in contact dermatitis with poison ivy?
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The lipid-soluble antigen enters the cells, it will bind to intracellular self proteins, changing the shape resulting in expression of this via MHC I to CD8 cells, and a heightened response upon reexposure to the antigen
-Additionally, hapten: peptide complexes can be processed and presented via MHC II to TH1 cells, leading to a response |
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What is IgE produced by?
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Plasma cells
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Where is IgE located primarily?
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In tissues
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Where does IgE bind to?
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Fc-epsilon-RI (which has a high affinity for IgE) on:
-Tissue mast cells, circulating basophils, activated eosinophils |
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What are the two types of Fc-epsilon R?
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Fc-epsilon RI and CD23 (Fc epsilon RII)
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What is the role of CD23?
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It has a low affinity for IgE and enhances the antibody response to a specific antigen
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What is the sequence of events when someone is exposed to an allergen?
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-The antigen, for instance pollen, crosses the epithelial barrier and is taken up by APC and are presented to TH2 cells resulting in the production of IgE against these pollens.
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What happens upon re-exposure to the antigen?
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The IgE molecules on the surface of the cell get polarized to one pole of the mast cell and the receptors get cross-linked. leading activation, release of inflammatory mediators, and development of type 1 hypersensitivity
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What type of effects would type I hypersensitivty have in the GI tract?
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Causes diarrhea and vomiting
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What type of effects would type 1 hypersensitivty have in the respiratory system?
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Coughing, weezing, and mucus production
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What type of effects would type 1 hypersensitivty have in blood vessels?
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Hypertension, arrythmias
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What is the principle of the allergy test?
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Scratch the skin of the person with the antigen, if they are allergic, there will be an immediate release of inflammatory mediators at the site of the test, resulting in redness and swelling
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What does the development of local or systemic symptoms depend on?
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-The nature/quantity of the allergen
-Route of introduction of the allergen -Other host factors (like Platelet activating factor) |
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What does it mean when PAF is high?
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You have a higher risk of anaphylactic shock
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Why do B cells produce IgE in allergic reactions?
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There are two signals that result in this:
1) Co stimulator of CD40 L on the surface of T cell to CD40 on the B cell 2) Secretion of IL-4/IL-13 which have receptors on the surface of the B cell |
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What is signal 1 generall needed for?
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Any type of class switching
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What are IL-4 and Il-13 produced by?
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TH2 cells, tissue basophils, and Mast cells
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What is similar between the IL-4 and IL-13 receptors on the B cell surface?
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They are both heterodimers and both share the common IL-4R alpha chains
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What is activated when IL-4 and IL-13 bind their receptor?
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STAT6 is activated,
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What happens when STAT6 is activated?
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It goes to the nucleus where it binds SREs, leading to the transcription of the constant region of IgE, the epsilon region
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What is the positive feedback loop that is created when mast cells recognize antigen?
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Once the IgE binds to mast cells, it upregulates its CD40-L, as well as increases expression of IL-4, resulting in further promotion of IgE production
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What does atopic mean?
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Have allergies and predisposition to produce IgE
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What are some genetic components that make someone more likely to develop allergies?
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-There might be a polymorphism in the IL-4 region, resulting in an increased amount of IL-4 produced
-Gain of function mutation in IL-4R making it constitutively active -Some haplotypes of MHCII are better able to present pollens to TH2 |
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What does filagrin encode for?
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A protein important in the skin barrier integrity
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Which disease are individuals with a defective filagrin gene predisposed to?
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Eczema or atopic dermatitis
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Why are individuals with a defective filagrin gene more inclined to get atopic dermatitis?
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The barrier isnt intact, so allergens arent prevented from getting inside, so they will be recognized by APCs, present Ag to TH2, and IgE will be produced
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What are individuals with filagrin gene mutations predisposed to?
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Asthma, only in association with the atopic dermatitis
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What type of environment would predispose an individual to having allergic diseases?
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Hygenic (not many microbes)
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What is the "hygenic hypothesis"?
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Less hygenic environments protect against atopic diseases
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Why does this occur?
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Neonates are more dependent on the Th2 arm, but if there were infections early in life that stimulated a Th1 response, this might reduce the likelihood of a TH2 response later in life (microbes induce the Th1 response)
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What is the modified hygenic hypothesis?
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Infections might protect against atropy by driving the production of regulatory Th3 cytokines (IL-10, TGF-beta)
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How does the Th3 response work?
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If you are exposed to a microbe or stimuli and will deviate to a particular response (TH1 or TH2) the Th3 response will dampen BOTH leading to tolerance
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What is the order of inflammatory mediator release by mast cells?
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-Immediate release of histamine
-Over minutes: prostraglandins and leukotrienes -Hours: cytokine production (IL-4 and IL-13) |
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What are mast cells derived from?
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CD34+ progenitor cells
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What is the major site of differentiation of mast cells?
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Connective tissue
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What is the major growth factor for mast cells?
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Stem-cell factor (SCF)
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Wthat does stem-cell factor act on?
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Receptor C-kit
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What is mast-cell cytosis?
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When people have a constitutive C-kit, leads to mast cells always being active and there is a massive proliferation of mast cells
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What is the life span of mast cells?
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Weeks to months
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What are the two subsets of mast cells?
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-Connective tissue mast cells
-Mucosal mast cells -Each release different enzymes |
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Why are mast cells so fundamental in innate immunity as well?
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They can recognize multiple pattern recognition receptors involved in recognizing broad classes of pathogens
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What are other cells that derive from the CD34+ progenitor cell?
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Eosinophils and basophils
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Where is the major site of eosinophl maturation?
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The bone marrow
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Which cytokine plays an important role in the production, differentiation, survival and release from bone marrow of eosinophils?
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IL-5
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What is the major chemotactic factor of eosinophils?
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Eosinotaxins
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When is Fc-epsilon expression upregulated?
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Upon eosinophil activation
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How do eosinophils fight off infection?
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Through release of toxic granule proteins
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What are these toxic granule proteins?
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-Major Basic Protein
-Eosinophil-derived neurotoxin -Eosinophil cationic protein |
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What are eosinophils important for?
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Defense against parasites
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How do eosinophils combat viral infection?
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THrough RNAses contained in their cytoplasmic granules
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How do eosinophils result in higher IgE production?
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THey produce Il-4 which acts on TH2
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How do eosinophils capture extracellular bacteria to promote their killing?
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THey inject DNA of mitochondrial origin to produce a sticky network
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Why are eosinophils important in asthma?
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They promote tissue remodelling and chronic inflammation
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What is the major site of basophil differentiation?
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Bone marrow
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Which cytokines induce production of basophils?
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IL-3/5, GM-CSF
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How do basophils compare to the rest of the WBCs?
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THey are the lowest in number
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What is the lifespan of basophils?
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Days
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When do basophils have a high level of Fc-epsilon RI?
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Before activation (opposed to eosinophils that only have a high level after activation)
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When are basophils especially important?
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In the immune response to parasitic helminths (live in humans)
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What do basophils lead to?
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augmented Ab production, and humoral memory
by producing large quantities of IL-4/13 and express CD40L |
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What are the two phases of allergic reactions?
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Immediate phase response (within seconds)
Late phase response (up to 12 hrs) |
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What is the immediate reaction due to?
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Histamine, prostaglandins causing a rapid increase in vascular permeability and contraction of smooth muscle
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What is the late phase reaction due to?
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Leukotrienes, chemokines, cytokines causing leukocyte recruitment to site of inflammation
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How does the clinical marks of an immediate reaction compare to that of a late phase reaction?
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The late phase reaction is less clinically marked than the immediate reaction
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What does the low incidence of autoimmune disorders (3%) suggest?
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There are control mechanisms in the body to prevent it from attacking itself
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Who coined the term "horror autotoxicus"?
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Paul Erlich
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What does this term reflect?
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The presence of mechanisms of self-tolerance that prevented the immune system from attacking self-tissues
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How can autoimmunity be associated with tolerance?
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Autoimmunity can be viewed as alteration in the normal homeostatic mechanisms of tolerance (which regulate self/non-self discrimination)
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What do the effector mechanisms of autoimmunity involve?
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Specific components (part of adaptive immunity) and nonspecific (part of innate immunity)
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How can VDJ combination result in autoimmunity?
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It is a random process, and can thus possible result in receptors targeting self antigen.
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What happens to these self reactive lymphocytes?
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-Some are eliminated in the maturation process
-Some are eliminated or inactivated after maturation -Some might be helpful in normal individuals (ie. help with immunity against non-self antigens) |
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What do most autoimmune diseases result from?
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Failure to maintain T cell tolerance
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What are thymocytes?
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All hematopoeitic stem cells that are entering the thymus from the bone marrow
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What is negative selection?
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95% of thymocytes undergo apoptosis because of excessive reactivity to self antigens
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What happens during positive selection?
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Cells that were not eliminated in negative selection are tested to make sure they have FUNCTIONAL RECEPTORS. Only cells that do not have excessive reactivity and cells that have functional receptors are able to leave the thymus as CD4+ or CD8+ cells
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Can any of the cells leaving the thymus after negative and positive selection have affinty for antigen?
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A small portion of the cells leaving the thymus have a LOW affinity for self antigen
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How are these low affinity self-reactive T cells controlled?
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Through intrinsic (by the T cell) and extrinsic mechanisms
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What are some instrinsic mechanisms to keep low affinity self reactive T cells in check?
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Ignorance, anergy, and phenotypic skewing and apoptosis.
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What are some extrinsic mechanisms to keep low affinity self reactive T cells in check?
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-Tolerogenic dendritic cells and regulatory T cells
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What is AIRE?
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Autoimmune regulator (a transcription factor) that is expressed in thymic medullary cells
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What does AIRE allow?
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Thymic medullary cells to produce TISSUE SPECIFIC ANTIGENS (ex to the retina/ovaries) so that the T cells that are responsive to these tissue specific antigens will be eliminated
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What do mutations in AIRE do?
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Cause the rare autosomal recessive disorder APECED
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What is APE of APECED?
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Autoimmune polyendocrinopathy
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What is the C of APECED?
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Candidiasis, a fungal infection
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What is the ED of APECED?
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Ectodermal dysplasia- resulting in an abnormal complexion
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What happens during receptor editing of B cell receptors during central tolerance? (If apoptosis is NOT induced)
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-The autoreactive B cell undergoes maturational arrest
-There is VJ rearrangement on the autochromosome resulting in the expression of a NEW light chain |
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What happens to this new light chain?
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It will assemble with the heavy chain of the antibody molecule, generating a new specificity and thus a whole new clonal B lymphocyte
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What happens if this new B cell clone recognizes self antigen?
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It will undergo apoptosis
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What happens when a mature B cell exits the bone marrow, and sees a given antigen?
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It tries to increase its affinity for the antigen by undergoing SOMATIC HYPERMUTATION
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What happens in somatic hypermutation?
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There are changes in the antigen recognizing portion of the BCR
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What happens if somatic hypermutation results in the generation of B cells that recognize self antigen with high affinity?
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These B cells will be deleted
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What is the function of T cells in the periphery that have a LOW affinity for self antigen?
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They remain ignorant of self but functional against non self
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When can T cell ignorance be overcome?
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-With the wrong stimulus (ie. infection)
-By dendritic cells expressing a high level of costimulatory molecules |
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How does infection result in overcoming T cell ignorance?
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Infection results in massive tissue injury, resulting in the release of self Ags
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How do dendritic cells have a greater ability to present self Ag?
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If there is a foreign antigen that help the dendritic cell in presenting self-antigen
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What is sequestration?
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Antigens are hidden in immunologically privileged sites
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Why is sequestration important?
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It keeps lymphocytes with the potential of self-reactivity against these antigens that are hidden, ignorant
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How does damaging one eye result in loss of vision in both eyes?
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Trauma to one eye results in the release of sequestered intraocular antigens
-These Ags are carried to lymph nodes, where T cells are activated and effector T cells return to the blood stream and go to both eyes |
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What happens normally when a T cell recognizes a non-self Ag?
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The T cell will activate, proliferate and become differentiated and able to respond to the Ag
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What happens when a self-reactive T cell recognizes a self-antigen?
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It will undergo deletion or anergy
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What leads to T cell anergy?
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The absence of co-stimultory molecules on the APC (presenting to T cell via MHCII) or in the presence of co-inhibitory molecules, antigen recognition by T cells leads to T cell tolerance
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What is phenotypic skewing?
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When an autoreactive T cell is allowed to undergo full activation, but might develop a phenotype in which they produce non-pathogenic chemokine and cytokine receptors.
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What is necessary following pathogen induced activation and proliferation of naive lymphocytes and following pathogen elimination?
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Deletion of all or most of the lymphocytes
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What is ALPS?
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Autoimmune Lymphoproliferative Syndrome
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What is ALPS characterized by?
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Mutations in molecules that are important for apoptosis, ex Fas or FasL
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What are two consequences of ALPS?
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-Lymphoproliferation
-And autoimmunity (autoreactive cells are NOT eliminated by apoptosis) |
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What are some examples of autoimmune disorders that an individual with ALPS could have?
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-Hemolytic anemia
-Idiopathic thrombocytopenic purpura -Neutropenia -Kidney diseases |
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What is idiopathic thrmobocytopenic purpura?
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Platelets are attacked
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What is neutropenia?
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Neutrophils are attacked and then eliminated
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What is regulatory tolerance?
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T cell specific for self antigen becomes a T reg cell
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What do these T reg cells do?
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Either interact directly with T cells, or produce cytokines IL-10 and TGF-beta that inhibit other self-reactive T cells
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What are four types of T reg cells?
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-CD4+, CD25+, FoxP3+, high levels of alpha chain of the IL-2 receptor
-TH3 cells -TR1 cells -CD8+ reg T cells |
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How do cytokines expressed by T reg cells affect APCs?
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-Cause decrease in MHC II expression
-Cause decrease in costimulatory molecule expression (CD40) -Decrease APC function (decreasing action of proinflammatory cytokines produced by the APC) |
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What is the end result of the action of T reg cells?
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Autoreactive T cells have a decreased potential for T cell proliferation
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What happens when T reg cells contact dendritic cells?
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The dendritic cells will become tolerogenic dendritic cells
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What does "tolerogenic" mean?
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Produces immunological tolerance
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How are Fox+ CD4+ T cells formed?
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-They are T lymphocytes with high affinity for self antigen that will express CD4+ and upregulate the expression of TF FoxP3
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What happens when these high affinity, FoxP3+ CD4+ T cells migrate to the periphery?
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They will contact an APC or autoreactive T cell clone and decrease their harmful potential
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What is IPEX syndrome caused by?
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Patients that have a mutation in FoxP3
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What does IPEX stand for?
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Immunodysregulation Polyendocrinopathy Enteropathy X-linked syndrome
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Where is the FoxP3+ gene located?
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On the surface of X chromosomes
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What is a consequence of this mutatnt FoxP3 in IPEX?
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Dysfunction of T reg cells and development of autoimmunity
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What happens to immature DCs normally?
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Immature DCs that see and present foreign peptides will upregulate the expression of costimulatory molecules
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What happens to DC cells once they mature (normally)?
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They will activate the T lymphocytes that exhibit specificity for the foreign antigens
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What are tolerogenic dendritic cells?
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Immature dendritic cells that are constantly sampling the environment for self-peptides and are presenting them via their MHC molecules. These APCs are NOT upregulating their costimulatory molecules
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What happens if this immature tolerogenic dendritic cell sees an autoreactive T cell?
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They will NOT activate that T cell, leading to T cell tolerance
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When would an altered cytokine secretion arise?
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During infection
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How could this altered cytokine secretion that arises in infection cause autoimmunity?
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Stimulates expression of co-stimulatory molecules
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What cytokines do TH1 cells produce?
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IFN-gamma
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Which cytokines do TH2 cells produce?
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IL-4, IL-5, IL-13, IL-10
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Which cytokines do T reg cells produce?
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IL-10, TGF-beta
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Whatcytokines do TH17 cells produce?
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They produce IL-17 and Il-12
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What is the function of TH17 cells?
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They have a high proinflammatory capability, and defend against microbes in epithelial and mucosal areas
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What is IL-22 important in?
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Candida albicans and Staphyloccocus aureus infections
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Which autoimmune disorders have a high level of TH17 cells?
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MS, psoriasis, rheumatoid arthritis
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How can autoimmune disorders be classified?
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-By which arm of the immune system they are on
-By which organ they affect |
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Which organ does MS affect?
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The brain
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Which organ does diabetes melitus affect?
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The pancreas
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Which organ does inflammatory bowel disease affect?
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The gut
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What are MS, diabetes, and IBD examples of?
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Tissue specific organ-related autoimmune disorders (have tissue specific antigens)
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What is SLE?
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Systemic Lupus Erythromatus
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What is SLE an example of?
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A multi-organ systemic autoimmune disorder
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Why are multiple organs involved in SLE?
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It involves Ags that are ubiquitous to many organs, and in the case of SLE, it involves ribonuclear proteins
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What is an example of a disease that antibodies play a major role?
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Graves disease- Abs are targeting against the thyroid stimulating hormone receptor
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What is an example of a disease where T cells play a major role?
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Insulin dependent diabetes mellitus
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How can you determine which immune arm causes the most harm in a particular disease?
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If you remove just the Abs, inject in a mouse and see similar conditions, know it is the Abs causing the disease
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What is autoimmune encephalomyelitis?
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A disease that resembles MS
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What is AE mediated by?
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TH1 cells specific for MYELIN BASIC PROTEIN
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Which component of the immune system is transferred during pregnancy?
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IgG antibodies (T cells are not able to travel across the placent from the mother to the foetus)
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What is AE mediated by?
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TH1 cells specific for MYELIN BASIC PROTEIN
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Which component of the immune system is transferred during pregnancy?
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IgG antibodies (T cells are not able to travel across the placent from the mother to the foetus)
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What happens when a mother with Graves disease or Myasthenia Gravis is pregnant?
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The baby will have what resembles the disease for a few weeks, but after that the maternal Abs are eliminated and the baby will return to a healthy state
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How can both autoreactive B cells and T cells be involved in the progression of a disease?
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-Autoreactive B cells can play an antigen presenting role
-Autoreactive T cells can stimulate B cells to produce antibodies |
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What is an example of a disease characterized by both arms of the immune system?
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SLE
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What factors are necessary for development of an autoimmune disorder?
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Genetic factors, environmental (ex: infectious diseases)
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Which type of autoimmune disorder is susceptible to genetic predisposition?
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Organ related autoimmune disorders
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What do dizogotic twins show about genetics of autoimmune disorders?
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They have a high incidence, showing its related, but that it is not the absolute factor since the concordance rate can actually be quite low
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What are some mechanisms that would cause twins to have different immune mechanisms?
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VJ, VDJ rearrangement, receptor assembly, somatic hypermutation
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How does HLA haplotype affect autoimmune disorders?
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There is an association between HLA haplotype and a particular autoimmune disorder
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What type of autoimmune disorder are people with HLA B27 more susceptible to?
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They have a higher risk of developing an autoimmune disorder that affects the back and causes back pain
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What is ankylosing spondylitis?
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Back pain
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Which MHC class are most autoimmune diseases associtated with?
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MHC II
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How can you explain the association of MHC genotype with autoimmune disease?
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-Susceptibility is determined by the ability of the cells to present autoreactive peptides to autoreactive cells
-T cell clones depend on MHC haplotype |
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What changes in an MHC will cause resistance or susceptibility to a disease?
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Aminoacids causing structural changes if mutated
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Can a particular MHC haplotype be responsible for a disease?
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No it is not sufficient
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Which gene is mutated in Graves disease?
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CTLA-4
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to cross
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cruzar
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What is Goodpasture's syndrom characterized by?
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The presence of auto antibodies and glomerulonephritis
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Why could pulmonary hemorraghe result in Goodpasture's?
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Lack of tissue integrity in the lungs (ex: due to smoking) could lead to autoantibodies having access to the lungs
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What does Procainamid cause?
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Induces lupus-like antibodies
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What is "haptenizing" by toxins?
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When they cause changes in the conformation of self antigesn so they are recognized as non-self
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What are four ways that infection can cause autoimmunity?
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-Causing release of proinflammatory cytokines
-Increasing the level of expression of costimulatory molecules at the surface of the dendritic cells/ decreasing level of expression of inhibitory costimulatory molecules -Dysregulation of the immune system -Molecular mimicry |
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How does increasing the level of costimulatory molecules at DC surfaces cause autoimmunity?
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This will activate bystander lymphocytes
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How is the dyrsregulation of the immune system characterized?
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-Apoptosis is prevented, molecules that resemble proinflammatory cytokines are released
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How does molecular mimicry in infection result in autoimmunity?
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There is cross-reactivity between the infectious antigen and a self molecule
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What are superantigens?
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Produced by infectious organisms, which can activate a small number of T cell clones, which will increase in number upon subsequent exposure to the antigen, and these lymphocytes that are activated have a potential to be autoreactive
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