Immunosensitivity Flashcards
Type I Immunosensitivity is aka?
Immediate type
What are some common sources of Type 1 reactions? 4 groups
inhaled materials like plant pollen, dander, feces, and mold spores
injected materials like insect venom, vaccines, drugs, therapeutic proteins
ingested foods (peanuts or shellfish) or oral drugs
contacted materials such as plant leaves, industrial products, metals, etc.
the Coomb’s and Gel classification of the various hypersensitivity responses groups these diseases into what four groups?
Type 1: Immediate-type
Type 2: Altered self
Type 3: Immune complex
Type 4: Delayed type
What are Immediate type hypersensitivity reactions?
Hypersensitivites that are initiated by mast cell degranulation, mediated by crosslinking of IgE bound to the high affinity IgE receptors of mast cells (FCeRI).
These reactions occur within minutes following the exposure to the allergen.
What are some examples of Type I reactions?
Allergic rhinitis, asthma, systemic anaphylaxis
What are Altered self hypersensitivity reactions?
These reactions are initiated by allergen-specific IgG antibodies, and the inflammatory response is mediated by the complement cascades, phagocytes and NK cells.
These reactions take longer to develop than the Type 1 hypersensitivity reactions (4-12 hours usually).
What are immune complex hypersensitivity reactions?
These hypersensitivities are the result of immune complex deposition and the inflammatory responses that ensue as phagocytes encounter these immune complexes deposited in the host tissues. The altered- self hypersensitivities (type II) often become immune complex hypersensitivities.
What are delayed type hypersensitivity reactions?
These are hypersensitivity reactions that are mediated by T cells (either CD4+ or CD8+ T cells, or both). Because it takes 24-72 hours for T cells to initiate symptomatic inflammatory responses, these are known as delayed-type hypersensitivity reactions.
T or F. No one is born with an effector response to any allergen
T. There must be a first exposure to the allergen in which the primary immune response is generated, but no symptoms of hypersensitivity are experienced.
After that, any subsequent exposure to that allergen elicits the hypersensitivity response and any symptoms that go along with that response.
What kinds of allergens can elicit a Type I reaction?
allergens must be proteins because they must be T-dependent antigens. A helper T cell response is needed for activation of B cells and class switching to IgE.
Allergens that trigger Type I reactions are often?
proteases.
Why do proteases tend to cause Type I reactions?
The most important effector function of mast cells is to expel parasite pathogens from the body. Parasites typically produce abundant enzymes as a means of remodeling tissue, allowing them to move through tissues in the body.
Somehow, the immune system is programmed to produce IgE responses in response to proteins that have proteolytic activity. Allergens are assumed to have some proteolytic activity
Why do inhaled allergens tend to elicit IgE responses and lead to type I hypersensitivity?
They have the following characteristics:
1) Low dose
2) Low molecular weight
3) High solubility
4) Highly stable (it must be stable to survive when part of a desiccated particle.)
5) Contain peptide that bind to MHC class II
Many allergens have proteolytic activity (not all)
Why does the low dose that is typical of inhaled allergens favor IgE response and subsequent Type I reactions?
Low doses of an antigen favor differentiation of a TH0 cell into a TH2-type effector CD4 T cell (needed for driving an IgE response).
Why does the low molecular weight that is typical of inhaled allergens favor IgE response and subsequent Type I reactions?
if the protein is small, it can more easily diffuse out of the dust particle that delivered it into the respiratory tract.
Why does the high solubility that is typical of inhaled allergens favor IgE response and subsequent Type I reactions?
the more soluble it is, the more efficiently the allergen will elute out of its dust particle.
What is the high affinity receptor for IgE antibodies on mast cells?
FceRI.
When mast cells degranulate, they release a variety of molecules. What are the main classes of molecules they release?
1) Enzymes
2) Toxic mediators
3) Cytokines
4) Chemokines (CCL3- granulocyte attractant)
5) Lipid mediators
What enzymes are released during mast cell degranulation and what do they do?
tryptase, chymase, cathepsin G, carboxypeptidase
these remodel connective tissue matrix
What toxic mediators are released during mast cell degranulation and what do they do?
Histamine and heparin
these are toxic to parasites, and increase vascular permeability and cause smooth muscle contraction
What cytokines are released during mast cell degranulation?
TNF-a, IL4- IL-13, Il-3, GM-CSF, and IL-5
What does TNF-a that is released from mast cells during degranulation promote?
inflammation, and it stimulates cytokine production by other cell types
It also activates endothelium for an inflammatory response
What do IL-4 and IL-13 that are released from mast cells during degranulation promote?
amplify TH2 response
What do IL-5, GM-CSF, and IL-3 that are released from mast cells during degranulation promote?
eosinophil production and activation
What lipid mediators are released during mast cell degranulation?
Leukotrienes C4, D4, and E5
Platelet-activating factor
What do Leukotrienes C4-E4 do?
cause smooth muscles contraction, increased vascular permeability, and cause mucus secretion
What is urticaria?
Hives
What is the primary role of mast cells in the body?
expulsion of parasites
How do mast cells work to expel parasites from the GI tract?
When mast cells become activated in the gastrointestinal system, the inflammatory response results in increased fluid secretion and increased peristalsis, that results in diarrhea and vomiting, which can both be violent responses that would expel pathogens from both the upper and lower GI tract.
How do mast cells work to expel parasites from the airways?
Mast cell degranulation in the airways results in an increase in mucous secretion and decreased diameter of the airways.
Collectively, this results in coughing and sneezing, violent processes that are designed to expel parasite pathogens from the airways.
How do mast cells work to expel parasites from blood vessels?
When mast cell degranulation occurs in local blood vessels, vascular endothelium is activated, causing edema and movement of fluid and proteins from the vasculature into the inflamed tissue. The resulting swelling pushes lymph (with antigens and APCs) to the draining secondary lymphoid tissue where T cells and then B cells can receive their two activation stimuli.
Although this design is important for eliciting a response to a parasite, in some people it results in priming of additional responses that are directed at a common allergen, an unwanted response.
What is anaphylaxis?
If an allergen gets into the circulation and is disseminated all over the body, systemic degranulation of mast cells can occur, and the results can be life threatening.
What are some of symptoms of anaphylaxis?
1) Rapid loss of fluids from the vasculature, causing swelling all over the body and low blood pressure. Loss of consciousness can result pretty quickly.
2) Contraction of smooth muscles causes constriction of the airways, making it hard to breath
3) Contraction of smooth muscles also occurs in the GI tract, causing cramps, vomiting, diarrhea…more fluid loss from both ends.
What is the preferred treatment for Type I reactions?
Epinephrine, or adrenaline is the treatment of choice.
epinephrine stimulates reformation of tight junctions between endothelial cells, thus reducing permeability of blood vessels, diminishing tissue swelling, and raising blood pressure; also relaxes constricted bronchial smooth muscle and stimulates the heart
What are Type II reactions again?
immune responses directed at altered self determinants that are mediated by IgG antibodies (primarily; IgM can participate).
What is an example of a very common Type II reaction?
The most notable of these conditions is caused by an abnormal response to penicillin-modified erythrocytes following treatment with penicillin.
How can Penicillin induce a Type II reaction?
When penicillin is administered to patients, some of the penicillin binds to red blood cells and modifies surface determinants of the RBCs (may or may not occur in all people)
Because there is typically an infection ongoing when a patient is being treated with penicillin, the complement cascades will be activated, and some of the C3b generated will bind to the surface of RBC’s that can then be taken up by phagocytes due to engagement of their complement receptors.
Some people are not tolerant to the modified determinants, and because there is an infection ongoing, the macrophages are likely to have upregulated their B7 expression and can productively present the altered RBC determinants to naïve T cells.
The resulting effector T cells can supply the second signal of activation to naïve B cells that have specificity for altered determinants on the RBCs.
This results in production of an antibody response that is directed against the altered determinants that are created on RBCs when penicillin binds to them.
Antibodies bind to RBCs, opsonizing them, and if the antibody isotype is one that fixes complement, RBCs will become coated with abundant C3b and will either be destroyed by MAC or taken up by phagocytes
These two mechanisms cause destruction of large numbers of RBCs, and this type of destruction will continue until the altered determinants have been recycled off of the surface of the RBCs. This takes several days after penicillin treatment is discontinued.
What are type III hypersensitivities?
aka immune complex hypersensitivities. These responses are mediated primarily by antigen-specific IgG (some IgM can also be involved), and the end result is inflammation that is driven by complement activation and phagocyte-derived cytokines and chemokines.
How do Type III reactions occur?
Typically they are localized,
Antibodies specific for an allergen bind to the allergen and then activate the classical complement pathway. Anaphylatoxins generated by the complement cascade mediate inflammation directly, as well as by binding to the C5a receptors on resident mast cells underlying the tissues, resulting in mast cell degranulation, releasing powerful inflammatory mediators.
Macrophages and neutrophils can also recognize the opsonized antigens, resulting in their production of inflammatory mediators.
This inflammatory response (referred to as an Arthus reaction) typically takes an hour or two to fully develop.
How are systemic Type III reactions different than localized ones?
When an allergen (such as penicillin) gains access to the vasculature, the anti-allergen IgG binds to the allergen creating an immune complex. If high enough concentrations of the allergen are in the vasculature, this results in too many immune complexes to be cleared efficiently. When this happens, immune complexes become deposited along the vasculature, especially within the kidney glomeruli. Systemic inflammation is caused by anaphylatoxins produced by complement activation as well as by phagocytes that recognize the immune complexes through their Fc and complement receptors, resulting in their production of inflammatory mediators. The end result can be systemic vasculitis, kidney dysfunction, and even neurological symptoms due to vasculitis in the brain.
These reactions can be life threatening because they can progress to an anaphylactic response (C5a initiates systemic mast cell degranulation). Patients presents much like a septic shock patient.
What are common causes of type III reactions ?
Most immune complex hypersensitivities that you will see clinically will follow intravenous drug administration or will be the result of chronic inhalation of allergen.
Immune complex hypersensitivities that result from inhalation of allergen are collectively referred to as ______, but there are many more specific names for these conditions
Farmer’s lung
The most common immune complex diseases that are not related to medical treatment are those resulting from chronic inhalation of allergen. Name them.
1) Farmer’s lung
2) Pigeon Breeder’s disease or poultry worker’s lung or bird breeder’s disease
What is Farmer’s lung?
a condition that results from inhaling mold spores and other allergens from hay, and the condition develops because the patient works with the allergen on a daily basis. Chronic inflammatory responses to these allergens that get deposited into the lower respiratory tract eventually cause a clinically-relevant inflammatory response.
What are Pigeon Breeder’s disease or poultry worker’s lung, or bird breeders disease?
all names for a condition that results from inhaling allergens that are found in the droppings of birds.
delayed-type hypersensitivity reactions are mediated by what cells?
T cells
How long do take delayed-type hypersensitivity reactions take to develop?
24-48 hours to develop.
What is a very common example of a DTH?
poison ivy
What is poison ivy mediated by?
both CTLs and TH1 CD4+ effector cells.
Can TH2 CD4+ effector cells ever mediate poison ivy reactions?
Yes, This is usually observed in chronic upper respiratory tract hypersensitivities such as allergic rhinitis and asthma. The mechanism of these reactions apparently involves activation of eosinophils by TH2 cells
How can TH1 cells cause inflammation?
1) Producing chemokines to recruit macrophages
2) IFN-y to activate macrophages and released inflammatory mediators
3) TNF-a and LT to cause local tissue destruction
4) IL-3/GM-CSF
What is the most commonly studied DTH?
tuberculin reaction
How does the subcutaneous tuberculin test work?
This test is performed by injection of mycobacterial proteins intradermally and then observing the site 2-3 days later to look for an inflammatory response.
If the test is positive, there is typically a very pronounced inflammatory response at and surrounding the injection site. This response is mediated primarily by TH1 CD4 T cells.
How do TH1 DTH’s work?
1) Antigen is introduced into subcutaneous tissue and processed by local APCs
2) A TH1 cell recognizes the antigen and releases cytokines which act on vascular endothelium
3) Recruitment of T cells, phagocytes, fluid and protein to site of antigen infection causes a visible lesion
What is poison ivy DTH caused by?
an oil produced by the plant called pentadecacatechol
What does pentadecacatechol do?
It penetrates the skin and causes alteration of normal self determinants in the underlying tissues. Some people are not tolerant to these altered antigens, and will make a T cell mediated response to these altered determinants. The DTH response is mediated by both TH1 CD4+ T cells and CTLs, and the inflammatory response will continue until all of the altered determinants are gone from the skin (normal recycling of proteins). It usually takes around a week (after all residual pentadecacatechol has been completely removed) for all of these determinants to be recycled.
This is considered a contact hypersensitivity. A similar response can be made in response to contact with nickel.
T or F. The first encounter with pentadecacatechol will result in the characteristic rash
F, because all of the altered determinants should be gone (recycled) by the time an antigen-specific acquired T cell response can be mounted.
How can some people be immune to poison ivy?
This is likely related to their MHC haplotype; if they cannot present the altered determinant because their MHC class I or MHC class II isoforms will not bind to those peptides, that person will not be able to make the immune response.
What is atopy?
term used to describe the approx. 40% of the Caucasian population of North America and Europe are more likely to produce IgE responses to common environmental antigens than the rest of the population.
atopic individuals have higher levels of soluble IgE and more circulating eosinophils than non-atopic individuals
