Week 4 Flashcards
Type 1 hypersensitivity
- name
- mediated by
- cells involved
- immediate hypersensitivity
- mediated by IgE
- Mast cells
Type 2 hypersensitivity
- mediated by
- cells involved
- occurs in solution?
- IgG but can sometimes be IgM
- none; the antibodies are directed against tissue
- no
Type 3 hypersensitivity
- mediated by
- describe what mediates it
- occurs in solution?
- immune complexes
- Antigen, antibody, and complement
- yes
Type 4 hypersensitivity
-mediated by
-T cells
Hygiene hypothesis
- what is it?
- why does it occur?
- epidemic of type 1 hypersensitivity in developed countries
- body doesn’t get experience that it needs and is not exposed to diff pathogens because we have vaccines, antibiotics, and clean water to bathe in
IGE and parasites
- IgE is supposed to protect body against parasites
- parasites are more similar to humans and have less antigenic properties
- parasites are not killed by macrophages/neutrophils (too big)
- attached to mast cells, basophils, eosinophils which will produce concerted mast-cell degranulation and violence dislodges embedded parasites from the tissues and ejects them
IgE and IgG3 in early immune response
- primary response to an antigen, IgM is first switched either to IgG or IgE
- IgG will then differentiate into 1 of 4 subtypes, with IgG3 being located first in gene
- both IgE and IgG3 are short lived and favor complement fixation, mast cell degranulation, and phagocytosis
What isotype of antibodies would be prevalent in atopic individuals
- IgG3
- Starts out as IgM and then goes to IgE or IgG
IgG1, 2, and 4
- longer-lived,
- increasingly less inflammatory,
- favor the formation of immune complexes
Isotype switching going back to IgE
Some B cells making high-affinity IgG, particularly IgG4, can switch to IgE at a late stage in the germinal center reaction.
IgE details
- not retained in blood, concentrated in tissue
- binds to FcεRI
- bent, asymmetrical ‘shrimp-like’ structure
- Fab arms have less movement
- highest affinity for antigen and irreversible binding
- can bind to its receptor without antigen bound first; this causes for it to better express binding site for antigen
IgE, FcεRI, mast cells and memory
- all IgE that did not get bound during infection will get bound to mast cell by FcεRI receptor and serve as memory cells
- there are a bunch of IgE molecules on mast cells with different specificity
FcεRII (CD23)
- role in the production of IgE and its maintenance in the circulation
- conformation of the IgE Fc region that permits binding to FcεRII has no affinity for FcεRI
- binds with low affinity
- when two or three binding sites on FcεRII are occupied by immune complexes of IgE and antigen, the binding strength approaches that of FcεRI.
ADAM10
- cleave CD23
- to produce either monomeric or trimeric forms of soluble CD23
Soluble form of CD23
- have cytokine-like activities that act in an autocrine or paracrine fashion
- effects are wide-ranging
- expressed in b-cells, T cells, monocytes, follicular dendritic cells, and bone marrow stromal cells
B cell, IgE, and CD23
-monomeric vs trimeric
- when B cell expresses IgE it begins to shed CD23
- absence of antigen, complex of soluble trimeric FcεRII interacts with B-cell receptor (surface IgE) and B-cell co-receptor which generates synergistic signaling that promotes the differentiation of the B cell into an IgE-secreting plasma cell
- monomeric form of soluble FcεRII inhibits such differentiation.
Mast cells and tissue they live in
- resident in mucosal, epithelial tissue, and all vascularized tissues except the central nervous system and the retina
- maintain the integrity of the tissue where they reside by alerting the immune system to local trauma and infection, and facilitating the repair of damage caused by infection or wounds.
Mast cells
- best known for destructive properties of their granules
- express Toll-like receptors; Fc receptors for IgA, IgG, and IgE.
- contribute to both the innate and the adaptive immune responses to infection
- create eicosanoids
- two kinds
eicosanoids
- small inflammatory mediators
- induces the productions and secretion of cytokines that recruit neutrophils, eosinophils, and effector T cells to the infected tissue, and also induces the secretion of growth factors that promote the repair of tissue damage.
mucosal mast cell
- produces the protease tryptase
- depends on the effector T cells
connective tissue mast cell
produces chymotryptase.
eosinophils
- what kind of cell
- where are they resident
- what happens when body is healthy
- what activates it?
- function?
- what induces degranulation?
- what allows for them to bind pathogen?
- granulocytes whose granules contain arginine-rich basic proteins
- tissues specifically in CT under epithelia of respiratory, GI, and urogenital tract
- activation leads to the staged release of toxic molecules and inflammatory mediators
- kill invading microorganisms and parasites directly and induce synthesis and secretion of prostaglandins, leukotrienes, and cytokines, which amplify the inflammatory response by the activation of epithelial cells and leukocytes, including more eosinophils
- number of eosinophils is kept low by restricting their production in the bone marrow
- IL-5 from TH2 cells
- expression of FcεRI and binding IgE
- Fcγ receptors (to bind to IgG) and complement receptors
Basophils
- cell type
- growth factors
- relationship with eosinophils
- role in adaptive immunity
- function
- effect on B cells
- granulocytes
- growth factors, including IL-3, IL-5, and GM-CSF
- TGF-β and IL-3 pro- motes the maturation of basophils while suppressing that of eosinophils
- key cell that initiates TH2 responses by secreting IL-4 and IL-13
- function is to degranulate in infected tissue and recruited to secondary lymphoid tissue to secrete IL4 and 13
- drives isotype switching to IgE and IgG4 by binding to CD40 on antigen-stimulated B cell
Mast cells, basophils, and Eosinophil effect on eachother
- Mast-cell degranulation initiates the inflammatory response, which recruits eosinophils and basophils.
- Eosinophil degranulation releases major basic protein which causes degranulation of mast cells and basophils which is augmented by one or more of the cytokines—IL-3, IL-5, and GM-CSF—that affect the growth, differentiation, and activation of eosinophils and basophils
Effector mechanism for type I hypersensitivity
- triggered by the interaction of an allergen with allergen-specific IgE bound to the FcεRI receptor of mast cells, basophils, and eosinophils.
- interaction causes these cells to degranulate and release a potent mixture of inflammatory mediators
Effector mechanism for type II hypersensitivity
- caused by an IgG response to chemically reactive small molecules that become covalently bound to the outside surface of cells
- chemical reaction modifies the structures of human cell-surface components, which are now perceived as foreign antigens
- B cells are stimulated to make IgG antibodies which cause cause the modified human cells to become subject to complement activation and phagocytosis
Effector mechanism for type III hypersensitivity
- caused by small soluble immune complexes of antigen and specific IgG that form deposits in the walls of small blood vessels or the alveoli of the lungs
- immune complexes activate complement and an inflammatory response that damages the tissue and impairs its function.
Effector mechanism for type IV hypersensitivity
- mediated by antigen-specific effector T cells, and in most instances by CD4 TH1 cells
- Peptides containing the residues are presented by HLA class II molecules and recognized as non-self by CD4 T cells that respond by attacking any area of the skin that comes into contact with antigen
- Some type IV hypersensitivity reactions are due to CD8 T cells (poison ivy)
How are allergens picked up?
dried up particles that are inhaled
What is the first exposure to an allergen called?
- sensitization
- first exposure to an allergen, you’re gonna make the antibodies, the antibodies have not been able to arm the mast cells yet and mast cells cannot degranulate and cause terrible allergic response.
sensitization and mast cells
- extraction of the antigen, it gets into the mucus, it will be solubilized, then gets into the APCs, it presents it to a Helper T cell (Th2), which will induce the B cell to make IgE.
- In the first response the IgE will be directed against the antigen, but everything that is left over that initial response gets taken up by mast cells, basophils, and eosinophils
- During sensitization, you have the weakest response in the first exposure bc mast cells will not have been armed with IgE
immediate and late-phase response
- immediate: wheal and flare; direct consequence of IgE- mediated degranulation of mast cells in the skin; Released histamine and other mediators cause increased permeability of local blood vessels, where- upon fluid leaves the blood and produces local swelling (edema). The swelling produces the wheal at the injection site, and the increased blood flow into the surrounding area produces the redness that is the flare. Immediate reactions can last for up to 30 minutes, and the relative intensity of the wheal and flare varies.
- 6–8 hours after the immediate reaction; more widespread swelling and is due to the leukotrienes, chemokines, and cytokines synthesized by mast cells after IgE-mediated activation
Allergic reaction and lungs
On inhalation of an allergen to which a patient is sensitized, mucosal mast cells in the respiratory tract that are armed with allergen-specific IgE will degranulate. The released mediators cause immediate constriction of the bronchial smooth muscle, which results in the expulsion of material from the lungs by coughing, and difficulty in breathing. It induces the recruitment of leukocytes, particularly eosinophils and TH2 lymphocytes, into the site and, if antigen persists, the late-phase response can easily develop into a chronic inflammatory response in which allergen-specific TH2 cells promote IgE production and a state of eosinophilia
What is the effect of leukotrienes
- cause pain, inflammation, dilation, bronchoconstriction
- are a lot more potent than histamine
IgE allergic reactions vary by tissue type
- gut: interactions between antigen, IgE, and mast cells trigger violent muscular contractions that can expel worms from the gastrointestinal tract and increase fluid flow to wash them out
- lungs: muscular spasms and increased secretion of mucus that result from mast-cell activation can be seen as a way to expel organisms
- blood vessels: increase blood flow and permeability causes increased flow of antigens in lymph to lymph nodes
Penicillen and anaphylactic shock
- β-lactam ring can be opened up to produce covalent conjugates with proteins of the body, creating new ‘foreign’ epitopes
- response is dominated by TH2 cells that help B cells produce IgE specific for the new epitopes.
- If penicillin is given to a person who has been sensitized in this manner, it causes anaphylaxis and even death
Systemic anaphylaxis
- allergen enters the bloodstream and cause widespread activation of the connective tissue mast cells associated with blood vessels
- causes an increase in vascular permeability and a widespread constriction of smooth muscle.
- causes the blood pressure to drop drastically and CT to swell
Epi and anaphylaxis
Epinephrine stimulates the reformation of tight junctions between endothelial cells. This reduces their permeability and prevents fluid loss from the blood, diminishing tissue swelling and raising blood pressure. Epinephrine also relaxes constricted bronchial smooth muscle and stimulates the heart
allergic rhinitis
-also called hay fever
- caused by allergens that diffuse across the mucous membrane of the nasal passages and activate mucosal mast cells beneath the nasal epithelium
- characterized by local edema, leading to obstruction of the nasal airways and a nasal discharge of mucus that is rich in eosinophils. There is also a generalized irritation of the nose due to histamine release.
-
allergic asthma
- allergic reactions cause chronic difficulties in breathing, such as shortness of breath and wheezing.
- triggered by allergens activating submucosal mast cells in the lower airways of the respiratory tract. Within seconds of mast-cell degranulation there is an increase in the fluid and mucus being secreted into the respiratory tract, and bronchial constriction caused by contraction of the smooth muscle surrounding the airway.
- overall effect of the asthmatic attack is to trap air in the lungs, making breathing more difficult
chronic asthma
- chronic inflammation that develops after allergic asthma perpetuated in the absence of further exposure to the allergen.
- airways can become almost totally occluded by plugs of mucus
- airways hyper-reactive to chemical irritants commonly present in air
- condition is exacerbated by immune responses to bacterial or viral infections of the respiratory tract
- classified as type IV hypersensitivity response
allergic reactions in the skin
- Allergens that activate mast cells in the skin to release histamine cause raised itchy swellings called urticaria or hives
- Activation of mast cells in deeper subcutaneous tissue leads to a similar but more diffuse swelling called angioedema
- prolonged allergic response in the skin is called atopic dermatitis or eczema; believed to be due to loss of the protective barrier function of the skin, allowing allergens to enter the skin and stimulate a TH2-cell mediated immune response
effects of ingested allergens
- IgE is made against an extremely small proportion of proteins ingested.
- Foods that commonly cause allergies include grains, nuts, fruits, legumes, fish, shellfish, eggs, and milk
- allergen passes across the epithelial wall of the gut and binds to IgE on the mucosal mast cell which causes degranulation. Local blood vessels become permeable, and fluid leaves the blood and passes across the gut epithelium into the lumen of the gut. Meanwhile, contraction of smooth muscle of the stomach wall produces cramps causing vomiting and diarrhea
Most commonly transplanted tissue
blood; which can cause hypersensitivity reaction
