immune ch 14

allergic rhinitis

(hay fever) mild allergies to inhaled allergens, cause sneezing or runny nose. inhaled antigen enters mucosa and activates mucosal mast cells locally. mast cell activation causes blood vessel permeability and activation of epithelium. eosinophils are recruited from blood and enter nasal passages with mucus

type II hypersensitivity reactions

caused by an IgG responses to chemically reactive small molecules that become covalently bound to the outside surface of cells. the chemical rxn modifies the structures of human cell surface components, which are now perceived as foreign antigens by the immune system. B cells make IgG antibodies against the new epitopes that when bound, the antibodies cause the modified human cells to become subject to complement activation and phagocytosis. results in inflammed damaged tissue. symptoms felt within hours of exposure

mast cell activation and degranulation

caused by cross-linking of Fc-epsilon-RI on the surface of mast cells by antigen and IgE.

type III hypersensitivity reactions

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. at these sites, immune complexes activate complement and an inflammatory response that damages the tissue and impairs its function. when antibodies or other proteins derived from non human animal species are given therapeutically to patients, type III rxns are risks. symptoms are felt within hours of exposure.

ADAM10

cell surface protease that can cleave the CD23 polypeptide at different sites to produce either monomeric or trimeric forms of soluble CD23.

wheal and flare

characteristic inflammatory reaction at the site of injection within a few minutes (immediate rxn). wheal is the raised area of the skin while the flare is the redness spreading out from the wheal. lasts for ~1hour

mast cell activation and degranulation in the airways

decreased diameter, increased mucus secretion--> expulsion of airway contents through coughing, sneezing, and expulsion of phlegm

eosinophilia

disease caused by abnormally high numbers of eosinophils. causes damage to the endocardium of the heart and to nerves,which can lead to heart failure and neuropathy

transfer of IgE and antigen from mother to child

during pregnancy, IgE and IgE bound to antigen can be transferred from the mothers circulation to fetal circulation. antigens can also bind to this maternal IgE in the fetus. Complexes of antigen and IgE are bound by the Fc-epsilon-RII on fetal APCs and are then processed and presented to naive antigen specific T cells. this gives rise to Th2 cells that help antigen specific B cells that have taken up antigen to become plasma cells secreting antigen specific IgE. by this, the mother could provide the fetus with protective immunity against helminths before the baby is born and first exposed to these parasites. conversely, an allergic mother can pass on the allergy to her children

allergen

environmental antigens that cause hypersensitivity reactions/allergic reactions

chronic asthma

eosinophils are the principal cause of the airway damage that characterizes a chronic allergic inflammation. airway can become almost totally occluded by plugs of mucus

sheddases

family of proteins that enable cells to shed soluble forms of their membrane proteins ex) ADAM10

basophils

granulocytes having granules that stain with basic dyes such as hematoxylin. production of eosinophils and basophils are reciprocally regulated in that the promotion of basophils suppresses eosinophils. basophils constitute less than 1% of WBC. basophil is key cell that initiates a Th2 response that is achieved by secreting IL4 and IL13 at the beginning of an immune response which further drives isotype switching to IgE and IgG4

eosinophils

granulocytes whose granules contain arginine-rich basic proteins. most found in tissues, especially connective tissue immediately underlying the epithelia of the resp, GI, and urogenital tracts.

histamine

has 3 kinds of histamine receptors: H1, H2, H3

CD4 Th2 cells in response to helminth infx

help B cells to switch to the synthesis of IgE and produces raised levels of IgE and increased number of eosinophils in blood and mast cells in tissue

omalizumab

high affinity humanized monoclonal IgG that is specific for human IgE has been shown to alleviate the symptoms of asthma and a range of allergic conditions. key feature of this ab is that its target epitope corresponds to the site on IgE bound by Fc-epsilon-RI

Fc-epsilon-RII

homotrimer of CD23 polypeptide and each stalk can bind an IgE. each one of the three CD23 polypeptides binds with low affinity to a different IgE molecule, but when 2 or 3 binding sites are occupied by immune complexes of IgE and antigen, the avidity is much higher than the affinity, and the binding strength approaches that of Fc-epsilon-RI. it functions as a cell surface receptor and soluble receptor for IgE and is also a receptor for immune complexes of antigen with IgE

epidemic of allergy

in the last 30 years the incidence of allergy has increased twofold to threefold in developed countries

leukotrienes

in the later stages of allergic reactions, leukotrienes are principally responsible for inflammation, smooth muscle contraction, the constriction of airways, and the secretion of mucus from mucosal epithelium

eicosanoids

include prostaglandins and leukotrienes which are lipids synthesized from fatty acids

mast cell activation and degranulation in the blood vessels

increased blood flow, increased permeability--> edema and inflammation, increased flow of antigens in lymph to lymph nodes

mast cell activation and degranulation in the GI tract

increased fluid secretion, increased peristalsis --> expulsion of GI tract contents by diarrhea and/or vomiting

food allergies

ingestion of antigen activates mucosal mast cells. activated mast cells release histamine which acts on epithelium, blood vessels, and smooth muscle. antigen diffuses into blood vessels and is widely disseminated, causing urticaria. smooth muscle contraction induces vomiting and diarrhea. fluid outflow in to gut lumen

Fc-gamma-RIIB

inhibitory receptor that preferentially binds IgG4

adaptive immune response late phase

involve IgG1, IgG2, and IgG4, which are longer-lived, increasingly less inflammatory, and favor the formation of immune complexes

adaptive immune response early phase

involves IgM, IgE, and IgG3, which are short-lived, and between them they favor the inflammatory effector functions of complement fixation, mast-cell degranulation, and phagocytosis.

IgG4

last IgG isotype to be made; its synthesis is favored by the persistence of antigen, as occurs in parasitic infection. IgG4 cant fix complement and is preferentially bound by the inhibitory receptor Fc-gamma-RIIB. when IgG4 molecules acquire Fab arms of different specificities, they can bind tightly to antigen with just one of their Fab arms, which drives cross-linking. some B cells making high affinity IgG, particularly IgG4, can switch to IgE at a late stage in the germinal center reaction which produces high affinity for antigen which is used to arm mast cells, basophils, and activated eosinophils

type IV hypersensitivity reactions

mediated by antigen-specific effector T cells, especially by CD4 Th1 cells. for example the nickel allergy. when the skin comes into contact with the nickel in coins, jewelry, and belt buckles, small amounts of the metal permeate the skin, and bivalent nickel ions are chelated by histidine residues in human proteins. peptides containing the nickel-chelated 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 nickel. some rxns are due to CD8 T cells (poison ivy). symptoms felt 1-3 days after exposure

penicillin

mimics the substrate for bacterial transpeptidase that is essential for bacterial cell wall synthesis. reactive bond in the beta-lactam ring opens and binds covalently to the active site of the transpeptidase. same mechanism causes PCN molecules to bind covalently to surface proteins of human cells. this creates new epitopes that are seen as foreign antigens (erythrocytes)

multicellular parasites

much more similar to humans than viruses, bacteria, or fungi so they are inherently less antigenic. they are too big to be killed by phagocytic cells so the body tries to expel them by coughing, sneezing, nose blowing, vomiting diarrhea, itch induced scratching, and increasing mucus flow.

IgE

not retained by blood but instead concentrates in the tissues, where it binds Fc-epsilon-RI. IgE three dimensional structure is bent and asymmetrical "shrimp-like"

B cell vs mast cell diversity

one B cell has only 50,000-100,000 B cell receptors. one mast cell displays 500,000 Fc-epsilon-RI receptors on surface so it can display a variety of different IgEs at high density.

antibody isotypes isotype switching

primary immune response switches IgM to either IgG or IgE. the majority of responding B cells witch to IgG3 and the minority switch to IgE. IgE switched B cells quickly leave the germinal center and become plasma cells to produce low affinity antibodies. switching to the four IgG isotypes occurs in the same order that the C-region genes are located in the heavy chain locus. IgG3 is first, followed by IgG1, IgG2, and lastly IgG4.

allergic conjunctivitis

produces itchiness, tears, and inflammation

prostaglandin D2

promotes the dilation and increased permeability of blood vessels and also acts as a chemoattractant for neutrophils

aspirin

reduces inflammation by inactivating prostaglandin synthase, the first enzyme in the cyclooxygenase pathway. the inactivation is irreversible

mast cells

resident in mucosal and epithelial tissues lining the body surfaces and function in alerting the immune system to local trauma and infection, and facilitate the repair of damage. mast cell cytoplasm contains 50-200 large granules containing inflammatory mediators. mast cell granules contain histamine, heparin, TNF-alpha, & other enzymes and inflammatory mediators

allergy

state of hypersensitivity

Fc-epsilon-RI

the high-affinity IgE receptor on mast cells. this receptor is a tetramer of a unit comprising one alpha chain that binds the IgE, and three signaling chains (one beta and two gamma) that activate the mast cell when antigen cross-links IgE. this receptor is also constituitively expressed by basophils. a second form of this receptor is a trimer that is expressed on numerous cells after their activation by cytokines

combined effect of chemical mediators released by mast cells

to attract circulating leukocytes to the site of mast-cell activation, where they amplify the reaction initiated by antigen and IgE on the mast cell surface

type I hypersensitivity reactions

triggered by the interaction of an allergen with allergen-specific IgE bound to the FcepsilonRI receptor of mast cells, basophils, and eosinophils. this interaction causes these cells to degranulate and release a potent mixture of inflammatory mediators. effects are of varying severity, ranging from the irritation of a runny nose to stressful breathlessness and even death by asphyxiation. also called immediate hypersensitivity. unique to allergic disease

TNF-alpha

tumor necrosis factor activates endothelial cells, causing an increased expression of adhesion molecules, thus promoting leukocyte traffic from the blood into the increasingly inflamed tissue

delayed-type hypersensitivity (DTH)

type IV hypersensitivity reaction because symptoms come 1-3 days after exposure to antigen

parasite specific IgE

used to arm basophils, eosinophils, and mast cells, providing these inflammatory cells with specific antigen receptors that allow them to respond to antigen specific parasites. IgE is heterogeneous and only small amount is shown to be parasite specific

systemic anaphylaxis

when an allergin enters the bloodstream it can cause widespread activation of the connective tissue mast cells associated with blood vessels. disseminated mast cell activation causes both an increase in vascular permeability and a widespread constriction of smooth muscle

anaphylactic shock

when fluid leaves the blood and causes the blood pressure to drop drastically. this causes the connective tissue to swell. damage is sustained by many organ systems and their function is impaired.

H1 receptor

when histamine binds to H1 receptor on nearby smooth muscle cells and on endothelial cells of blood vessels, an acute allergic reaction occurs. stimulation of H1 receptor on endothelial cells induces vessel permeability and the entry of other cells and molecules into allergen-containing tissue, causing inflammation. smooth muscle cells are induced to contract on binding histamine, which constricts the airways. histamine acts of mucosal epithelia to increase the secretion of mucus.

eosinophil control mechanisms

when the body is healthy, the number of eosinophils is kept low by restricting their production in the bone marrow. in presence of infection or antigenic stimulation, the migration of eosinophils into tissues in controlled by a group of chemokines. they also regulate the expression of Fc-epsilon-RI. in resting state, eosinophils dont express Fc-epsilon-RI, dont bind IgE, and cant be induced to degranulate by antigen

atopy

word derived from Greek that allergists use, meaning 'out of place' or 'peculiar'. 40% of Caucasian populations of Europe and North America are atopic, meaning they have a genetic predisposition to allergy

late-phase reaction

6-8 hours after the immediate rxn has subsided, a second reaction occurs at the site of injection. this consists of a more widespread swelling and is due to the leukotrienes, chemokines, and cytokines synthesized by mast cells after IgE mediated activation

hygiene hypothesis

Excessive hygiene reduces childhood exposure to commensal and pathogenic microorganisms as well as to other humans and to animals. Vaccination reduces the developing immune system's experience in facing natural infections, fighting them to a successful conclusion and terminating them. Overreliance on abx to terminate infections reduces the use of the immune system and its education in the discrimination of self from foreign pathogenic microorganisms. abx also select for resistant superbacteria, which also perturb the immune system. In childhood the development of the immune system is held back. it becomes poorly educated, exercised, and inexpreienced in fighting real world infections. It turns to fighting imaginary infections and in the process causes a range of debilitating allergic diseases

Mastzellan

German for "fattened" or "well-fed" cells

skin allergies

allergen introduced into the skin of a sensitized individual causes mast cells in the connective tissue to degranulate. the histamine released dilates local blood vessels, causing rapid swelling due to the leakage of fluid and proteins into tissues.

allergic asthma

allergic reactions cause chronic difficulties in breathing, such as SOB and wheezing