what is hypersensitivity?

inappropriate secondary responses against harmless antigens

result in more harm than benefit (the reaction is worse than the antigen)

types of classification of hypersensitivity?

time until response

mechanisms

types of damage caused

type I hypersensitivity mechanism

IgE

type I hypersensitivity allergy

peanuts

type II hypersensitivity mechanism

IgG/IgM (cells)

type II hypersensitivity allergy

hemolytic anemia

type II hypersensitivity transplantation

hyperacute rejection

type II hypersensitivity autoimmunity

autoimmune hemolytic anemia

type III hypersensitivity mechanism

IgG/IgM (IC)

type III hypersensitivity allergy

serum sickness

type III hypersensitivity transplantation

chronic rejection

type III hypersensitivity autoimmunity

SLE

type IV hypersensitivity mechanism

T cells

type IV hypersensitivity allergy

poison ivy

type IV hypersensitivity transplantation

acute rejection

type IV hypersensitivity autoimmunity

type I diabetes

which characteristics make parasites different than other pathogens?

they are multicellular organisms that are similar to humans

they are too big for phagocytosis

in general, what is the body's strategy to eliminate a parasite?

physical force for expulsion (coughing, sneezing, vomiting, diarrhea)

increased mucus for protection

what are the characteristics of type 2 immunity?

T(H)2 cells secrete cytokines that lead to IgE

parasite specific IgE antibody binds to FceR on basophils, eosinophils, and most cells

explosive reaction that dislodges that parasite from tissue that leads to expulsion

attempts to minimize collateral damage

example of type 2 immunity

IL-13 leads to mucous secretion; enterocyte turnover

early phase isotype switching

complement fixation

mast cell degranulation

phagocytosis

late phase isotype switching

immune complex formation

IgG4 preferentially binds to

FcyRIIB which is inhibitory

what are the unique structural/functional characteristics of IgE?

not soluble, but binds to FceRs

IgE has asymmetric shrimp shape that binds with high affinity

allergy associated with IgE

a type I hypersensitivity is an inappropriate IgE response against a harmless antigen

most individuals will have response against these antigens but it's usually another antibody isotype

two phases of hypersensitivity

the sensitization stage is the primary immune response to an antigen

the effector stage is a secondary immune response to the same antigen

what is omalizumab?

high affinity monoclonal antibody IgG specific for human IgE

recognizes and binds the Fc region of the IgE; binds soluble IgE but not bound IgE

prevents arming or sensitizing to the allergen

does not lead to susceptibility to disease

what are basophils?

basic-staining granulocytes: contain granules

similar developmental program to eosinophils, but are then reciprocally regulated

make up a very small percentage of leukocytes in the blood

how do basophils help initiate TH2 response?

secrete TH2 polarizing cytokines (IL-4 and IL-13)

express CD40L, which can bind to CD40 on B cells and drive isotype switching

what are eosinophils?

granules are loaded with arginine-rich basic proteins

named because they stain strongly with eosinophil

like mast cells, external stimulus causes them to release toxins and inflammatory mediators

reaction is highly toxic and damaging to host and parasite

eosinophilia

abnormally high numbers of eosinophils

damage to heart endocardium and to nerves

what are mast cells?

present in all vascularized tissues

maintain the integrity of the surrounding tissue

alert immune system to trauma and infection

repair damage caused by wounds and infection

recruit neutrophils, eosinophils, and effector T cells, and growth factors

what is the role of histamine in defense against parasites?

binds to one of four possible histamine receptors

acute allergic reactions are often caused by histamine binding to H1 of smooth muscle and endothelial cells

mast cells release TNFa which is complementary to histamine

histamine release is immediate

H1:

binding induces contraction of intestinal and bronchial smooth muscles, increased permeability of venules, and mucous secretion

H2

binding increases vasopermeability and vasodilation, stimulates exocrine glands, and increases stomach acid; also suppresses degranulation of mast cells/basophils in a negative feedback loop

H3

less involved in type 1: modulates neurotransmitter activity in CNS

H4

mediates mast cell chemotaxis

secondary mediators

formed when membrane phospholipids are enzymatically cleaved into eicosanoids

active at nanomle levels

the overall function of mast cells degranulation is to circulating leukocytes. to the site of activation to amplify the reaction initiated by antigen cross-linking of IgE

what is the purpose of tryptase, chymotryptase, and other proteases?

mast cells also make tryptase, chemotryptase, and other proteases; to help dislodge parasites

molecular type of inhaled allergens that favor type 2 immunity and IgE production

proteins; they induce T-cell responses

functions of inhaled allergens that favor type 2 immunity and IgE production

many allergens are proteases

low dose of inhaled allergens that favor type 2 immunity and IgE production

favors activation of IL-4 producing TFH2 cells

low molecular mass of inhaled allergens that favor type 2 immunity and IgE production

allows allergen to diffuse from particle to mucus

high solubility of inhaled allergens that favor type 2 immunity and IgE production

allergen readily elutes from particle

high stability of inhaled allergens that favor type 2 immunity and IgE production

allergen survives in desiccated particles

peptides presented by MHC class II of inhaled allergens that favor type 2 immunity and IgE production

needed for T-cell activation

what is sensitization?

the condition of a person who has been exposed once to an allergen and has made IgE antibodies against it

common examples of sensitization

dried feces of the dust mite

the specific antigen is a cysteine protease

circulated currents from HVAC

particles trapped in the mucous and carried to MHC II

predisposing environmental factors of allergy

air pollution

westernized countries

low gut microbial diversity

low fiber diet

protective environmental factors of allergy

farm environment

developing countries

high gut microbial diversity

high fiber diet

MHC class II alteration

affects coding sequence

enhanced presentation of allergen-derived peptides

T-cell receptor alpha chain alteration

noncoding

enhanced T-cell recognition of antigen-derived peptides

TIM family alteration

promoter and coding sequence

regulation of type 1/type 2 balance

IL-4 alteration

promoter altered IL-4 expression

IL-4 receptor alpha chain alterations

coding sequence

increased signaling in response to IL-4

high-affinity IgE receptor beta chain alteration

coding sequence

variation in the ligation of IgE by antigen

5-lipoxygenase alteration

promoter

variation in leukptriene production

what are important cytokines involved in allergy?

IL-4,3,9,12,13, GM-CSF

isotype switching, eosinophil survival, mast cell proliferation

what is atopy

the tendency to develop abnormal TH2 responses to harmless antigens

what are some examples of atopy?

allergic rhinitis

asthma

atopic dermatitis

food allergies

what is the wheel and flare?

a reaction observed when small amounts of allergen are injected into the dermis of an individual who is allergic to the antigen. it consists of a raised area of skin containing fluid (wheel) with a spreading, red, itchy reaction surrounding it (flare)

what is the effector phase?

the effects of IgE-mediated allergic reaction will vary according to the site of cell activation

early response

occurs within minutes of allergen exposure

mediated by mast cell granule release of histamine, leukptrienes, and prostaglandins

late response

occurs within hours later of allergen exposure

a result of recruited cells

cytokines released from mast cells increase expression of chemokines and CAMs on endothelium facilitating influx of neutrophils, eosinophils, and TH2

eosinophils play a large role in late-phase recruiting neutrophils and degranulation

what are the symptoms of allergies in the blood?

increased vascular permeability; constriction of smooth muscle; blood pressure reduction; swelling (edema) in connective tissues

leads to organ damage, impaired function, cause of death is often asphyxiation due to constriction of airway and swollen epiglottis

anaphylaxis

release of IgE leads to mass activation of mast cells and basophils via IgE -> FceR interactions

how is anaphylaxis treated?

stop exposure to the antigen

manage ABC

epinephrine injection

trendelenburg position

oxygen

antihistamines

corticosteroids

epinephrine

epinephrine

stimulates reformation of tight junctions in the vascular endothelium

reduces permeability

increased blood pressure

relaxes bronchial smooth muscle

stimulates the heart

allergic rhinitis

hay fever

allergens diffuse across mucous membrane and activate mucosal mast cells beneath it

local edema causing obstruction of the nasal airways and nasal discharge

allergic conjunctivitis

itchy, scratchy, watery eyes

similar to allergic rhinitis, but at the eye

allergic asthma

allergens activate submucosal mast cells in the lower airways of the respiratory tract

leads to mast-cell degranulation and increased secretion of fluid and mucus into the respiratory tract

bronchial constriction caused by contraction of smooth muscle

chronic inflammation

can lead to chronic asthma

what are examples of allergies in the skin?

atopic dermatitis (eczema)

atopic urticaria (hives)

how do food allergies occur?

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

how is type I sensitivity tested for?

skin testing is commonly used (it's cheap):

injection of small quantities of known allergens under skin

swelling and redness (resulting from local mast cell degranulation) indicate allergic response

how is type I treatments tested for?

antihistamines bind and block H1 receptors on target cells

leukotriene antagonists work in a manner similar to antihistamines

inhalation corticosteroids inhibit innate immune cell activity in airways

desensitization immunotherapy

blood transfusions (type II hypersensitivity)

blood group antigens are carbohydrates

people possess antibodies against the blood type they do not have

if an individual receives a transfusion of the "wrong" type of blood, their antibodies will quickly attach to the donor blood cells and trigger complement proteins

erythroblastosis fetalis (type II hypersensitivity)

hemolytic disease of the newborn; develops when maternal IgG antibodies specific to expressed RhD allele cross the placenta

destroys fetal RBCs by binding and activating complement; causes child to be anemic as well as a build-up of toxic RBC

hemolytic anemia (type II hypersensitivity)

can be drug induced

some drugs can absorb nonspecifically to proteins on RBC membranes

these drug-protein complexes may stimulate antibody production

antibodies then bind to RBCs when the drug is present, stimulating complement mediated destruction

penicillin can induce all four types of hypersensitivities under the correct circumstances for each other

what mediates destruction in type III hypersensitivity?

immune complexes

how does type III hypersensitivity occur?

if immune complexes aren't cleared effectively, they may deposit in tissues and can cause damage

may trigger release of inflammatory mediators and vasoactive mediators

proteases released may damage connective tissues

clots may form as complexes activate platelets

what are the symptoms of type III hypersenstivity?

fever, rashes, joint pain, lymph node, enlargement, and proteinuria

vasculitis if in blood vessel

autoantigens

glomerulonephritis if in kidney

arthritis in joints

what is contact dermatitis?

sensitization can occur if a reactive chemical compound binds to skin proteins, which are modified and then presented to T cells

could be induced by cosmetics, pharmaceuticals, industrial chemicals, metal ions, poison ivy, poison oak

can cause strong cell mediated responses against skin cells, inducing blister like lesions and rashes

what is chronic inflammation?

inflammation doesn't always resolve in a short period of time; it may last indefinitely, contributing to numerous other problems