Hypersensitivity

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Definition of hypersensitivity: innappropriate immune response;

not always increased, but inappropriate
immediate hypersensitivity: -initiators -manifested how soon after ag-encounter: anaphylactic reactions within the humoral branch, initiated by antibody or ag-ab complexes.

-symptoms manifest w/in min/hr or even days
dth: delayed type hypersensitivity;

delayed symptoms - days after exposure.
cell-mediated
humoral types of hypersensitivity:: 1. IgE mediated
2. Ab-mediated
3. immune complex-mediated.
Allergen: nonparasitic antigens that stimulate type 1 hypersensitivity.

humans are not usually stimulated by these ag, but are genetically predisposed to inappropriate stimulation of IgE.
which cells have Fc receptors and induce tpe 1 hypersens.: Mast cells (in tissue)
Basophils (in circulation)

both release vasoactive and smooth-muscle-contracting mediators.
categories of allergens that induce type 1 hypersens:: proteins
plant pollens
drugs (penicillin, anesthetis)
foods
insect products (bee venom, dust mites)
mold spores
animal hair/dander
what causes the allergic response in type 1 hyps?: the crosslinking of IgE that is on the membrane of basophils and mast cells. this causes degranulation and release of stimulating factors.
describe the sensitization phase of Type 1 hypersensitivity:: First exposure to antigen stimulates Ab production, class-switching to IgE. These bind to mast cells/basophils

Second exposure antigens cross-link IgE and induce degranulation of the mast cells and basophils.
why does IgE bind mast cells and basophils?: they have Fc receptors for the antibody.
Type 1 Hypersens. is really just a normal humoral response... but what is the key distinguishing feature?: Plasma cells secrete IgE
What are the two main effects of degranulation?: -Smooth muscle contraction
-Vasodilation

Either systemic or local depending on amount of antigen, degree of toxicity
Requirement of Antigens in order to crosslink IgE:: Must be divalent, not monovalent
What role do cytokines play in Type 1 hypersens.?: -They are inflammatory mediators like histamine and leukotriene, released from granules of MAST cells and eosinophils; recruit inflammatory cells, neutrophils and eosinophils.
What are the 4 mediators of the inflammatory response in type 1 hypersensitivity?: Histamine
Leukotrienes
Prostaglandins
Cytokines
what is allergic rhinitis?: hay fever
what is atopy?: the inherited tendency to manifest localized anaphylactic reactions to an allergen
4 types of common IgE-mediated disorers - Type 1 Hypersensitivity:: -Hay fever
-Food allergy
-Asthma
-Atopic dermatitis Eczema
Symptoms of hay fever, caused by what?: Runny nose and eyes, sneezing.
Due to localized vasodilation and increased capillary permeability from mast cell degranulation
What triggers Asthma, where does the reaction occur?: Mast cell degranulation; in the lower respiratory tract. Causes broncho-constriction, airway obstruction.
why is there a difference in the late and early asthmatic responses?: Early response primarily consists of constitutive inflamm. mediators - hist, prostagl., lktrienes. these vasodilate, bronchoconstrict.

Late response shows action of mediators synthesized after allergen exposure - cytokines, chemotactic, and PAF. These increase CAMS ad recruit inflamm. cells
two types of inflammatory mediators produced in Type 1 hypers. based on time: primary - stored in granules, released immediately -- histamine

secondary - synthesis is activated upon degranulation; prostaglandins/ leukotrienes broken from phospholipids.
what are the effects of histamine, how are they mediated?: -contraction of bronchial/intestinal smooth muscles
-vasodilation

binding to H2 receptors on mast cells is negative feedback, inhibits degran.
why are leukoriene/prostaglandin effects seen after histamine?: degranulation induces their production from phospholipids.

longer lasting effects than histamine.
bronchoconstriction, vascular permeability.
What does epinephrine do?: increases cAMP levels; prevents degranulation
4 main symptoms of early asthmatic response:: vasodilation
increased endothelial permeability
mucus production
bronchoconstriction
2 main symptoms of late asthmatic response:: -cell influx
-tissue damage
what are the steps of degranulation?: 1. Crosslinking activates PTK, transmembrane signalling.

2. Phospholipid methylation; increased Ca2+ channels. Arachidonic a. forms -> prostagl.leukotr.

3. Transient incr/decr of cAMP - necessary for degranulation
5 drugs for treating type 1 hypersens:: Antihistamines
Cromolyn sodium
Theophylline
Epinephrine
Cortisone
Action of Antihistamine:: blocks H1 and H2 receptors on target cells
Action of Sodium cromolyn: blocks ca2+ influx into mast cells
Action of theophylline: prolongs high cAMP levels; decrease is necessary for degranulation so this does not occur
method of epinephrine in preventing Type 1 hypersens:: stimulates caMP production
Action of cortisone:: prevents histamine production, stimulates cAMP production
is antihistamine alone sufficient to treat asthma? why?: no. because leukotrienes/prostaglandins are also released; these are more potent in action than histamine.

more effective for hay fever
what is the choice treatment for systemic anaphylaxis - what should you reach for first?: EPI PEN -> epinephrine increases muscle tone fast and prevents continued vasodilation.
Hallmark of Type 2 hypersensitvity:: RED BLOOD CELL LYSIS
-Ab binding Ag on RBC surface
-Transfusion reaction
2 types of incompatibility that cause type 2 hypersens:: ABO incompatibility of RBC
Allotypic incompatibility of RBC.
What is the principle of a type 2 hypersens. response? What is it really?: Antibody-mediated cell destruction:
1. by activating complement MAC attack, 2. opsonization for phagocytosis
3. ADCC -> NK cells, granulytic cells bind Fc of antibody, cause lysis.
ABO antibody is what isotype? Allotypic antibody is what isotype?: IgM - induced by intestinal organisms w/ similar epitopes. result is within hours.

IgG - induced by repeated blood transfusions with minor allelic difernces that stimulate minor Ab production. result is days later
Clinical manifestation of ABO incompatibility:: Huge lysis of RBC via complement; Within hours can see:
-hemoglobinuria
-toxic bilirubin levels
-fever, chills, blood clots,
-acute tubular necrosis
Clinical manifestation of allotypic incompatibility:: fever, hemoglobinemia, bilirubin, mild jaundice, anemia. less severe response than ABO because IgG is less efficient in activating complement.
What type of hypersensitivity causes hemolytic disease of the newborn?: type 2
hemolytic newborn disease is aka: erythroblastosis fetalis
what causes eryth. fetalis?: Baby is rH+ and mom is rH-.
Mom exposed during delivery; develops Anti-rH IgM antibody.
2nd pregnancy, anti-rH IgG can cross placenta and lyse baby's cells.
How does Rhogam work?: Binds any rH antigen in mom's circulation just after delivery; prevents immune response or production of any antibody.
Why do type 3 hypersensitivity responses develop?: Antigen-antibody complexes are not cleared, but still activate complement. cleaved compl. products are chemotactic/inflammatory mediators, so wherever the complex is deposited, lytic enzymes cause much damage. Can be local or generalized (serum)
what is a great example of a localized type 3 hypersensitivity reaction?: Arthus reaction - subcutaneous or epidermal injection of Ag.

Immune complex forms; complement activates, inflammation occurs. Tissue damage, IgG response
-TB skin test, Insect bite
what is the name for systemic Type 3 hypersensitivity?: Serum sickness
what is serum sickness caused by?: large amounts of Ag-Ab complexes in the circulatory system --> wherever they deposit is where an inflammatory response will develop with much tissue damage.
what can induce serum sickness?: injection of antibody from another species (horse antiserum)
what autoimmune diseases, drug reactions, or infectious diseases are examples of type 3 response: lupus
rheumatoid arthritis
penicillin allergy
post strep glomerulonephritis
meningitis
hepatitis
mono
malaria
manifestation of type 3 hyp in lupus:: red face -> small arteries are damaged by Ab/Ag complexes deposited in the kidney.
Why does glomerulonephritis develop in type 3 hyp?: Circulatory Ag-Ab complexes are deposited in the basement membrane; chemotactic factors call inflamm. response resulting in tissue damage.
what type of hypersens. response occurs after insect bite in a sensitive person?: initially type 1 -> crosslink of IgE

but 4-8 hrs later, Type 3 -> edema, buildup of pus, etc!
what is the major difference between type 3 and type 4 hypersens. cells recruited?: Type 3 calls up neutrophils

Type 4 calls up macrophages.
How is it that Type 4 hypersens. is INNATE and NONSPECIFIC, but it's CELL-MEDIATED?: Starts off by activated Th cells. They secrete cytokines that tell monocytes to adhere to endothelial cells, extravasate into tissues and differentiate into Macrophages.
When is DTH good, and when is it bad?: Good: buildup of phagocytic cells destructs intracellular pathogens nonspecifically. Eliminates pathogen.

BAD: when pathogen won't eliminate; persistant buildup leads to tissue necrosis via GRANULOMA
What is a granuloma? why is it bad?: a fused ball of activated macrophages that formed a multinucleated giant cell.

Displaces normal tissue, releases lytic enzymes, destroys tissue.
What type of response results in Mycobacterium Tuberculosis infections?: DTH --> tubercle forms --> this is a huge granuloma of macrophages surrounding the infected cell. causes lung tissue damage.
what are the 2 APC in DTH?: langerhans cells
macrophages
what type of bacteria is DTH especially effective in combating?: intracellular --> antigen is presented on MHC2 and activates Th cells; subsequent exposure causes cytokine release and inflammation
what type of hypersensitivity is induced during a TB skin test?: Type 4; injection of bacterium antigen causes release of cytokines and influx of macrophages.
cytokines secreted by Th cells in DTH:: IFN-y, TNF-a/B, IL-2, Chemokines
What is the effect of activating macrophages?: Increased MHC2 enhances Ag presentation
Increased TNF receptors enhances phago.

Increased O2 radicals and Nitric oxide enhance respiratory burst for killing bacterial cells during phagocytosis.
what types of substances cause contact dermatitis?: chemicals, nickel, hair dye, poison oak/ivy
what is contact dermatitis?: small molecules complex w/ skin protein;
after phagocytosis of complex, it's presented as Ag on APC. Activates Th1 cells for DTH response.
Role of TNF-a in type 1 hyp:: -secondary mediator that stimulates chemotaxis of neutrophils and eosinophils;

-contributes to systemic anaphylactic shock
what do the early and late responses of asthma generally consist of?: early: histamine/leukotriene/prostagl.

late: cytokines (IL-4,5,6, Eosin chemotactic factor, PAF) to increase endothelial CAMS and recruit inflammatory cells
what do skin lesions in Type 1 atopic dermatitis contain? What about in Type 4?: Thelper2 cells and eosinophils

Macrophages and not many Th1 cells
WHY is IgE the mediator of Type 1?: PAtient suffers regulatory defects for IgE;

nonparasitic antigens can stimulate inappropriate activity of IgE.

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