Ch14 (from the book)

exaggerated response to a typically harmless antigen that results in injury to tissue

anaphylactic hypersensitivity

exposure to antigen induces production of IgE antibody, which binds to mast cells and basophils

degranulation with release of chemical mediators that produce allergy symptoms

antibody-mediated cytotoxic hypersensitivity

IgG and IgM

complement-mediated lysis;
dysfunction of the cell by blocking the binding of a ligand to a surface receptor;
over stimulation of cell's function

complex-mediated hypersensitivity

IgG or IgM

react with soluble antigens to form complexes that precipitate in the tissues and activate complement;
recruits PMNs to site causing injury

uses sensitized T cells rather than antibodies

cell-mediated hypersensitivity

release of cytokines that induce inflammation and tissue damage

Types I, II, and III

symptoms develop within minutes to hours after antigen exposure

type IV

reaction not seen until 24-48 hrs after antigen contact

allergies

allergens

IgE

bind to receptors on mast and basophils

reactions produce a large amt of IgE in response to small concentration of allergen

inherited tendency to develop classic allergic responses to naturally occurring inhaled or ingested substances

IgE, mast, basophils, eosinophils

when individual is exposed to allergen and produces specific IgE

B cells and plasma cells

Type 2 helper T cells (Th2)

balance between Th2 and Th1 to provide protective immunity and not harm host

immune response shifted so that Th2 cells predominate, resulting in production of cytokines

IL-4, IL-13

final differentiation of B cells that codes IgE

sensitization
activation

the IgE antibody attaches to FcɛRI that binds to Fc

mast cells and basophils

Langerhans and dendritic cells

transported to MHC class II to lymphoid tissue where IgE synthesis occurs

IgE

mast cells

around small blood vessels, lymphatics, nerves, and granular tissue

have cytoplasmic granules that store numerous preformed inflammatory mediators

peripheral blood

basophils have fewer (but larger) granules than mast

chemotactic stimuli during inflammation

triggers degranulation with release of inflammatory mediators

adjacent cell-bound IgE crosslinked causing aggregation of the surface FcɛRI receptors

initiates complex intracellular signaling events that increase intracellular calcium

multiple phosphorylation, influx of Ca+, and secretion of cytokines

triggers degranulation of mast and basophils, releasing chemical mediators that were stored in granules

histamine, heparin, ECF-A, neutrophil chemotactic factor, and proteases

early-phase symptoms of allergic reactions by binding to receptors on target organs

late phase

platelet activating factor (PAF), prostaglandins (PG) D2, leukotrienes (LT), B4, C4, D4, E4, cytokines

cells exit circulation and infiltrate allergen filled tissue, releasing additional mediators that prolong the hyperactivity and lead to tissue damage

eosinophils

release variety of toxic molecules and inflammatory mediators from granules, contribute to ongoing damage

structural changes due to persistent inflammation
(thickening of smooth muscle, changes in connective tissue, bld and lymph vessels, mucus glands, nerves)

genetic and environmental triggers

1. affects where & how microbes and allergens enter;
2. recognition of ag by innate
3. susceptibility due to adaptative immunity (cytokine and T cell ability)
4. influence long term consequence of allergies

early exposure to diverse microbial populations protect against allergies by inducing beneficial Th1 responses (and away from Th2 atopic reactions)

severe system response caused by inflammatory mediators from mast and basophils

rhinitis (hay fever), asthma, food allergies, urticaria (hives), eczema, angioedema (deep in dermal area), systemic anaphylaxis

allergen introduced into bloodstream, absorbed in gut or skin

bronchial constriction, decreased BP, laryngeal edema, rapid secretion of mast mediators

1. allergy avoidance
2. drug therapy
3. monoclonal anti-IgE antibody
4. allergy immunotherapy (AIT)

antihistamines, bronchodilators, mast cell stabilizers, corticosteroids, Epi pens, leukotriene receptor antagonists

binds to C3ɛ on IgE so that IgE can't bind to FcɛRI receptors

induce immune tolerance to specific allergen by gradually increases doses over time

shift patients immune response to Th1 type and induce Tregs that release IL-10

redirects immune to produce allergen-specific IgG4 'blocking' antibodies that combine with antigen before it can attach to IgE and trigger degranulation

percutaneous test or intradermal that can detect hypersensitivity to allergens, indicated by wheal and flare reaction

procedure is less expensive, more sensitive to serologic, and provides immediate results

percutaneous: allergens applied to upper layers of skin
intradermal: higher doses of allergens between layers of skin (greater risk of anaphylaxis)

specific IgE

sensitization to the allergen

used to detect allergen-specific IgE in pt serum

total serum - uses anti-IgE bound to solid phase
allergen specific - uses antigen bound to solid phase

fluorescence is in proportion to the amount of allergen-specific IgE in the sample

radio immunosorbent test

uses labeled IgE to compete with pt IgE for binding sites on a solid phase coated with anti-IgE

antibody-mediated cytotoxic hypersensitivity

involved IgG and IgM antibodies direct against antigens found on cell surfaces (self or heteroantigens)

abnormal production of IgG or IgM directed against tissue antigens or a normal reaction to foreign antigens expressed on host

1. cell is destroyed
2. function of cell is inhibited
3. function of cell is increased above normal

1. activation of classical complement and formation of MAC (for cell lysis)
2. coating cell surface promotes opsonization and phagocytosis
3. ADCC

1. through binding of IgG to mq and PMNs or
2. binding surface C3b to complement receptors on phagocytic cells

binding stimulates release of cytotoxic enzymes that destroy the cell
binding of IgG to antigen on cell surface and to the Fc receptors on mq and NK

HDN, transfusion reactions, autoimmune hemolytic anemia

when antibody blocks the binding of ligand to its receptor, resulting in dysfunction

myasthenia gravis (autoimmune disease)

patients produce autoantibodies to receptors on muscle cells for the neurotransmitter acetylcholine (ACH)

binds to receptors on muscle cells, stimulating contraction and movement

ACH receptor blocks binding of ACH, leading to muscle weakness

binding of antibody to self-antigen stimulates the cell; leading to overproduction of cell product

Graves disease (autoimmune disorder of the thyroid gland)

patients produce antibodies against the receptor for TSH

binds to TSH receptors and stimulates thyroid cells to produce hormones that increase metabolism

autoantibody binds to TSH receptor, resulting in unregulated production of thyroid hormones (increased metabolism = hyperthyroidism)

transfusion reactions, HDN, autoimmune hemolytic anemia, Goodpasture's syndrome, Hashimoto's disease

naturally occurring Anti-A and Anti B antibodies from ABO blood group

patient has been exposed to the antigen before and has preformed antibodies to it

ABO blood group incompatibilities and IgM antibodies

IgG

Rh, Kell, Duffy, Kidd

antibody-coated RBCs are removed extravascularly in the spleen or in the liver

in infants of mothers who have been exposed to blood-group antigen on the baby cells that differ from their own

erythroblastosis fetalis

D antigen (of Rh blood group)

during the birth process when fetal cells leak into mothers in first born

exchange transfusion to replace antibody-coated RBCs, Rhogam

directed against self-antigens; form antibodies against their own RBC

warm reactive antibodies (at 37 degrees) and cold reactive antibodies (below 30 degrees)

formation of IgG antibody that reacts most strongly at 37 degree

underling cause of antibody production is unknown

viral or respiratory (mono, cytomegalovirus, chronic hepatitis)
immunoproliferative (chronic lymphocytic leukemia and lymphomas)

drugs capable of attaching to RBCs directly or of forming immune complexes that attach to RBC

1. act as haptens
2. modify RBC membrane
3. stimulate production of anti-drug antibodies
4. stimulating production of autoantibodies

act as haptens after binding to proteins on RBC membrane; stimulate the production of anti-drug antibodies that destroy RBCs (through extravascular hemolysis)

modify RBC membrane by facilitating binding of immunoglobulins and complement

stimulate production of anti-drug antibodies that bind to drug to form soluble immune complexes; loosely attach to RBC and cleared by intravascular hemolysis after complement binding

induce hemolytic anemia by production of autoantibodies against RBC membrane

because of clearance of antibody-coated RBCs by mq in liver and spleen

IgG is not as efficient as IgM in activating complement

autoantibodies that react with antigens on the RBC membrane at cold temperatures

IgM

below 30degrees, antibodies bind to RBCs to form lattices which can obstruct the small capillaries in the skin (acrocyanosis)

produce a biphasic autoantibody that binds to RBCs are cold temps and activates complement at 37C to produce intermittent hemolysis

measles, mumps, chickenpox, and mono

organ-specific disease in which antibody is directed against a particular tissue due to combination with antibody

antibody binds to glomerular BM and alveolar capillaries and triggers the complement cascade

Hashimoto's, myasthenia gravis, insulin dependent diabetes

to detect transfusion reactions, HDN, and autoimmune hemolytic anemia

patient RBCs (coated with antibody)

patient's serum (containing ig) along with donor blood sample

used in crossmatching of blood to prevent a transfusion reaction

presence of a particular antibody in a patient or type patient RBCs for specific blood group antigens

1. immune complex formation
2. immune complex deposition
3. inflammatory reaction

IgG or IgM are involved and destruction is complement mediated

antigens bind to antibodies, forming circulating immune complexes. Which can later migrate out of plasma and deposit in tissues

antigen is soluble

complexes are formed that precipitate out of the serum (normally cleared by phagocytic cells)

complexes formed at deposited in tissues, binding to complement and causing damage to tissue

complexes are insoluble, do not circulate, and are phagocytosed by mq in the lymph nodes and spleen

glomeruli and joints

the aggregates are smaller, freely filter out of circulation where the blood is transformed into other fluids (like urine / synovial)

causes a release of mediators that increase vasodilation, Vaso permeability, attract mq and PMN, and enhance binding of phagocytic cells by C3b-mediated opsonization

granule and lysosome contents are released by exocytosis

damage to host tissue; long term can be loss of tissue elements that cannot regenerate and accumulation of scar

inflammatory response caused by antigen-antibody combination and subsequent formation of immune that deposit in small dermal blood vessels

complement is fixed, attracting PMNs and causing aggregation of platelets

release toxic products (oxygen-containing free radicals and proteolytic enzymes)

because C3a and C5a generated activate mast cells to release permeability factors

after booster injections (with tetanus, diphtheria, measles vaccines)

passive immunization of humans with animal serum

1. produces antibodies against nuclear constituents (like DNA and histones)
2. produce antibody against IgG (RA)
(autoantibodies combine with antigen to produce immune complexes)

SLE and RA

joints, skin, glomerular BM in kidneys

joints

components of vaccines, bee stings, treatment with drugs, infections, viral hep, and group A strepto

indirect immunofluorescence, enzyme-linked immunosorbent assay, fluorescent microsphere multiplex immunoassays

measuring complement levels

complement levels decreased due to binding of some of the complement to antigen-antibody complexes

sensitized T cell

delayed hypersensitivity

Th1 subclass of Th cells

Langerhans cells and mq capture antigen and migrate to lymph nodes to present to Th cells; APCs release cytokines that promote differentiation of T cells into Th1 and other Tcell subs

When Th1 cells migrate to the site where antigen is located, inducing inflammatory reaction

cytotoxic T cells

monocyte chemotactic protein (MCP-1 / CCL2)

release cytokines to induce hematopoiesis of cells and chemokines to recruit mq to site

becomes activated mq by IFN-y and TNF-B, releasing ROS, nitric oxide, and proinflammatory mediators that require more mq and turn mq into APCs

organized clusters of cells developed by chronic persistence of antigen
clusters = epithelioid-shaped multinucleated fused mq with an infiltrate of WBC

wall of the organism in a contained area (preventing spread)

cells released large amount of lytic enzymes that destroy surrounding tissue and promote fibrin deposition

intracellular pathogens
contact antigens

Mycobacterium tuberculosis (MTB), m. leprae, P. carinii, Leishmania, herpes

poison ivy, poison oak, chemical urushiol (plant sap and leaves), metals

skin eruptions caused by erythema, swelling, and formation of papules

haptens that bind to glycoproteins on skin cells and then processed by Langerhans and eventually presented to T cells

exposure to chemicals, poison ivy, latex

allergic disease of the lung parenchyma characterized by inflammation of alveoli and interstitial spaces

inhaled antigens

the absence of positive reactions for all of the common antigens used in skin test