1 Hypersensitivity Reactions

7/31/2019 1 Hypersensitivity Reactions

1/55

HYPERSENSITIVITY

Kathrina S. Perez, MD, DPSP


2/55

Exposure to antigen

SENSITIZATION

Repeat exposure to same antigen

HYPERSENSITIVITYREACTION


3/55

Hypersensitivity reactions

May be elicited by exogenous or endogenousantigens

Endogenous Agautoimmune diseases

Minor trivial forms to fatal reactions

reflects an imbalance between the effectormechanisms of immune responses and the

control mechanisms that serve to normally limitsuch responses


4/55

Types of hypersensitivity reactions

Type I Immediate

Type II Antibody-mediated

Type III Immune complex-mediated Type IV - Cell-mediated


5/55

Immediate (type I) hypersensitivity

Rapid, occurs within minutes

mediated by IgE antibody-dependent activationof mast cells and other leukocytes

Ag + Ab bound to mast cells in persons withprevious sensitization to Ag

Reaction may be systemic (e.g. after injection ofAg) or local (depending on portal of entry of

allergen) Examples: Skin allergy, conjunctivitis, rhinitis,

bronchial asthma, gastroenteritis


6/55


7/55

IMMEDIATE OR INITIAL REACTION

Vasodilation, vascular leakage, smooth muscle

spasm, glandular secretion

Seen 5-30 minutes after exposure

Subside in 60 minutes

LATE-PHASE REACTION

infiltration of tissues with eosinophils, neutrophils,

basophils, monocytes, CD4+ T cells

Tissue destruction (mucosal epithelial damage)

Seen in 2-24 hours without additional exposure to

allergen, may last for days


8/55


9/55


10/55


11/55

Mast cells

Widely distributed in tissues (bloodvessels, nerves, subepithelium)

have cytoplasmic membrane-bound

granules that contain a variety ofbiologically active mediators

activated by the cross-linking of high-

affinity IgE Fc receptors, complementcomponents C5a and C3a(anaphylatoxins)


12/55

Mast cells

chemokines (e.g., IL-8), drugs such ascodeine and morphine, adenosine, mellitin(in bee venom), and physical stimuli (e.g.,

heat, cold, sunlight)

Basophils- same as mast cells but are notnormally present in tissues - circulate in

the blood in very small numbers


13/55


TH2 has a central role in the initiation andpropagation of immediate hypersensitivity

reactions by stimulating IgE production and

promoting inflammation; they produce IL-4 switching of Ab class to IgE

IL-5 - development and activation of eosinophils

IL-13 - enhances IgE production and acts onepithelial cells to stimulate mucus secretion


14/55

Preformed mediators

Vasoactive amines Histamine smooth muscle contraction,

increased vascular permeability & mucussecretion

Enzymes neutral proteases (chymase, tryptase) and

several acid hydrolases Cause tissue damage

Proteoglycans Heparin, chondroitin sulfate Pack the amines into granules


15/55

Lipid mediators

synthesized by sequential reactions in the mastcell membranes that lead to activation ofphospholipase A2 yield arachidonic acid

Leukotrienes

Prostaglandin D2 Platelet-activating factor

CytokinesPromote leukocyte recruitment, additional sourcesof cytokines and of histamine-releasing factorsthat cause further mast cell degranulation


16/55

Mast cell mediators.Upon activation, mast cells releasevarious classes of mediators that areresponsible for the immediate andlate-phase reactions.

ECF, eosinophil chemotactic factor;NCF, neutrophil chemotactic factor(neither of these is biochemicallydefined);PAF, platelet-activating factor


17/55

dependent on the coordinated actions of avariety of chemotactic, vasoactive, andspasmogenic compounds

Activated eosinophils and other WBCs alsoproduce mediators which directly activate mastcells to degranulate -- recruited cells amplify

and sustain the inflammatory response withoutadditional exposure to the triggering antigen



18/55


Atopy

predisposition to develop localized immediatehypersensitivity reactions to a variety of inhaled

and ingested allergens higher serum IgE levels, and more IL-4-producing TH2 cells

positive family history of allergy found in 50% of

atopic individuals


19/55


Non-atopic allergy

triggered by temperature extremes and exercise,and do not involve TH2 cells or IgE

mast cells are abnormally sensitive to activationby various non-immune stimuli


20/55

Systemic anaphylaxis

vascular shock, widespread edema,difficulty in breathing

Triggers:

foreign proteins (e.g., antisera), hormones,enzymes, polysaccharides, and drugs(e.g. penicillin)

food allergens (e.g. peanuts, shellfish)

insect toxins (e.g. bee venom)


21/55

Systemic anaphylaxis

itching, hives, and skin erythema appear withinminutes, followed shortly thereafter by a strikingcontraction of respiratory bronchioles and

respiratory distress Laryngeal edema hoarseness, dyspnea

Vomiting, abdominal cramps, diarrhea

patient may go into shock and even die withinthe hour!


22/55

Local Immediate Hypersensitivity Reactions

urticaria, angioedema, allergic rhinitis (hayfever), and bronchial asthma

Seen in 10-20% of the population


23/55


Summary:

complex disorder resulting from an IgE-mediated triggering of mast cells andsubsequent accumulation of inflammatorycells at sites of antigen deposition


24/55


regulated mainly by the induction of TH2 helperT cells that stimulate production of IgE (whichpromotes mast cell activation), cause

accumulation of inflammatory cells (particularlyeosinophils), and trigger secretion of mucus

clinical features result from release of mast cell

mediators as well as the eosinophil-richinflammation


25/55

Antibody-mediated (type II)hypersensitivity

caused by antibodies that react withantigens present on cell surfaces or in theextracellular matrix

Intrinsic Ags Extrinsic Ags adsorbed on cell

surface/matrix

Resultant injury due to inflammation,complement- & Fc receptor-dependentreactions


26/55


27/55


Occur in the following settings:

1) Transfusion reactions

cells from incompatible donor react with and are

opsonized by preformed antibody in the host

2) Hemolytic disease of the newborn(erythroblastosis fetalis)

Maternal IgG Abs cross placenta & destroy fetalred cells


28/55


3) Autoimmune hemolytic anemia, agranulocytosis& thrombocytopenia

Person with Abs against his own blood cells

4) Certain drug reactions

drug acts as a "hapten" by attaching to surfacemolecules of red cells Abs are produced

against the drug-membrane protein complex


29/55

Antibody-mediated (type II)diseases

Autoimmune hemolytic anemia Autoimmune thrombocytopenic purpura Pemphigus vulgaris Vasculitis caused by ANCA Goodpasture syndrome Acute rheumatic fever Myasthenia gravis (Ab impairs receptor function)

Graves disease (hyperthyroidism) (Ab stimulatesreceptor function) Insulin-resistant diabetes Pernicious anemia


30/55

Immune complex-mediated (type III)hypersensitivity

Results from antigen-antibody complexesproducing tissue damage by elicitinginflammation at the sites of deposition

ICs typically deposited in vessel walls

Some ICs in extravascular sites where Ag mayhave been "planted" previously (in situ immunecomplexes)

Ags may be exogenous or endogenous Diseases may be systemic or localized


31/55

Systemic immune complex disease

Prototype: Acute Serum Sickness

sequela to the administration of largeamounts of foreign serum (e.g., serumfrom immunized horses used for protectionagainst diphtheria)


32/55

Introduction of protein Ag

Formation of Abs after 1 week

Abs secreted into blood

1st phase: Abs react with Ag still present in blood, forming Ag-Abcomplexes

2nd phase: circulating antigen-antibody complexes deposited in various

tissues

3rd phase: Immune complexes initiate acute inflammatory reaction (10 daysafter)


33/55


34/55


Complexes of medium size are most pathogenic(slight Ag excess)

Organs where blood is filtered at high pressureto form other fluids, like urine and synovial fluid,are favored (glomeruli, joints)

3

rd

phase: fever, urticaria, joint pains(arthralgias), lymph node enlargement, andproteinuria appear


35/55


complement-fixing Abs (i.e., IgG and IgM) andAbs that bind to leukocyte Fc receptors (somesubclasses of IgG) involved

Consumption of complement in active phase ofdiseasedrop in serum C3 level can be usedfor monitoring

Single exposure to Ag lesions resolve Prolonged exposure to Ag results in chronic formof serum sickness (e.g. SLE)


36/55

Local immune complex disease (ArthusReaction)

localized area of tissue necrosis resulting fromacute immune complex vasculitis, usuallyelicited in the skin

Injection of Ag in sensitized animal with circulating Abs vs the Ag

Ag diffuses thru vascular wall, binds with Ab & forms immune complexes

Complexes precipitate in vessel walls

Fibrinoid necrosis, thrombosis, ischemic injury


37/55

Immune complex vasculitis. The necrotic vessel wall is replaced by smudgy, pink" "


38/55

Immune complex-mediated (type III)hypersensitivity

SLE nuclear antigens

PSGN - streptococcal cell wall antigen(s); may be "planted" in glomerularbasement membrane

Polyarteritis nodosa HBV Ag in some cases Reactive arthritis bacterial Ag (e.g. yersinia)

Serum sickness various proteins (e.g. foreign serum protein)

Arthus reaction - various proteins


39/55

T-Cell mediated (type IV)hypersensitivity

initiated by antigen-activated (sensitized) Tlymphocytes, including CD4+ and CD8+ T cells

Adaptive immune system plays a vital role

(immune inflammation) Reactions by CD4+ T cells initially called

delayed-type hypersensitivity (DTH)

Responsible for chronic reactions vs self-tissues


40/55


phases:

Proliferation & differentiation of CD4+ T cells

Responses of Differentiated Effector T Cells


41/55

Proliferation & differentiation of CD4+ Tcells

Peptides displayed bydendritic cells, APCs

Nave CD4+ T cells

Secrete IL-2, proliferation ofAg-responsive forms

APCs produce cytokines

TH1 subsetmacrophage-mediated

reactions

TH2 subset-PMN-mediated

reactions


42/55

Responses of DifferentiatedEffector T Cells

Repeat exposure to antigen

Previously activated T cells respond to Ag presented by APCs

TH1 cells secrete IFN-

Macrophages activated,augmented power, secrete

more cytokines to amplify TH1response

Ag eliminated

TH17 secrete cytokines

Neutrophils & monocytesrecruited to the reaction

Promoted inflammation


43/55

A, In delayed-type hypersensitivity reactions, CD4+ TH1 cells (and sometimes CD8+ T cells, not shown) respond to tissue antigensby secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. CD4+ TH17 cells contribute to

inflammation by recruiting neutrophils (and, to a lesser extent, monocytes).B, In some diseases, CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells

C


44/55


CD8+ CTLs kill antigen-bearing target cells

CTLs vs cell surface MHC Ags graft rejection

Kill virus-infected cells responsible for tissue

damage seen in infections (e.g. viral hepatitis) Involved in tumor rejection

Killing mechanism involves perforins&

granzymes Cytokines also involved, notably IFN-

T C ll di d ( IV)


45/55


Associated medical conditions

Type I diabetes mellitus -Antigens of pancreatic islet cells(insulin, glutamic acid decarboxylase, others)

Crohn disease - Unknown antigen; role for commensal bacteria Rheumatoid arthritis - Unknown antigen in joint synovium

Multiple sclerosis - Protein antigens in CNS myelin

Peripheral neuropathy, Guillain-Barr syndrome

- Protein antigens of peripheral nerve myelin Contact dermatitis - Various environmental antigens (e.g., poison ivy)

T C ll di d ( IV)


46/55


Tuberculin reaction

Injection of PPD/tuberculin

reddening and induration of the site appear in 8-

12 hours, peak in 24-72 hours, and thereafterslowly subside

accumulation of mononuclear cells, mainlyCD4+ T cells and macrophages, aroundvenules, producing perivascular "cuffing"


47/55

intradermal injection of exactly one tenth of a milliliter (mL) of PPD tuberculin


48/55

size of induration is measured 4872 hours later; erythema (redness) should not bemeasured


49/55


50/55

A, Perivascular infiltration by T cells and mononuclear phagocytes.

B, Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that markspositively with antibodies specific to CD4.

T C ll di t d (t IV)


51/55


Granulomatous inflammation

With persistent nondegradable Ag (e.g. TB)

Activated macrophagesepithelioid cells

associated with strong T-cell activation withcytokine production

an also be caused by foreign bodies thatactivate macrophages without eliciting an

adaptive immune response


52/55

A section of a lymph node shows several granulomas, each made up of an aggregate of

epithelioid cells and surrounded by lymphocytes. The granuloma in the center showsseveral multinucleate iant cells.

T C ll di t d (t IV)


53/55


Contact dermatitis

may be evoked by contact with urushiol (Agcomponent of poison ivy or poison oak)

vesicular dermatitis


54/55


55/55

Contact dermatitis. The lesion shows an epidermal blister (vesicle) with

Documents

1 Hypersensitivity Reactions