hypersensitivity and allergy notes

8/17/2019 Hypersensitivity and Allergy Notes

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HYPERSENSITIVITY AND ALLERGY

what are the key features of the 4 hypersensitivity reactions

How do allergens mediate type I (immediate) hypersensitivity reactions

(with examples)

The adaptive immune response - RE!"#E $" I#%E&$I"#' generally enecial- *ut these immune responses can also cause tissue in+ury and disease'

hypersensitivity diseases- I#,!!R"!RI,$E RE!"#E $" I##"&" *$,#&E '

,llergy.Hypersensitivity- RE!"#E $" E/% ,#$I0E#' autoimmune disease - RE!"#E $" $R,#!/,#$E1 "R0,#' graft re+ection

ALLERGIES

$he hallmark of allergic diseases is the production of IgE antiody2 which isdependent on the activation of I/-43producing helper $ cells

- ensitivity to iological and non-iological materials- !ollens2 mites2 food2 drugs2 cosmetics2 pollutants- Inconvenient to highly dangerous- Incidence rising- $he typical se5uence of events in immediate hypersensitivity consists

of'o exposure to an antigen2

o activation of lymphocytes ($H6 cells2 I/-43producing follicular

helper $ 7$%H8 cells and * cells) specic for the antigen



o production of IgE antiody

o inding of the antiody to %c receptors of mast cells

,lso called E#I$I9,$I"# ecause IgE-coated mast cells

are ready to e activated on antigen encountero triggering of the mast cells y re-exposure to the antigen

o resulting in the release of mediators from the mast cells and thesuse5uent pathologic reaction

- ,llergy is the prototypic $H6-mediated disease:

o ;any of the early events and pathologic features of the reactionare triggered y $H6 cytokines2 which may e produced y $%H

cells in lymphoid organs and y classical $H6 cells in tissues:

- $he clinical and pathologic manifestations of allergy consist of thevascular and smooth muscle reaction that develops rapidly afterrepeated exposure to the allergen (immediate hypersensitivity) and adelayed late phase in<ammatory reaction:

- ,llergic reactions are manifested in di=erent ways2 depending on thetissues a=ected2 including skin rashes2 sinus congestion2 ronchialconstriction2 adominal pain2 diarrhea2 and systemic shock

- $he development of allergies is the result of complex and poorlyunderstood gene-environment interactions:

- ,topic individuals produce high levels of IgE in response toenvironmental allergens2 whereas normal individuals generally produceother Ig isotypes2 such as Ig; and Ig02 and only small amounts of IgE

o IgE antiody is responsile for sensiti>ing mast cells and providesrecognition of antigen for immediate hypersensitivity reactions:

- $H6 cells2 mast cells2 asophils2 and eosinophils are the ma+or e=ector

cells of immediate hypersensitivity reactions and allergic disease:

What causes tpe I a!!er"icreactions

- ,llergen ? IgE ? ;astcell

- Inhaled material0rass !ollen2 Housedust mite

- %oods egg- &hemicals nickel- @enoms ee2 wasp - 1rugs !enicillin



Anaph!a#is (not to e confused withthe 4 hypersensitivity reactionsA)

- ,naphylaxis is a systemic immediate hypersensitivity reactioncharacteri>ed y edema in many tissues and a decrease in loodpressure2 secondary to vasodilation:

- Result from the systemic presence of antigen introduced y in+ection2 aninsect sting2 or asorption accorss and epithelial surface such as gut mucosa

- tage I 0eneralised itching2 rticaria- tage II welling away from the sting2 incontinence- tage III 1iBculty in reathing- tage I@ %all in lood pressure2 loss of consciousness- ,naphylaxis' ystemic allergic reaction to a ee sting (tage II)

House dust mite (Dermatophagoides pteronyssinus -DerP)

$ast ce!!s

- ;ast cells are activated y cross-linking of %cCRI molecules2 whichoccurs y inding of multivalent antigens to the IgE molecules that areattached to the %c receptors

- ,ctivation of mast cells results in three types of iologic response'

secretion of the preformed granule contents y exocytosis(degranulation)2 synthesis and secretion of lipid mediators2 andsynthesis and secretion of cytokines:

- ;ast cell degranulation is a central component of many allergicdiseases2 and the clinical and pathologic manifestations of the diseasesdepend on the tissues in which the mast cell mediators have e=ects aswell as the chronicity of the resulting in<ammatory process:

o ? leukotrienes synthesi>ed via arachidonic acid pathwayA- /ocation'

o In &$ skin2 intestinal mucosa

o In mucosal tissue alveoli2 intestinal mucosa

% Histamine2 erotonin (short-lived) *: &ytokines and /eukotrienes(sustained)

o @asoactive' increased local lood <ow D vascular permeaility

<uid accumulationF in<ux lood cellso mooth muscle cell contraction expel

e:g: gut' vomiting2 diahorreaF ronchial



constriction'increase mucus D cough

o &ytokines' e:g: IL%&' TN( sustained in<ammatory signal

Dia"nosis)

- kin test 3 wheat and <are- Immunoassay

o En>yme or Radio laelled anti-IgE ? IgE antiody in test sample

? ,llergen coated paper disco Radioallegosorent test (R,$)



A*T+I$$*NE DISEASES

Ghat are the main features of autoimmune diseases

"utline the tissue damage (pathology) associated with R,2 1iaetesand 0oodpastures2 /E:

How do genetics and environment in<uence the development of

autoimmune conditions

A*T+I$$*NIT reaction against self antigens- %ailure of the normal mechanisms of self-tolerace results in reactions

against ones own cells and tissues- ,t least 6-JK of the population has autoimmune diseases- ,utoimmune diseases are chronic- ,ntiody-mediated diseases are produced either y anti- odies that

ind to antigens on particular cells or in extracellular tissues or yantigen-antiody complexes that form in the circulation and aredeposited in vessel walls

- In or"an%speci,c autoimmune disease2 exemplied y Hashimotosthyroiditis2 0raves disease and type L diaetes2 the targetautoantigens and lesions are restricted to a particular organ: Innonor"an%speci,c -sstemic. autoimmune diseases2 such as /Eand R,2 the autoantiodies have widespread reactivity and the lesionsinvolve deposition of circulating immune complexes:

- !atients 5uite often develop more than one autoimmune disease:

E/ector mechanisms o0 anti1od%mediated disease2

3. ,ntiodies opsoni>e cells and may activate complement2 generatingcomplement products that also opsoni>e cells2 leading to phagocytosisof the cells through phagocyte %c receptors or &M receptors:

4. ,ntiodies recruit leukocytes y inding to %c receptors or yactivating complement and therey releasing yproducts that arechemotactic for leukocytes:

5. ,ntiodies specic for cell surface receptors for hormones or

neurotransmitters maya2 stimulate the activity of the receptors even in the asence of the

hormone2 as in Graves6 diseases (hyperthyroidism)12 inhiit inding of the neurotransmitter to its receptor2 as in

masthenia "ravis



Autoimmune diseases are mu!ti0actoria!

- ,utoimmune diseases generally involve multiple genetic contriutions2including polymorphisms associated with H/,2 autoantigens2 !RRs2cytokines2 cytokine receptors2 co-stimulatory and signaling molecules2and transcription factors:

- eventy-ve percent of autoimmune disease occurs in females2 mostcommonly etween puerty and the menopause:

- &hanges in disease severity can occur during pregnancy:- %eedack control of lymphocytes through the cytokine3hypothalamus3

pituitary3adrenal loop may e defective in rheumatoid arthritis andsome other autoimmune diseases:

- $win studies reinforce the importance of genetic contriutions ut alsoindicate a strong environmental in<uence:

- *oth microial and nonmicroial environmental factors are implicated:

Genetic- eg An7!osin" spond!itis H/,-*6N (RR ON)- ; H/,-1R6 (RRJ)- I11; H/,-1RM.1R4 hetero>ygote (RRL4-6J)- R, H/,-1R4 (RR4:6-N)

Hormona!8se# e" 0ema!e)ma!e

- , P:M- ; LP- R, M- /E LP-6P

Environmenta! co%0actors- eg Goodpastures (autoas to type I@ collagen 3$ype II

hypersensitivity)o !resent in asement memranes throughout the ody including

lungs2 kidney and inner earo ,ll patients get glomerulonephritis2only 4PK get lung

hemorrhage2 none get ear prolems- 1isease !attern explained y autoantigen availaility

o 0lomeruli lter plasma therefore *; accessile

o &ochlear *; not accessile to autoas

o In lung2 *; seperates alveolar epithelium from capillary

endothelium- soo 4PK lung disease caused y damage due to smoking



*nidenti,ed tri""ers- viral *acterial- @arious proposed mechanisms for the induction of autoimmunity y

infectious agents:- Eg: Rheumatic (ever- streptococcal ;-antigen ,s cross-reactive

with myosin heart muscleSstemic !upus erthematosus -Tpe III hpersensitivit.

- kin rash caused y complexes of 1#, and anti- 1#, antiodiesecoming locali>ed in the skin to cause in<ammation

- 0enetic and environmental factors contriute to a reakdown oftolerance in self-reactive * and $ lymphocytes

- &hronic2 remitting and relapsing2 multisydrome autoimmune diseases- ,=ects mainly women L in NPP woman- Rashes2 arithritis2 glomerulonephrititis ? hemolytic anemia2

thromocytopenia and &# involvement can e oserved

Tpe I Dia1etes

- &hronic in<ammatory inltration and destruction of the insulin-producing * cell of the pancreatic islets of /angerhans

- $ype I@ hypersensitivity



Rheumatoid arthritis -Tpe II' III 9 IVhpersensitivit.

- %emale'male ratio M'L

- ,=ects 6K of the population- &rippling disease- Qilling disease- High social costs' divorce2 loss of work- &ost to Q economy L illion annually- &ellular involvement'

o $ cells

o * cells (,s2 R%2 I&)

o ;onocytes

o macrophages

o rolasts

o neutrophils- ;ain feature of R, is +oint erosion leading

to deformity and disaility

Autoimmune Diseases- &entral $olerance not LPPK foolproof- ,utoreactive $ and * cells controlled y peripheral tolerance

mechanisms- ,utoimmune diseases can result when peripheral tolerance fails- &entral tolerance does not delete ,// potentially dangerous

lymphocytes

PERIPHERAL T+LERAN:E a state of tolerance ac5uired y maturelymphocytes in the peripheral tissues2 as opposed to central tolerance2 whichis ac5uired y immature lymphocytes during their development:

The importance o0 maintainin" periphera! to!erance- self reactive lymphocytes can escape -ve selection in the thymus



(central tolerance) due to low aBnity to self ;H&.antigen and theexclusive expression of some proteins in the periphery:

- these upon recognition of specic autoantigens can cause direct and.orindirect tissue damage

- autoimmune diseases such as R,2 type I 1iaetes and lupus

$echanisms o0 maintenance o0 periphera! to!erance- 1eletion.,poptosis- ,nergy (unresponsive)

o /ack of 6nd signal or co-stimulation

- Immunological Ignorance 3 #o contact with self ,go eg: $ype I@ collagen in lung 30oodpastures syndrome2 antigens

of the eye and testis- Immune 1eviation 3 $hL(generally ad for autoimmune disease) to $h6

(ad for allergy.asthma) ias- ,ctive uppression (Immune Regulation) - Regulatory $ cells

hypersensitivity and allergy notes

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