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IMMUNOLOGY OVERVIEW (1) innate immunity produce bodys earlyline of defense against invader,it has 4 barriers(i)anatomic(physical) skin,mucous membrane

(ii)physiologic(temperature,PH,chemicals) (iii)phagocytic(monocytes,neutrophils,macrophages) (iv)inflammatory event innate immune defenses hve in common in (i)all present intrinsically !ith"!ithout previous stimuli (ii)have limited specificity for microbes (iii)arent enhanced in acitivity by repeated e#posure (iv)limited diversity of e#pression ($) adaptive immune response (i)lymphocytes(t"b cells) and plasma cells lend cells of %&lymphocytes differentiation) (ii)antigen&presenting cells(macrophages,% cell,dendritic cells) adaptive immune system has in common that (i)specific for particular antigen (ii)diverse in specificity (iii)e#press immunologic memory (iv)capable of self"nonself recognition (i#)self&limiting (') phagocytic cells process and display antigen to facilitate stimulation of specific ( lymphocytes macrophages secret cytokines,help trigger specific immune response )ntibodies by plasma cells bind to pathogens,activate complement system,destruct invader )ntibodies by % cell bind to pathogens and assis !ith phagocytosis(oposoni*ation) CELLS OF IMMUNE SYSTEM )+ origin (1) from pluripotent stem cell in bone marro! ($) differentitation occur in $ path!ay common lymphoid progenitor cell or myeloid progenitor cell (') common lymphoid progenitor cell give % cell,( lymphocytes and natural killer cell (4) myeloid cell give rise to

%+ (1) ($) (') (4) (3) -+ (1)

($) (') (4) (3)

,%-,.%-,basophilis,mastcells,eosinophils,neutrophilis,macrophage,dendritic cells function cells of myeloid heritage perform relatively stereotyped response(innate) cells of lymphoid heritage perform finely turned,antigen specific immunity(adaptive) %&lymphocytes from bone marro!,( lymphocytes from thymus,/0 cells are large,granular lymphocytes that recogni*e certain tumor"virus infected cells lymphocyte1lymph nodes,spleen,submucosa,epithelial % cell produce antibody,( helper cell regulate immune response,cytoto#ic ( cells(-(2s) kill infected cells /0 cell1blood stream,kill tumor"virus cell target"antibody coated cell Plasma cells1lymphoid tissue and bone marro!,end cell of % cell, produce antibody antigen recognition molecules of lymphocytes antigen receptor of %& lymphocyte also called membrane& bound immunoglobulin heavy chain4light chain disulfide bond form hinge region only one idiotype(antigenic specificity) is e#pressed per cell ( cell receptor has a"b chain,it binds
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peptides presented by antigen presenting cells, molecule is rigid,its al!ays cell&bound (5) %&cell recogni*e unprocessed antigens Compare B and T lymphocyte ant!"en receptor %&cell antigen receptor 6olecule"lymphocytes idiotypes isotypes 8s secretion possible:: /umber of binding site mobility <ignal transduction 177,777 1 $(8g648g9) yes $ ;le#ible(hinge region) 8ga,8gb,-91=4$1 (&receptor antigen receptor 177,777 1 1(a"b chain) no 1 ,igid only -d'

FIRST RES#ONE TO $NTIGEN (1) an antigen(immuogen) is a substance that can elicit an immune response,it must be foreign,chemically comple# and large ($) % cell is able to recogni*e molecules of any chemical composition, antigen bind to idiotype portion,this small binding portion is called epitope(antigen determinant of antigen) si*e of molecule is crictial factor for its immunogenicity(as % cell can be only activated !hen response are cross linked, this serves as first signal to send message) molecule has only one epitope is called haptens as they only occupy one idiotype of double arm % cell receptor (') )cute inflammatory is first response to invasion, cytokines increase e#pression of selectin&type adhension molecules (i)activation of vascular endothelium in breached epithelial barrier (ii)cytokines and other inflammatory mediators released in surface(result of tissue damage induce e#pression of selectin type adhesion molecules on endo cells (iii)neutrophils firstly bind to inflamed endothelium and e#travasate into tissue(peak !ith 5 Hr) (4) >#travasation of phagocytes into area (i)rollingphagocyte attach loosely to endothelium by interactions, force of blood flo! cause cell to detach and retach repeatedly,rolling along endo surface (ii)activation by chemo attractants, chemokines released !hen inflammation(82&?,-3a,/&formyl peptides), @ protein mediated activating signal, this signal induce a conformational change in intergrin molecules in phagocyte membrane (iii)arrest and adhesioninteraction bet!een intergrins and 8g&superficial cellular adhesion molecules(g& -)6s) stabili*e adhesion of phagocyte of endo cells (iv)transendothelial migrationphagocyte e#tend pseudopodia through vessel !all and e#travasate into tissue )cute 8nflammatory response (issue damage (i)complement activation-3a1mast histamines,prostagladins to blood, leukotrienes cell&&& %lood reaction (i)neutrophils82?chemota#is-3 ),chemota#is(neutrophils into tissue) (ii)lymphocytes2;)1,8g-)61lympho -yte into tissue

(ii)bacteria-3a or activated macrophages result in 821"5,(/; a prostaglandins,leukotrienes (iii)endothelial damage result in Abradykinin,fibrin firinopeptides,plasmin to blood (3)

(5)

Phagocytosise#tensionof pseudopodia, formation of phagosome,fusion !ith lysosome and form phagolysosome,digestion,e#ocytosis both macrophages and neutrophils has membrane receptors for certain type of antibody(8g@ and certain complement components -'b), both are called oposins, they enhance phagocytosis(oponi*ation) 8killing mechanismto#ic o#ygen metabolites,to#ic halide radicals,lysosomal
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content(lyso*ome,defensins,lactoferrin,hydrolytic en*ymes)B/)9PH o#idase(reduce o#ygen to C$ radicals,generate hydro#yl radical(&CH), and hydrogen pero#ide(H$C$), myelopero#idase in lysosome act on H$C$ and -l to produce hydrochlorite %UMOR$L EFFECTOR MEC%$NISM (1) humoral immunity is mediated by antibody from % cells and secreted their fully differentiated end cell(plasma cell) Dthis type of response aim to defense against >- microbes or to#ins(via phagocytosis) D% cell are attracted to follicular areas of lymphy node and spleen(fist activation signal is antigen enter $nd lymphoid organ and binds cross linked idiotypes of receptors) Dmost antiges enter body are thymus dependent antigens,response to this need direct contact of % cell and (H cell and cytokines D% cell contact !ith (H cell need 6H- 88(peptide presentation), -o&stimulatory molecule(%E),-947"472 biding Dantigen !ithout peptides structure cant be recogni*ed by ( cell(thymus independent antigen), they only stimulate 8g6,create no memory Dmitogen activate many clones of % cell and are used clinically to assess lymphocyte function D% ell make ne! classes(isotypes) in response to cytokine&directed instruction from (H$ cell, isotype dictate effector function of anibody molecule ($) formation of ("% cell conFugates (i) % cell %E4(H cell -9$? % cell -9474(H cell -9472 (ii) )fter combine,% cell release 82 $,4,3,(H cell release cytokines (iii) (his lead to activated % cell for proliferation (') 8g6plasma 8g6 valenceG17(pentamer),Dfunction in trapping free antigen,Daffinity(binding strength) may be lo! Davidity(multiple binding) highest of all isotypes D8g6 is most effective isotype at activating complement,it s not oposinin,not mediate )9--,D8g6 is main immunoglobulin of primary immune response(acute infection),Drecovery serum !ill have most 8g@,!ith subthreshold level of 8g6 (4) 8g@maFor antibody produced after 8g6,e#ist in 4 subisotypes, it activate complement opsoni*es, mediates )9--,is actively transported across placenta (3) 8g)is produced in submucosa, it s a dimmer !ith Foining(H) chain,8g) inhibits binding of adhesive substances to mucosal surface, its important for milk breast (5) 8g>is bound to mast cell,and basophils,mediates type 1 allergic reactions, protect against parasites (E) -omplement systemenhance inflammation and phagocytosis, cause lysis (i)alternative path!ay is initiated by simple attraction of early factors to surface of microbes (ii)classical path!ay is activated by )ntigen&)ntibody comple# (iii)complement cascade is controlled by -1,',3 CELL ME&I$TE& EFFECTOR MEC%$NISM (1) cell mediated immunity is to identify and clean antigenic stimuli arise from inside cells of body,(H1 cells stimulate macrophage,cytoto#ic -9?4( lymphocytes(-(2s) and /0 cells ($) macrophages killing(8-) specificity of response arise from ( cells, but actual effector function is mediated by phagocytes, this provide link bet!een adaptive and innate immune response,convert phagocytes into agents of adaptive immune response, most important cytokines of -9?4( cells and (H1 cells is 8;/&?,as !ell as (;/ a"b !hen (H1 cytokines activate macropahes and casue tissue damage,result is delayed type
'

(')

(4)

(3)

hypersensitivity(9(H) -(2 stimulation reIuires non self peptide(class 1 6H-) -9$?&%E,82&$,-(2 kill targets by delivery of to#ic granule contents that induce apoptosis of cell to !hich they attach (<(>P1)&attach to target by P-,,-9?,2;)1 integrin (<(>P$)&activation(cytoskeletal rearrangement to concentrate granules against attached target) (<(>P')e#ocytosis of granules contents(perforin and gran*ymes) (<(>P4) deattachment from target /0 cell killingvia same mechanism of apoptosis !ith -(2(granu*ymes,perforin),/0 cell activity is increased in presence of interferons(8;/ a"b)(8;/ stimulated during viral infection) and 82&1$(produced by phagocytoic cells during induction of (H1 response),thus /0 cell is enhanced by 8;/ a"b and 82&1$,inhibited by 6H- class 8 )9--(antibody dependent cell&mediated cytoto#icity)number of cells(/0 cells,macrophages,monocytes,neutrophils,eosinophils) has membrane receptor for ;c region of 8g@ !hen 8g@ is bound to target,these cytoto#ic cells can bind to free ;c (ail,cause lysis of target cell specificity of idoitype of antibody direct cytoto#icity, involve lytic en*ymes, (/;, perforin

IMMUNOLOGIC MEMORY (1) as pathogens are eliminated,immunologic memory is generated ($) both %"( lymphocytes !ill respond to primary antigentic challenge by production of long&lived memory cells (in % lymphocytesplasma cell !hich is antigen dependent,meaning antigen disappear,stimulus for differentiation is removed) plasma cell function as factory for 8g synthesis(short lived) memory % lymphocytes differe from naJve % cell undergo isotype s!itching memory % lymphocytes has surface 8g ),>,@ (') )8-9(activation&induced cell death)removes activated ( cell after primary response,memory cells home to inflamed tissue (4) 6emory cells return to tissue !hen they first meet antigen T lymphocyte migration >ffector function -ell cycling 82&$ receptor B lymphocyte 8sotype of 8g )ffinity(strength) of 8g >ffect function 6orphology 8g6 and 8g9 2o! /one <mall little cytoplasm 8g ) > @ 8ncreasing )ntibody secretion 2arge more cytoplasm 8g ) > @ High /one small /aJve cell (o peripheral lymphy node none aabsent 2o! )ctivated or effector lymphocytes (o inflamed tissue -ytokines,cytoto#icity Present High memory (o inflamed tissue mucosa none 4"& lo!

#r!mary re pon e (ime lag after immuni*ation Peak response )ntibody isotype )ntibody affinity 8nducing agent 8mmuni*ation protocol (3) 3&17 days <mall 8g6 then 8g@ Kariable to lo! )ll antigen High dose of antigen(!ith adFuvant)

Secondary re pon e 1&' days 2arge 8ncreasing 8g ) > @ High(affinity maturation) Cnly protein antigens 2o! dose of antigen(!ithout adFuvant)

mucosal&associated lymphoid tissue(6)2() include tonsils and peyer patches also numerous less !ell&organi*ed lymphoid accumulation in lamina propria 6)2( contains (H$ cells assisting 8g) production,secretory 8g) is a dimmer !ith secretory component,secretory component has trans&epithelial transport protection from proteolytic cleavage

%Y#ERSENSITIVITY )+ hypersensitivity diseasese#cessive response to foreign antigen failure of self&tolerance(autoimmunity) %+ classification (1) type 8(immediate)8g>(immune mechanism) mast cells and mediators(tissue mechanism) ($) type 88(antibody mediated)8g6,8g@ antibodies(immune mechanism) against cell or tissue antigens opsoni*ation(tissue mechanism) and phagocytosis of cells complement and ;c receptors&mediated recruitment and activation of neutrophils and macrophages abnormal in cellular functions(hormone receptor signaling) (') type 888(immune comple# mediated)immune mechanism,immune comple# of antigens and 8g6"@ antibodies tissue mechanism,complement";c receptor&mediated recruitment and activation of leukocytes (4) ( cell&mediated(type 8K) (i)-944( cell(delayed type hypersensitivity),macrophage activation,cytokine&mediated inflammation (ii)-9?4-(2s(( cell mediated cytolysis),direct target cell kill,cytokines mediate inflammation (3) 8n all hypersensitivy reactions,first e#posure to antigen sensiti*e lymphocytes subseIuent e#posure lead damage,reaction is antigen&specific -+ (ype 8(immediate) hypersensitivity (1) 8g> mediated,protective response to helminthes atopic"allergic person develop type 8 in response to inappropriate stimuli ($) Procedure Dfirst e#posure to allergen(H$ release 82&4 to stimulate % cell to produce 8g>,class s!itching occurred % cell produce 8g>,it attaches ;c receptor on mast cell$ nd e#posure to allergenallergen cross links several 8g> molecules on mast cell and cell degranulates to release po!erful chemicals (') (ype 8 effector cellsmast cells, basophils,eosinophils Dactivated mast cell(basophils)biogenic amines(histamines)vascular leakagelipid mediators(P);) bronchoconstriction or intestinal hypermotility >osinophilscationic granule protein(eg+maFor basic protein)killing parasites and host cell en*ymes(eg+eosinophil,pero#idase)tissue damage 9+ (ype 88 hypersensivitytissue specific auto antibodies,opsoni*e or activate complment,recruit inflammatory cells, interfere !ith cellular function >+ (ype 888 hypersensivitysystemic damage,immune comple# activate complement,self or foreign antigens ;+ (ype 8K hypersensitivitydelayed type(4?&E$hrs),-9L4(H cell mediate,activate macrophage,cause inflammation,common in chronic 8- infections

$UTOIMMUNITY (1) result from a failure of mechanism of self&tolerance ($) genetics class 88 6H- genes,environmental(infection) or hormone triggers failure (') autoimmune reactions against oneself antigen may inFure other!ise,e#posing other potential self&antigen for recognition,thus autoimmune disease is chronic and progressive (4) infection trigger autoimmune response by (i)bystander activationrecruit .%- increase e#pression of co& stimulators, lead activate ( cell(although its not specific for infectious pathogen) (ii)molecular mimicryantigen cross&react !ith"mimic itself antigens (iii)inflammation (3) therapies for immune diseasemodification of ( cell, inhibit proliferation and function,kill ( cell, antagonists to pro&inflammatory cytoknes(or co&stimulatory molecule) (5) immuneologic therapiesDdesensi*ation(inFection of small allergen to reduce specific 8g> production overtime) Dplasmapheresis(decrease circulating level of antibody) Dhigh dose of intra&venous 8g@(may bind to ;c receptors and inhibit antibody synthesis) Dtolerance induction(high dose administration of antigens or its altered form)