Pharma-6-immuno.pptx

8/19/2019 Pharma-6-immuno.pptx

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IMMUNOLOGY


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Definitions and outline structure of

the immune system

• Primary function of the immune system is to defend against and

eliminate ‘ foreign ’ material, and to minimize any damage that may

be caused as a result of the presence of such material

• Pathogen - organism which has the ability to cause disease

• Virulence - used to indicate the degree of pathogenicity of a given

strain of microorganism

• Attenuation - Reduction in the virulence of a pathogen

• Antigen - gives rise to the primary interaction with the body’s immune

system

• Immunogen an antigen that elicits an immune response


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the immune system

• !ithin a given antigen, e"g" a protein, there will be antigenic

determinants or epitopes , which actually represent the antigen

recognition sites for our adaptive immune system

• monoclonal antibody - antibody nominally recognizing only a single

antigen and within which only a single common epitope is recognized

• polyclonal antibody - an antibody nominally recognizing only a single

antigen but within which a number of different epitopes are

recognized


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the immune system

• #he immune system is broadly considered to e$hibit two forms of

response%

• #he innate immune response, which is non - specific, displays no

time lag in responsiveness, and is not intrinsically affected by prior

contact with infectious agent

• #he adaptive immune response , which displays a time lag in

response, involves highly specific recognition of antigen and affords

the generation of immunological memory


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the immune system

• #he adaptive immune system is further subdivided into%

• Humoral immunity - the effector cells are B- lymphocytes and where

antigen recognition occurs through interactions with antibodies"

• Cell - mediated immunity - the effector cells are T - lymphocytes

• &n cell - mediated immunity the peptide antigen must be presented to# - lymphocytes by other cell types 'antigen-presenting cells or (P)s%

macrophages* in association with a class of plasma membrane

molecules termed major histocompatibility complex !HC" proteins


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)ells of the immune system

• !ononuclear phagocytic cells monocytes to macrophages

• #ranulocyte cell - neutrophil, basophil and eosinophil

• !ast cell $ release numerous initiating factors leading to aninflammatory response

• %atural &iller '+* - elicit cytoto$ic actions against host cells infected

with virus and those host cells that have acuired tumour cell

characteristics

• B $ lymphocytes - mature or differentiate in the bone marrow

• T $ lymphocytes - undergo maturation in the thymus


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#he innate immune system

• &nnate barriers at epidermal and mucosal surfaces

• &nnate defence once epidermal or mucosal barriers have been

compromised


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&nnate barriers at epidermal and mucosal surfaces

• &nvolves a range of non - specific mechanisms

• &ntact s.in• /low of fluid secretions from tear ducts, the urogenital tract and the

s.in 'sweat*

• 0any of these secretions possess bacteriostatic or bactericidal

activity


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&nnate defence once epidermal or

mucosal barriers have been

compromised

• 0ononuclear phagocytic cells

• 1ranulocyte cell populations

• Phagocytosis

• (lternative complement pathway


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0ononuclear phagocytic cells

• &nclude monocytes and macrophages

• #he mononuclear phagocytic cells secrete a wide range of molecules%

• lysozyme or cathepsin 1

• Cyto&ines - provide innate protective antiviral 'e"g" interferon '&/+*

- 2 or - 3 * and antitumour 'e"g" #+/ - 2 * activity against other host

cells

• Bioactive lipids - promote the inflammatory response


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1ranulocyte cell populations

• &nclude the neutrophils, basophils and eosinophils

• +eutrophil - the most abundant granulocyte and is the most important

in terms of phagocytosis

• 4osinophils - have a specialized role in the e$tracellular .illing of

parasites


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Phagocytosis


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)50P6404+# P(#7!(89

i" )6(99&) P(#7!(8

ii" (6#4R+(#4 P(#7!(8


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)lassic Pathway

• &nitiation

• :inding of ); comple$ to (b’s bound to (g

• )omponents

• ); to )<

• 9tages

i" Recognition

ii" (mplificationiii" 0()


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Mg++

7undreds of )= and )>

molecules

7ighest conc than any

other complement)?b% opsonin


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&ntermediate

comple$

';>-;@*


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(lternate Pathway

• &nitiation

• +on-(b-initiated pathways

• )omponents

• /actor : and /actor D

• )?, )@ - )<


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(lternate Pathway

9tablized by 0gAA

B mins ?C mins


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#he humoral adaptive immune system

• : - lymphocyte antigens

• :asic structure of antibody molecule

• )lonal selection and e$pansion

• 7umoral immune effector functions


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: - lymphocyte antigens

• ( substance or molecule specifically interacting with an antibody, and

which may lead to the further production of antibody and an

immunological response

Molecules Characteristic Immunogenicity

Protein 7igh 0!, )omple$structure

4$cellent AAAA

Polysaccharides'blood grp (gs*

6arge, lac. comple$ity 0ust be lin.ed to aprotein or lipid

AA

6ipid 9imple structure and low

stability

0ust be lin.ed to a

protein orpolysaccharide

A

+ucleic acid 9imple, fle$ible, degradesrapidly

poor A


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14+4R(6 )7(R()#4R&9#&)9 5/ (+#&:5D&49

• (ntibodies

• &mmunoglobulins

• 9pecific glycoproteins

• 0ost 'not all* are found in the gamma-region inelectrophoresis• 7ence immunoglobulinE

• Present in plasma and body fluids 'tears, saliva, colostrum*


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

• /ive )lasses

• Differ in 0! and sedimentation coefficients

;" &g0

>" &g1?" &g(

=" &g4

@" &gD


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

• (ntibodies

• (ll have a common, basic polypeptide structure

• /our polypeptide chains lin.ed together by covalent andnoncovalent bonds• wG identical heavy and light chains

• 0onomers% &g1, &gD, &g4

• 0onomer and polymer% &g(

• Pentamer% &g0 '@ four-chain subunits*


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

• (ntibody 0olecule

• 8E shaped

• Domain• :asic unit ';>*

• )hains 'lin.ed by disulfide bonds*• 7eavy chain '>*

• 6ight chain '>*

• Hariable 'H* region

• )onstant ')* region


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

• &g1

• 7as = subclasses determined by thehinge region

• /ab region

• 0obile and can swing freelyaround the hinge region


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

IgG

CHARACTERISTICS INCREASE ECREASE

-0aIor &g in normal serum 'JC

J@K*-)rosses the placenta-0!% ;@C,CCC D-9)% J9-+H% LCC-;LCC mgGd6

&nfectious diseases-

hepatitis, rubella, &0

7ematologic disorders-Polyclonal gammopathies,monoclonal gammopathies,06, 7odg.in’s Disease

Primary and

secondary &gdisorders


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

• &g0

• Pentamer

• M-chain 'disulfide bond*• 6in.s the @ subunits in a circular

fashion


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

IgM


-;C K of &g pool-

Produced early 'first* inimmune response-0!%


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

• &g(

• Dimer

• > &g( mols Ioined by M-chain at the /c portion


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

IgA


-;@ >CK in &g pool-

Predominant &g insecretions 'tears, saliva,colostrum, mil., intestinalfluids*-0!% 'dimer* ?L@,CCC D-9)% 'dimer* ;;9-+H%


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(+#&:5D8 9#RF)#FR4 (+D&00F+5165:F6&+ )6(9949

Ig IgE

-6ess than ;K of &g pool-4$tremely susceptible to proteolysis dueto e$posed hinge region and lac. of

interchain disulfide bonds bet 7)s

-)an mediate hypersensitivity 'allergic*reactions- &mmunity to invading parasites

- #riggers the release of histamines and

heparin from mast cells and basophils


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(+#&:5D8 98+#749&9

• )lonal selection

• (ctivation and proliferation of : lymphocytes in response to an

antigen

• Production of (b specifically for that (g• ?-@ days

• (ntigenicity

• Related to portal of entry• &H, intraperitoneal N subcuataneous, &ntramascular


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(+#&:5D8 98+#749&9

• Primary (ntibody Response

• /our Phases

;" 6ag% no (b detectable

>" 6og% inc in (b titer ?" Plateau% (b titer stabalizes

=" Decline% (b is catabolizes


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(+#&:5D8 98+#749&9

• 9econdary '(namnestic* Response

• 0emory response due to subseuent e$posure to same (g

• Differs from Primary

• #ime% shorter lag phase, longer plateau 'tenfold*, more gradualdecline

• #ype of (b• Primary% &g0 9econdary% &g1

• (b titer% higher titer


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(+#&:5D8 98+#749&9


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)ell - mediated adaptive

immune system

• #-6ymphocytes 9ubsets

)D=A subset

• helper-inducerE # cell

)DLA subset

• suppressor-cytoto$icE # cell

i" 7elper # 6ymphocytes

ii" )ytoto$ic # 6ymphocytes


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# 6ymphocyte 9ubsets

• 746P4R # 680P75)8#49

• #-helper '#h* cells

• 9ubsets

i" 7elper # type ; '#h;*N for cell-mediated effector mechs

ii" 7elper # type > '#h>*

N regulation of (b production

iii" Regulatory # '#reg*

N immunoregulatory type of #h cells


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• 746P4R # 680P75)8#49

• /unction mainly in cyto.ine production

• #h;

• &/+O% direct and inderect activation of phagos to .ill ingested microbes• #h>

• &6-=% stimulates &g4 production

• &6-@% activates eosinophils

• 9timulates &g1= production


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• 746P4R # 680P75)8#49

• Reacts w (g-07) && comple$ on (P)

• 6eads to cyto.ine production

• )D=A #)R


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• )8#5#5&) # 680P75)8#49

• #-cytoto$ic '#c* cells

• Direct destruction of virally infected target cells

• )DLA• &nteracts w (g-07) & comple$ or 07)-& alone

• Hirus infected cells or tumor cells

• 0aIor effector in allograft organ reIection


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(ntigen Processing and (ntigen Presentation to #

cells

• (ntigen-Presenting )ells '(P)s*

• )ells capable of ta.ing up (gs and presenting them to lymphocytes

• Dendritic cells, macrophages, : cells, tissue cells

• (g processing pathwaysi" 4ndogenous - #c

ii" 4$ogenous - #h


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(ntigen Processing and (ntigen Presentation to #

cells


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#ransplantation reIection

• #ransplantation is the process of transferring cells, tissues or organs

Q termed a graft Q from one location to another

• (n autologous graft is a transplant between two sites within the sameindividual, e"g" s.in graft from the thigh to the hand

• (n allogeneic graft is a transplant between two genetically different

individuals of the same species

• ( xenogenic graft is a transplant across different species, e"g" pig to

human


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#ransplantation reIection

• Hyperacute rejection occurs within minutes to hours" #his should now

be a rare event clinically as recipients are tested 'cross - matched*

before transplantation for the presence of antibodies reactive with

cells of the donor

• Acute rejection occurs within wee.s to months following

transplantation and involves humoral 'antibody* and cell - mediated

induced cytoto$icity" Damage may be reversed with early diagnosis

and more aggressive immunosuppressive therapy

• Chronic rejection occurs many months or even years following

transplantation"


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7ypersensitivity

• Defined as an e$aggerated response of the immune system leading

to host tissue damage

• Type I Q immediate hypersensitivity " #his is also called anaphylactic

or acute hypersensitivity" &t involves &g4 antibody and is mediated via

degranulation of mast cells for rapid inflammatory reaction

• Type II hypersensitivity Q antibody- mediated cytotoxicity " #his is

caused by antibodies that are directed against cell surface antigens"

&g1 and &g0 are the .ey antibodies involved that direct cytoto$icevents against the cell surface with which they interact

#ype && hypersensitivity disorders include blood transfusion reactions

arising from mismatch of the blood (:5 antigens


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7ypersensitivity

• Type III hypersensitivity Q complex - mediated " #his involves the

formation of large antigen antibody comple$es that circulate in the

blood

• &f this process is compromised for any reason then the antigen

antibody comple$es will be deposited in tissue capillary beds that can

lead to a condition termed glomerulonephritis in .idney

• Type IV hypersensitivity Q cell - mediated " #his results frominappropriate accumulation of macrophages at a localized site, and

may or may not involve the presence of antigen

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