IMMUNOLOGY

HOST PARASITE INTERACION

• Mutalism• Komensalism• Opportunism• Parasitism

Factors that determine the kind and number

availability of oxygen pH of the host site other microorganism availability of nutrien immunological state

ParasitesExtracelluler parasites

persist and multiply outside of the host cellsIntracelluler parasites

must resist digstion by the host cells

Intracelluler Parasites

Facultative intracellulerSalmonella species

M .tuberculosis Brucella Obligate intracelluler

viruses, rikettsiae and certainprotozoa

Diseases - shift in the equilibrium between man and the infecting agent

- ability to cause disesase can be termed as pathogen

- individual who harbor and shed infectious agent but show no symtoms called carrier

Microorganism cause disesase by

. Competition for metabolits

.production of virulent

factors

.production of toxins

.hypersensitivity

.vascular obstruction

Microbial Factors

• Adhesive factor• Invasive factors• Toxin• Antiphagocytic factor• Antigen variation

Host factors

• Genetic• Age• Socio-economic• Immune status

HUMANBODY

Bacteria

Fungal Riketsial

Mycoplasm Chemical

Virus

IMMUNE RESPONSE

RECOGNITIONELIMINATION

Autoimmunity Immunodeffisiency

Hypersensitivity

Foreign Antigent

Enter

Humanbody

Specific Non-specific

Pathologic

EliminationElimination

PHASE OF IMMUNE RESPONSE

1. Cognitive phaseBinding of foreign Ag to specific resep-

tor on mature lymphocytes.2. Activation phase

Proliferation & differentiation of lym-phocytes

3. Effector phase Elimination of Ag by lymphocytes that

have been specifically activated

Humoral ImmunityMediated by molecules in the bloodthat are reponsible for spesific recog-nition & elimination of Ag

Cell-mediated-immunity (celluler immunity) mediated by Tlymphocytes

Lymphoreticular system :1. Cells :

T cells , B cells & subsets of lymphocytes that involved in specific and nonspecific immune response

2. Organ and tissue a. primary : thymus, bonne marrow and

equivalen of bursa fabricus b. secondary/perifer : spleen & lymp nodes

SISTIM IMUN

NONSPESIFIK SPESIFIK

BIOKIMIA SELULERFISIK /

MEKANIK

HUMORALSEL B

SELULERSEL T

KulitSel.lendirSiliaBatukBersin

BIOKIMIAAs.lambungLisosimLaktoferinAs.neuraminik

HUMORALKomplemenInterferonCRP

FAGOSIT monosit makrofag neutrofil eosinofilSEL NULL sel NK sel KSEL MEDIA-TOR basofil sel mast

ThTcTs

antibodi

Non-speciic Specific- Action immediate - Action requires day

todevelop- Respnonse is non- - Specific specific- Response is not - Response enhance on enhance by repeat repeat unfection infection-Recognition molecule - Clonal selection naturally express in all cells types

Non-specic Specific-Complex carbohydrate - Small segments of or lipoprotein that form protein or glicopro- the wall of microbe tein ( B cells) or pro- cessed protein (T cell)

-Circulating molecules : Complement Antibody

-Cells : Phagocytes ( macropha- Lymphocytes ges, neutrophils) NK cells

IMMUNOLOGY

• ANTIGEN• ANTIBODY• IMMUNOGEN• ANTIGENICITY• IMMUNOGENICITY• COMPLEMENT• EPITOPE• VALENCE• ADJUVANS

IMMUNE .SYTEM

HumoralCells

mediated

-B cells-Antibodies-Complement

-Macrofages -Granulocytes-NK cells-Complement-Other chemicals HCl, lysozym

Innat immunityAdaptive immunity

-APC -T cells

TYPES OF ANTIGEN

1. T-dependen Ag require Th cells in order to evoke

immune response.2. T- independen Ag without involvement of T cells

- primary response- don’t yield immunological memory- don’t produce hight affinity Ab- Ig M- e.g : LPS of Gram (-) bact

3. Auto AntigenAg from a person that initiated immune response in that individual

4. Allo-AgAg from different individual of the samespesies ( different genetic make up)

5. Iso-AntigenLike Allo-antigen with identical geneticmake up

Immunogenicity depent on

1. Properties of Ag- foreigness- molecular size- chemical complexity- Solubility- rigidity

2. Host factors- enzymes of the host- availability of appropriate lymf. Clone- ability of APC

- age- nutritional status- MHC locci

3. Mode of Ag adiminstration - dose - route

- form - scedule

BACTERIAL ANTIGENTSFlagellar

-Antigenic protein ( H-Ag)-protective : Cholera

Pilli two form : ordinary pilli & sex pilli -ETEC

-N. gonorrhoeaeBacterial somatic Ag

a. capsule or slime layerb. O-antigen (LPS outer membrane)

Bacterial Toxin : I. Exotoxin II.Endotoxin

I. EXOTOXIN

1. Hemolysin : S. aureus , V. cholerae C. tetani , C,

septicum2. Leucocidine : S aureaus3. Hyaluronidase

: S. aureus , Strep. pyogenes

C. welchii4. Colagenase : C. welchii5. Coagulase : S. aureus

II. ENDOTOXIN

Has several biological properties

- induce of fever

- elicit early IgM & latter IgG

- stimulate endocrine gland

- activates complement

- induce Swartman reaction

- cause release of lasma kinin

ENDOTOXIN

1. Dermonecrotizing agent- schick toxin : C. diphteriae- - toxin : C.welchhi

2. Cardiotoxic agent- streptolysin-O : S. pyogenes- tetanolysin : C.tetani

3. Deoxyribonuclease- toxin : C. septicum- sterptodornase : C. botulinum

V. cholerae

Mayor cells types involved in immune response

B T NK Mono- Neutro Eosi- Baso- Mastcells cells cells cyt phil nophil phil cells Macro- phage

GRANILOCYTES

LEUKOCYTESLYMPHOCYTES PHAGOCYTES AUXILLARY

AQUIRED INNATE IMMUNE RESP

Lymphocytes

- Capable of specifically recognizing and disttinguishing different antigenic diter- minat

- Responsible for adaptive IR

B Cells - Comprise 5 - 10 %

- Atibody production

- Spcific Ag reseptor : surface Ig

- Ag-reseptor complex (CD79)

- bind to foreign protein,polysacc,

lipoprotein in soluble form

2. Sel B- Pemasakan pada sumsum tulang

(bone marrow)- 5-10% total limfosit- dpt membentuk antibodi- dpt mengenal antigen langsung- mempunyai surface immunoglobu-

lin (sIg).- Dpt berfungsi sebagai sel penyaji

antigen (APC)- berperan dlm imunitas spesifik

T cells

- Small , non granular lymphocytes- Antigen receptor (TCR) - small peptides prosesed by APC- Surface marker : CD4 : Th and CD 8 : CTL

Sel T - pemasakan di timus

- 65-80% dr total limfosit- membentuk roset dgn eritrosit

domba (sel B tdk)- glikoprotein permukaan (CD)- tdk dpt mengenal antigen langsung- imunitas spesifik- subset : CD4 (Th) dan CD8 (Tc) dan

Ts (supresor)

3. Sel null- tdk mempunyai petanda permukaan- mempunyai reseptor C3 dan Fc- 10-15% total limfosit- dapat membunuh sel tumor dan

sel yang terinfeksi virus- tdr dari 2 subset :

1. sel K : memerlukan bantuan antibodi untk membu-

sel sasaran2. sel NK :tdk memerlukan bantu-

an antibodi

NK cells- subset found in blood & lymphoid tissues- derived from bone marrow- primitive CTLs- possess ability to kill tumor cells & normal

infected by virus- express CD2 & low affinity reseptor for

IgG called FcRIII (CD16)

Phagocytic Cells

1. Professional phagocytes :- PMN leukocytes- Monocytes- Macrophages

2. Paraprofessional-Dendritic cells (DC) have selective phagocyte activity

3. Non professional :- fibroblast & ephithelial cells

4. Sel fagosit

Fungsi :- fagositosis Ag- membunuh- memproses Ag - mempresentasikan Ag ke

sel limfosit- mempunyai banyak reseptor dipermukaannya

Macrophage function

1. Detection of microbial invasion Opsonic and nonopsonic receptor for microbe and their product2. Restriction of microbial spread Phagocytosis

Granuloma formation Intracelluler killing

3. Recruitment of immune cells Cytokines & inflamatory mediators

4. Accessory cells in lymphocyte activ.-Ag processing & and presentation-Costimulatory molecules : ligand for

CD40 L, CD28 and CTLA4 (T cells)-Cytokines

5. Effector cells in CMI-Increase phagocytosis-Increase intracelluler killing-Clearence of apoptotic cells

6. Participation in humoral immunity

Properties of Macrophages

1. Membrane receptor-Scavenger receptor-C receptor-Fc- eceptor-Macrosialine-Cytokines receptor -CD14 (LPS receptor)

2. Production of cytokines-IL-1

- TNF - IL-12- IL-10- IL-4- FGF

3. Antigent processing and presentation4. Produce enzymes

- colagenase- elastase- lysozymes - lysosomal enzymes

5. Production of bioactive lipid and small radical

- Prostaglandin- Platelet activatig factor- reactive oxygen & nitrogen interme-

diate.

Phagocytosis

1. Microbial recognition - PRRs (pattern recognition reseptor a. membrane bound b. free in plasma - Recognize wide variety of microbial molecules - As reeptors for binding & entry of many intraclluler pathogens

2. Microbial uptake- actin polymerization- engulfment and internalization

3. Phagosomal maturtion- depolymerization of actin- fussion with endosome- final step : fussion with lysosome

---> phagolysosome generating low pH and containig degradative hy- lases

4. Microbial killing Accomplished by :

- low pH of phagosom- limitation of nutrien (iron)- generation of reactive oxygen and

nitrogen intermediates- Nramp-1 : removal of iron and di-

valen cation from phagosom- phox ---> reactive oxygen intermed.- inos ----> reactive nitrogen intermed.

Phox : phagocyte NADPH oxydase

O2

NADPH NADPH+

O2-

O2 - + H2O H2O2 + OH*

H2O2

MPO

Cl-

HOCl- + OH*

antibacterial

phox

LPSIL-1TNFIFN-

INOSDeaminasioxydativeL-arginin

NO+

H2O2

peroxynitrit

NO+

Thiol groups

nitrosothiol

5. Production of soluble mediator- signal & recruit other cells to the

side of infect.. Stimulate adaptive immune resp.

6. Antigen presentation- Histocompatibility molecule(HLA)- HLA-I --> CD8 cells- HLA-II --> CD4 cellsa- Costimulatory molecules

Ag

MHLA-II

CD4

Th1

Th2

BCGF, BCPF, BCDF

BPAb

CD8

HLA-I

IL-1

IL-4 , IL-12

NK

IFN-

IL-2

ADCC

Exogenous antigen processing: MHC class II peptide presentation

RE

golgi

CD 4

lysosom

phagolysosom

PhoxInos

Nram-1

phagosom

microbe

Endogenous antigen processing: MHC class I peptide presentation

proteasom

TAPRE

golgi

CD 8viral

Ag-HLA

TCR

CD28

B7-1

CD40L

CD40

APC

T cells CTLA4

B7-2

COMPLEMENT SYSTEM

- Heat labil protein- Inactive- After being activated : some protein act as enzymes, while other as substrat.

Lysis of foreign cells:- pathogenic microorgsnism- enhancement of phagocytosis- inflamation of host tissue- stimulation of chemotactic

- Regulated by several soluble and cell- membrane-assoiated protein

1. Limit or stop complemen activ2. Prevent abnomal or constitutiv activation in the absent of micro-

be and antibodies 3. Prevent formation of the MAC on self tissue and excessive generation of inflamatory mediators

Overviewe of Complement - Synthesized : hepatosytes , blood mon- cytes , epithelial cells of GE tract and tissue macophages

-Four mayor functions :1. opsonization 2. target cytolysis 3. inflamation 4. immune complex clearence

ACTIVATION OF COMPLEMENT

1. Classic pathway- IgG (IgG1, IgG2, IgG3) & IgM , DNA retrovirus , mycoplasma , protein-A ,

heparin , CRP , MBP , Tripsin

2. Alternative pathway- Not require formation Ag- Ab complex.- IgA , IgE , cobra venon , LPS gram(-)

1. Classic pathway

a. Binding C1 on Fc region of Ag-Abb Poduction of C3 convertase ( C4b2b)c. Production of C5 convertase ( C4b2b3b)d. Production of MAC ( C5b 678). C5b67 insert

itself into membrane of target cells. C8 bind to the complex ( C5b678) forming smal pore in the membrane. Finally C9 poymerize araound the C5b678 ---> hole---> lysis oftarget cells.

C1

C4C4b

C9

C3

C2a

C4b2bC4a

C2C2b

C3b

C5

C3a

C4b2b3b

MAC

C5aC5b

C8

C7

C6

C5b6

Target celllysis

Ag-Ab

Alternative pathwy

-Not require specific Ab for initiation-Does not utilize C1 , C4 & C2 activ. -Utilize at least 3 serum protein :

1. Factor B2. Factor D3. Factor P (properdine)

C3

C3b

C3a

C3

C3bBb

Ba

C3b

C3a

C3bBb

C3bB

Microbial surface

B D

PC3 convertase

C3bBb3b As C5 convert.

Additional role of complement fragment

- C3a , C4a and C5a are anaphylatoxin.- C5a : - chemotaxis

- increases production of reactive oxygen intermediates - increase adhesiveness

- C3B : - opsonin - enhance phagocytosis - elimination immune complex

circulating in the blood

Regulation of Complement cascades

1. Regulation of classical pathway a. C1INH- inhibit C1 activation

- halting initiation of clasical pathway. - in the blood C1 is bound to

C1INH - C1INH deficiency cause -->

hereditary angiodema

b. protein that interfere with C3 & C5 C4bp &DAF (decay accelerating (factor) ---> inhibit formation and dis- sociation C3 convert ---> cofactor for Factor-1mediated

ted cleavage of C3b & C4b

MCP (CD 46) : mediated inactiva- tion C4b.

2. Regulation of alternative pathway a. inhibit binding B to C3b : Factor-H b. inhibit formation C3 convertase alter- native pathway (C3bBb) : Factor-1 (mediated proteolysis C3b)

3. Regulation of MAC formation

a. CD59 also called MIRL (membrane inhibitor of reactive lysis) and HRF

(homologous restriction factor) also called C8bp.--> block binding C9 to C8--> preventing MAC formation b. S-protein (vitronectin) : bind to C5b-7 complex --> prevent membrane insertion of the MAC bp : binding protein