Immune Responses (Dr.diana)

7/30/2019 Immune Responses (Dr.diana)

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Immune responses to

parasitic infections

Dr. Diana Natalia

Departemen ParasitologiFakultas Kedokteran Universitas Tanjungpura


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sistemimun

benda asing= antigen

Respons imun

Antigen -- Imunogen


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IMUNITAS

Mekanisme pertahanan tubuh

terhadap benda asing

Mikroorganisme & produknya Makanan

Bahan kimia

Obat

Dll


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sistemimun

benda asing= antigen

Respons imun nonspesifik

(innate)

spesifik

(adaptive)

selular homural


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Sifat sistem imun

Kemampuan membedakanselfdannonself.

kemampuan suatu molekul protein

yaitureseptor antigen:surface Ig & TCR

Berdasarkan

untuk mengenali molekul lainnya:antigensecara spesifik


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INNATE ADAPTIVE

Sinonim Natural

Nonspesifik

Acquired

Spesifik

Sifat Antigen nonspesifik

Respons cepat

Tidak ada memori

Antigen spesifik

Respons lambat

Ada memori

Komponen Barrier alami

(kulit, mukosa)

FagositMediator solubel:

mis.:komplemen

Pattern-recognition

molecules

Limfosit

Ag-recognition mol:

B cell dan T cellreceptors

Molekul yg disekresi:

mis.:antibodi

IMUNITAS


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IMUNITAS


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IMUNITAS INNATE

Semua unsur yang berperan dalam

proteksi tubuhterhadap benda asing,

yang sudahtersedia sejak lahir

danbekerja segera setelah terjadi paparan.


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KOMPONEN INNATE IMMUNITY

Permukaan tubuh

Kulit Mukosa

Refleks batuk

pH

Asam lemak

Internal Komplemen

Reaksi demam

Interferon

Substansi yang dilepas oleh lekosit Pattern-recognition molecules

(TLRs: Toll-like rceptors) Protein serum, a.l: b-lysin,

lisozim,

poliamin,kinin

Fagosit: granulosit,

makrofag,

mikroglial


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SEL-SEL YANG BERPERAN DALAM

RESPONS IMUN INNATE

1. Polymorphonuclear Leukocytes (PMN).

2. Macrophages3. Natural-Killer Cells (NK Cells).

4. NK T Cells.


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FAGOSITOSIS Fagositosis dapat dipermudah oleh

berbagai faktor yang dikenal sebagai

opsonin proses opsonisasi


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MEKANISME KILLING SEL NK


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Pattern recognitionreceptor = PRR

Pathogen-associatedmolecular pattern = PAMP

RESEPTOR YANG BERPERAN DALAM INNATE IMMUNITY


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IMUNITAS ACQUIRED

Bekerja-sama dengan innate immunity.

Diperoleh setelah ada paparan antigen

acquired.

Spesifik untuk antigen terpapar.

Bekerja relatif lebih lambat dari innateimmunity.


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Paparan Ag

(imunisasi)

Aktivasi limfosit& sel lainnya

Sintesis protein

Spesifik Ag Lain-lain

PENGENALAN

EFEKTOR

AKTIVASI


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konsentra

si

antibodi

infeksiprimer

infeksisekunder

IgG

IgM

IgG

IgM

SIFAT SIFAT RESPONS IMUN ACQUIRED


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SIFAT-SIFAT RESPONS IMUN ACQUIRED

Spesifisitas: Memberikan respons terhadapsatu molekul secara spesifik.

Adaptif: Dapat memberikan respons terhadap molekulyang belum pernah terpapar sebelumnya.

Diskriminasi antara self dan nonself:Kemampuan membedakan molekul yang bersifat

asing dengan yang tidak asing.

Memori: Kemampuan mengingat kontak dengan Agyang pernah terjadi sebelumnya

memberi respons yang lebih cepat

dan lebih kuat.


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SEL-SEL YANG BERPERAN DALAM

RESPONS IMUN ACQUIRED

1. Sel B: pematangan di bone marrow.

2. Sel T: pematangan di thymus

3. Antigen-Presenting Cells = APCs

makrofag

sel dendritik

4. Sel-sel lain:

netrofil

sel mast

Fase efektor


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APCs

Mem-proses dan mempresentasikan Agkepada T Cell Receptor di permukaan sel T.

Mempunyai molekul MHC di permukaannya


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Clonal Selection Theory

Sel T dan sel B dengan berbagai spesifisitas

sudah tersedia sebelum paparan Ag.Sel T dan sel B mempunyai reseptor dipermukaannya

yang spesifik untuk Ag tertentu:

T cell receptors (TCRs) pada sel T

Surface Ig pada sel B

l f h f


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C

lonalSele

ctionThe

ory

Tiap limfosit hanya mempunyai satu spesifisitas

terhadap Ag


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Membrane Ig recognition

Secreted Ig effector


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recognition effector


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Cell surface

peptides

of Ag

Antigen recognition by T cells requires peptide antigens and

presenting cells that express MHC molecules

YT

T cell

response

No T cell

response

No T cell

response

No T cell

response

No T cell

response

Soluble

native Ag

Cell surface

native Ag

Soluble

peptidesof Ag

Cell surface peptides of Ag

presented by cells that

express MHC antigens


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Cell Membrane

Peptide

MHC class I MHC class II

MHC molecules

Peptide

binding groove


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Pengenalan Ag oleh TCR

MHC restricted

MHC structure and function


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MHC structure Class I and II

Class I all nucleated cells

Petroica traversi

Class II antigen presenting cells (B-

lymphocytes, macrophages, etc.)

MHC structure and function


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MHC function

Adaptive immune response

Class I Class II


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EFEKTOR

T HELPER


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Ligasi APC ( Sel dendritik) dan polarisasi Thelper

(Th1, Th2 Treg)

V B P


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Virus Bacteria Parasites

Pattern Recognition Receptors (e.g. TLRs)

IL-1, IL-6, IL-8, TNF, IL-10, IFNMonocyte/macrophages

IL-12, TNFDendritic cells

TNF, IFNLymphocytes

IL-6, TNF, IFNFibroblast/endothelial cells

Systemic inflammationHypothalamus Liver

FeverAcute phaseresponse


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Parasite Immune EvasionEvasion

strategies.

Parasites need time in host - development,reproduce & ensure vector transmission.

Chronic infections normal.

Parasites evolved variety immune evasion

strategies.


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Susceptible, resistance, and pathology


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Vertebrate Immune responses to

helminth infections.

Most extracellular & too large for phagocytosis.

Some gastrointestinal nematodes - hostdevelops inflammation & hypersensitivity.

Eosinophils & IgE initiate inflammatory response

in intestine / lungs.

Histamine elicited - similar to allergic reactions.


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Helminth immune evasion strategies.

1. Large size - difficult to eliminate.

Primary response inflammation.

Often worms not eliminated.


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2. Coating with host proteins. Tegument

cestodes & trematodes adsorb host

components, e.g. RBC ags.

Immunological appearance of host tissue.

Worms seen as self.


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3. Molecular mimicry. Parasite mimics hoststructure / function. E.g. schistosomes have E-selectin - adhesion / invasion.

4. Anatomical seclusion - 1 nematode larvadoes this -Trichinella spiralis inside mammalianmuscle cells.

5. Shedding / replacement surface e.g.trematodes, hookworms.


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6. Immunosupressionmanipulation of theimmune response. High nematode burdens -apparently asymptomatic.

Parasite may secrete anti-inflammatory agents -suppress recruitment & activation effectorleukocytes or block chemokine-receptor

interactions. E.g. hookworm protein binds integrin CR3 &

inhibits neutrophil extravasation.


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7. Anti-immune mechanisms e.g. liver fluke larvae

secretes enzyme that cleaves ab.

8. Migration e.g. Hookworms - move about gut

avoiding local inflammatory reactions.


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9. Production of parasite enzymes - Filarial

parasites secrete anti-oxidant enzymes

e.g. glutathione peroxidase & superoxidedismutase - resistance to ADCC & oxidative stress?


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Acute response - IgE & eosinophil mediatedsystemic inflammation = worm expulsion.

Chronic exposure = chronic inflammation:

DTH, Th1 / activated macrophages - granulomas.

Th2 / B cell responses increase IgE, mast cells &

eosinophils = inflammation.

V t b t I t


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Helminths induce Th2 responses - IL-4, IL-5, IL-6, IL-9,IL-13 & eosinophils & ab (IgE).

Characteristic ADCC reactions, i.e. killer cells directed

against parasite by specific ab.

E.g. Eosinophil killing of parasite larvae by IgE.

Th2

IL-4 Lymphocyte B IgE

IL-5 Maturation of eosinophil

P t ti Th 2 d i i t ti l h l i th i f ti


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Protective Th-2 response during intestinal helminth infection

Infective larvae invade the epithelia and reside in the submucosa after which they re-enter

lumen. Primary infections become established and chronic. Secondary infections, parasite

antigens are presented to CD4 T-cells in mesenteric lymph nodes and gut-associated lymphoid

tissues, driving the induction of Th2 effector cells.


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Th2-cell functions during helminth infection

Three broad outcomes associated with specific


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Three broad outcomes associated with specificimmune responses to filarial infection


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PROTOZOA


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Protozoan immune evasion strategies.

1. Anatomical seclusion in vertebrate host.

Parasites may live intracellularly - avoid hostimmune response.

E.g. Plasmodiuminside RBCs - when infected notrecognised by TC & NK cells. Other stagesPlasmodium inside liver cells.

Leishmania parasites & Trypanosoma cruziinsidemacrophages.


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3. Antigenic variation.

In Plasmodium, different stages of life cycleexpress different antigens.

Antigenic variation also in extracellular protozoan,

Giardia lamblia.


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African trypanosomes -1 surface glycoproteinthat covers parasite = VSG.

Immunodominant for ab responses.

Tryps have gene cassettes of VSGs allowing

regular switching to different VSG.

Host mounts immune response to current VSGbut parasite already switching VSG to anothertype.


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Parasite expressing new VSG escapes ab

detection, replicates & continue infection.

Allows parasite survival - months / years.

Up to 2000 genes involved.


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Parasitaemia fluctuates.

After each peak, tryp population antigenically differentfrom that earlier / later peaks.

After Ross, P. (1910), Proc. Royal Soc. London, B82, 411

M l i


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Malaria

Immunity to malaria is complex and isessentially both species and stage specific.

Innate or adaptive immune effectormechanisms can limit the peak ofparasitemia, prevent severe pathology and

reduce the load of circulating infectedcells


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Immunity in malaria

Immune to parasite: aparasitemia

Immune to disease: parasitemia with no ormild clinical symptom

Immunity to malaria


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Immunity to malaria

Variation of malarial antigen either on the

surface of infected erythrocyte or insertedas protein transmembrane is encoded by manygenes (example PfEMP coded by vargenes)

Immunity to parasite


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Immunity to parasite

Therefore, existing antibody might notrecognize infection by new antigenvariation, and this will causeuncontrolled parasite multiplication

severe disease

clinical immunity developes gradually


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The black line shows the blood-stage parasitemia followingsporozoite infection (sp). There is prepatent period (p) betweensporozoite inoculation and the detection of parasites in the blood. Theblue line shows the microscopic threshold (ie, limit of detection) andthe yellow area represents a subpatent parasitemia. The orange arearepresents an asymptomatic patent parasitemia. The red line shows aclinical threshold, or the parasitemia which produces paroxysms orother clinical symptoms (pink area). As immunity develops this clinicalthreshold increases. The incubation period (i) is the time between

infection and the appearance of symptoms.

H t


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Host responseUpon biting, the malaria-infectedmosquitoes deposit parasites inthe skin, many of which eventuallyexit to the bloodstream andinfect hepatocytes.

However, certain antigens,including the circumsporozoiteprotein, remain in the skin and arepresented in the draining lymph

node.

These antigens prime specificCD8+ T cells, which migrate tothe liver where they eliminate

parasitized hepatocytes


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Immunity to malaria

H l i it


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Humoral immunity

Several mechanism of antibodies as antiparasite:

- inhibition of cytoadherence

- inhibition of erythrocyte invasion- ADCC (antibody dependent cytotoxicity)

Cell mediated immunity as


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Cell mediated immunity asanti parasite

Phagocytosis of infected erythrocyte bymacrophage induced by NK cell, T cell

or Th1- derived IFN- NO (nitric oxide) produced by

macrophage and T-cell IFN- has

parasiticidal activity CD+8 and IFN- in hepatic stage


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What is cytokines????

Cytokines are the chemicals producedby cells in order to communicate andavoid attack of foreign body.

Cytokines can act on other immune cells,particularly nearby cells.


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Pro inflamatory cytokines(TNF-, IL-1,IL-6,IFN-)Cytokines that increase inflamation reaction(elevation of body temperature, increasedblood flow, enhanced vascular permeability,accumulation of cells)

Anti inflamatory cytokines (IL-10,TGF-b):Cytokines that inhibit activities of immune

cells to decrease the production of pro-inflamatory cytokines.


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Inflamation mediators of the disease

Complicated malaria has been related tohigh level of inflamatory cytokines(TNF-, IL-1, IL-6 & IFN-)????

High level of IFN- (up regulated TNF-) is associated with severe disease and

antiparasitemia

l


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TNF- in malaria

In optimal concentration, TNF-together with IFN- stimulate NOproduction and other free radicals to

eliminate parasites.


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TNF IL1 IL6 IFN

TNF,IL1,IL6

IFN

IFN

1st

2nd

Immune Responses (Dr.diana)

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