DASAR DASAR ANESTESIA ( IIb - III) Dr.Diana Lalenoh,M.Kes,SpAn
Immune Responses (Dr.diana)
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Transcript of 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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Helminth immune evasion strategies.
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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Helminth immune evasion strategies.
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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Helminth immune evasion strategies.
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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Helminth immune evasion strategies.
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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Helminth immune evasion strategies.
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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Vertebrate Immune responses to
helminth infections.
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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Vertebrate Immune responses to
helminth infections.
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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Protozoan immune evasion strategies.
3. Antigenic variation.
In Plasmodium, different stages of life cycleexpress different antigens.
Antigenic variation also in extracellular protozoan,
Giardia lamblia.
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Protozoan immune evasion strategies.
2. Antigenic variation.
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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Protozoan immune evasion strategies.
2. Antigenic variation.
Parasite expressing new VSG escapes ab
detection, replicates & continue infection.
Allows parasite survival - months / years.
Up to 2000 genes involved.
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Protozoan immune evasion strategies.
2. Antigenic variation.
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