Immune responses to parasitic infections

Dr. Diana Natalia Departemen Parasitologi Fakultas Kedokteran Universitas Tanjungpura

benda asing = antigen

Respons imun

sistem imun

Antigen -- Imunogen

IMUNITAS
Mekanisme pertahanan tubuh terhadap benda asing
Mikroorganisme & produknya Makanan Bahan kimia Obat Dll

benda asing = antigen

Respons imun nonspesifik (innate) spesifik (adaptive) selular homural

sistem imun

Sifat sistem imun

Kemampuan membedakan self dan nonself.

Berdasarkan
kemampuan suatu molekul protein yaitu reseptor antigen: surface Ig & TCR untuk mengenali molekul lainnya: antigen secara spesifik

IMUNITAS
INNATE Sinonim
Sifat

ADAPTIVE Acquired Spesifik Antigen spesifik Respons lambat Ada memori Limfosit Ag-recognition mol: B cell dan T cell receptors Molekul yg disekresi: mis.:antibodi

Komponen

Natural Nonspesifik Antigen nonspesifik Respons cepat Tidak ada memori Barrier alami (kulit, mukosa) Fagosit Mediator solubel: mis.:komplemen Pattern-recognition molecules

IMUNITAS

IMUNITAS INNATE Semua unsur yang berperan dalam proteksi tubuh terhadap benda asing, yang sudah tersedia sejak lahir dan bekerja segera setelah terjadi paparan.

KOMPONEN INNATE IMMUNITY

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

Permukaan tubuh
Kulit Mukosa Refleks batuk pH Asam lemak

SEL-SEL YANG BERPERAN DALAM RESPONS IMUN INNATE 1. Polymorphonuclear Leukocytes (PMN). 2. Macrophages

3. Natural-Killer Cells (NK Cells).

4. NK T Cells.

FAGOSITOSIS

Fagositosis dapat dipermudah oleh berbagai faktor yang dikenal sebagai opsonin proses opsonisasi

MEKANISME KILLING SEL NK

RESEPTOR YANG BERPERAN DALAM INNATE IMMUNITY Pattern recognition receptor = PRR

Pathogen-associated molecular pattern = PAMP

IMUNITAS ACQUIRED Bekerja-sama dengan innate immunity. Diperoleh setelah ada paparan antigen acquired. Spesifik untuk antigen terpapar. Bekerja relatif lebih lambat dari innate immunity.

Paparan Ag (imunisasi)

PENGENALAN

Aktivasi limfosit & sel lainnya

AKTIVASI

Sintesis protein
Spesifik Ag Lain-lain EFEKTOR

konsentrasi antibodi

IgG

IgG IgM

IgM

infeksi primer

infeksi sekunder

SIFAT-SIFAT RESPONS IMUN ACQUIRED

Spesifisitas: Memberikan respons terhadap satu molekul secara spesifik.

Adaptif: Dapat memberikan respons terhadap molekul yang belum pernah terpapar sebelumnya.
Diskriminasi antara self dan nonself: Kemampuan membedakan molekul yang bersifat asing dengan yang tidak asing.

Memori: Kemampuan mengingat kontak dengan Ag yang pernah terjadi sebelumnya memberi respons yang lebih cepat dan lebih kuat.

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:

Fase efektor
netrofil sel mast

APCs

Mem-proses dan mempresentasikan Ag kepada T Cell Receptor di permukaan sel T. Mempunyai molekul MHC di permukaannya

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

Tiap limfosit hanya mempunyai satu spesifisitas terhadap Ag

Clonal Selection Theory

Membrane Ig Secreted Ig

recognition effector

recognition

effector

Antigen recognition by T cells requires peptide antigens and presenting cells that express MHC molecules

Soluble native Ag Cell surface native Ag

Soluble peptides of Ag

No T cell response

No T cell response

No T cell response

Y
Cell surface peptides of Ag No T cell response

Cell surface peptides of Ag presented by cells that express MHC antigens

T cell response

MHC molecules
MHC class I
Peptide Peptide binding groove

MHC class II

Cell Membrane

Pengenalan Ag oleh TCR MHC restricted

MHC structure and function

MHC structure Class I and II

Petroica traversi

Class I all nucleated cells

Class II antigen presenting cells (Blymphocytes, macrophages, etc.)

MHC structure and function

MHC function

Class I

Class II

Adaptive immune response

EFEKTOR T HELPER

Ligasi APC ( Sel dendritik) dan polarisasi Thelper (Th1, Th2 Treg)

Virus

Bacteria

Parasites

Pattern Recognition Receptors (e.g. TLRs)

IL-1, IL-6, IL-8, TNF, IL-10, IFN Monocyte/macrophages

IL-12, TNF Dendritic cells

TNF, IFN Lymphocytes

IL-6, TNF, IFN Fibroblast/endothelial cells

Hypothalamus

Systemic inflammation
Fever
Acute phase response

Liver

Parasite Immune Evasion Evasion strategies.

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

Chronic infections normal.

Parasites evolved variety immune evasion strategies.

Susceptible, resistance, and pathology

Vertebrate Immune responses to helminth infections.

Most extracellular & too large for phagocytosis. Some gastrointestinal nematodes - host develops inflammation & hypersensitivity. Eosinophils & IgE initiate inflammatory response in intestine / lungs. Histamine elicited - similar to allergic reactions.

Helminth immune evasion strategies.

1. Large size - difficult to eliminate.
Primary response inflammation. Often worms not eliminated.

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.

Helminth immune evasion strategies.

3. Molecular mimicry. Parasite mimics host structure / function. E.g. schistosomes have Eselectin - adhesion / invasion. 4. Anatomical seclusion - 1 nematode larva does this -Trichinella spiralis inside mammalian muscle cells. 5. Shedding / replacement surface e.g. trematodes, hookworms.

Helminth immune evasion strategies.

6. Immunosupression manipulation of the immune response. High nematode burdens apparently asymptomatic. Parasite may secrete anti-inflammatory agents suppress recruitment & activation effector leukocytes or block chemokine-receptor interactions. E.g. hookworm protein binds integrin CR3 & inhibits neutrophil extravasation.

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.

Helminth immune evasion strategies.

9. Production of parasite enzymes - Filarial parasites secrete anti-oxidant enzymes e.g. glutathione peroxidase & superoxide dismutase - resistance to ADCC & oxidative stress?

Vertebrate Immune responses to helminth infections.

Acute response - IgE & eosinophil mediated systemic inflammation = worm expulsion.

Chronic exposure = chronic inflammation:

DTH, Th1 / activated macrophages - granulomas. Th2 / B cell responses increase IgE, mast cells & eosinophils = inflammation.

Vertebrate Immune responses to helminth infections.

Helminths induce Th2 responses - IL-4, IL-5, IL-6, IL-9, IL-13 & eosinophils & ab (IgE).
IL-4 Th2 IL-5 Maturation of eosinophil Lymphocyte B IgE

Characteristic ADCC reactions, i.e. killer cells directed against parasite by specific ab.
E.g. Eosinophil killing of parasite larvae by IgE.

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.

Th2-cell functions during helminth infection

Three broad outcomes associated with specific immune responses to filarial infection

PROTOZOA

Protozoan immune evasion strategies.

1. Anatomical seclusion in vertebrate host. Parasites may live intracellularly - avoid host immune response. E.g. Plasmodium inside RBCs - when infected not recognised by TC & NK cells. Other stages Plasmodium inside liver cells.
Leishmania parasites & Trypanosoma cruzi inside macrophages.

Protozoan immune evasion strategies.

3. Antigenic variation.
In Plasmodium, different stages of life cycle express different antigens. Antigenic variation also in extracellular protozoan, Giardia lamblia.

Protozoan immune evasion strategies.

2. Antigenic variation. African trypanosomes -1 surface glycoprotein that 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 VSG but parasite already switching VSG to another type.

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.

Protozoan immune evasion strategies.

2. Antigenic variation. Parasitaemia fluctuates.

After After each tryp population antigenically different Ross, P. peak, (1910), Proc. Royal Soc. London, B82, 411 from that earlier / later peaks.

Malaria
Immunity to malaria is complex and is essentially both species and stage specific. Innate or adaptive immune effector mechanisms can limit the peak of parasitemia, prevent severe pathology and reduce the load of circulating infected cells

Immunity in malaria
Immune to parasite: aparasitemia Immune to disease: parasitemia with no or mild clinical symptom

Immunity to malaria
Variation of malarial antigen either on the surface of infected erythrocyte or inserted as protein transmembrane is encoded by many genes (example PfEMP coded by var genes)

Immunity to parasite
Therefore, existing antibody might not recognize infection by new antigen variation, and this will cause uncontrolled parasite multiplication severe disease

clinical immunity developes gradually

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

Host response
Upon biting, the malaria-infected mosquitoes deposit parasites in the skin, many of which eventually exit to the bloodstream and infect hepatocytes.

However, certain antigens, including the circumsporozoite protein, remain in the skin and are presented in the draining lymph node.
These antigens prime specific CD8+ T cells, which migrate to the liver where they eliminate parasitized hepatocytes

Immunity to malaria

Humoral immunity
Several mechanism of antibodies as anti parasite: - inhibition of cytoadherence - inhibition of erythrocyte invasion - ADCC (antibody dependent cytotoxicity)

Cell mediated immunity as anti parasite

Phagocytosis of infected erythrocyte by macrophage 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

What is cytokines????
Cytokines are the chemicals produced by cells in order to communicate and avoid attack of foreign body. Cytokines can act on other immune cells, particularly nearby cells.

Pro inflamatory cytokines(TNF-, IL-1,IL-6,IFN-) Cytokines that increase inflamation reaction (elevation of body temperature, increased blood 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 proinflamatory cytokines.

Inflamation mediators of the disease

Complicated malaria has been related to high level of inflamatory cytokines (TNF-, IL-1, IL-6 & IFN-)???? High level of IFN- (up regulated TNF) is associated with severe disease and antiparasitemia

TNF- in malaria
In optimal concentration, TNF- together with IFN- stimulate NO production and other free radicals to eliminate parasites.

IFN

IFN 2nd

TNF,IL1,IL6

1st

TNF,IL1,IL6

IFN