RESPONS IMUN TERHADAP PROTOZOA Yoes Prijatna Dachlan Facultas Kedokteran Universitas Wijaya Kusuma Surabaya June 2014

Jenis respons imun yang berkembang dan keefektifan respons bergantung dari, a.l. lokasi parasit didalam host Protozoa bisa hidup: • didalam usus → amoeba •di sirkulasi darah → African trypanosomiasis •dalam makrofag → Leishmania spp., Toxoplasma gondii •dalam otot → Trypanosoma cruzi Protozoan diseases Protozoa yang bebas berada di sirkulasi darah selama menjalani siklus hidupnya → humoral antibody yang paling efektif Protozoa yang sedang tumbuh secara intraseluler selama menjalani siklus hidupnya → cell-mediated immune response yang efektif (Yoes Prijatna Dachlan 2014)

. . . . . . . . . . . . ANTIBODY SINGLE ACTION Infected Red Blood Cells at schizont stage . . . . . . . . . . . . Prevents spread by neutralizing attachment site (Yoes Prijatna Dachlan, 2014)

~Respons imun innate terhadap protozoa yang terpenting adalah fagositosis ~namun banyak protozoa mampu bertahan hidup terhadap efek fagositosis → replikasi dalam sel makrofag ~Protozoa mengekspresikan molekul permukaan yang dikenal oleh TLR/PRR dan kemudian mengaktivasi sel fagosit ~Mekanisme pertahanan yang terpenting dalam melawan protozoa yang hidup dalam makrofag adalah cell-mediated immunity, terutama makrofag yang diaktifkan oleh sitokin yang bersumber dari sel Th1 (Abbas, Lichtman, Pillai, 2010) (Yoes Prijatna Dachlan, 2014)

The way by which protozoa that multiply within macrohages escape digestion by lysosomal enzymes Toxoplasma gondii . MØ Parasit tetap hidup didalam endosome – (tidak terjadi fusi dengan lysosome) . . Lysosome Parasit mati didalam fagosom yang telah berfusi dengan lysosom (Male, Brostov, Roth, Roitt, 2006) (Yoes Prijatna Dachlan, 2014)4)

Mechanism of INNATE Macrophage protozoan Complement Classical pathway Lectin receptors Ab C1 Lectin pathway Macrophage C4-C2 Alternative pathway TLRs C3b opsonization PAMP scavenger receptors (Male, Brostoff, Roth, Roitt, 2006) protozoan (Yoes Prijatna Dachlan, 2014)

Steps of the three complement activation pathways (Yoes Prijatna Dachlan, 2014)

Leishmania major (in mice), a protozoan that survives within the endosomes of macrophages Activation of Th-2 by protozoa Activation of Leishmania-specific Th-1 CD4+ T cell ↓ Produce IFN-γ Activate MØ Destroy intracellular parasites ↓ Produce IL-4 MØ-suppressive actions of Th-2 Increased parasite survival and excerbation of lesions (Yoes Prijatna Dachlan, 2014)

Development of the immune response to protozoan IL-12 Naive cell DC PRR T Th1 IFNγ IL-2 TCR MHC class II Protozoa Development of the immune response to protozoan (Male, Brostov, Roth, Roitt, 2006) Yoes Prijatna Dachlan 2014

Immune Responses to Disease-Causing Protozoan DISEASES Principal mechanisms of protective immunity Plasmodium species Malaria Abs and CD8+ CTLs Leishmania donovani Leishmanisis (mucocutaneous, disseminated) CD4+ Th1 cells activate MØ to kill phagocytosed parasites Trypanosoma brucei African trypanosomiasis Abs Entamoeba histolytica Amebiasis Abs, phagocytosis Abbas, Lichtman, Pillai, 2010. Cellular and molecular immunology (Chiodini, Moody, Manser, 2001)Atlas of Med .Helminth.& Protozool. (Yoes Prijatna Dachlan 2014)

reseptor innate yang terlibat dalam mengenal parasit FAMILY MEMBER PARASITE LIGAND Collectins MBL Mannose-rich sugars from numerous protozoans Pentraxins CRP Phospholipids and phosphosugars Leishmania spp C-type lectins MØ mannose receptor Trypanosoma cruzy Scavenger receptors CD36 P. falciparum (PfEMP1) C’ receptor CR1/CR3 Leishmania spp. lipophosphoglycan TLRs TLR2 (with TLR1/TLR6) GPI anchors from many protozoans TLR9 Protozoal DNA Malaria pigment hemozoin (Male, Brostoff, Roth, Roitt, 2006) (Yoes Prijatna Dachlan 2014)

Invasi kedalam usus besar Entamoeba histolytica penyebab amoebiasis Invasi kedalam usus besar (Yoes Prijatna Dachlan, 2014) (PL Chiodini, AH Moody, DW Manser, 2003)

Malarial Parasites Human Host Immune Response Effective Not effective Pathology Response No Response • Anemia • Cerebral Malaria Sterilization Hyper-parasitemia • Respiratory- of Infection Distress Immune response Parasitemia (Troye-Blomberg, Weidanz, v.d. Heyde, 2005)

The identification proteins of a malarial parasite (Marcus B, 2009) Marcus B. Deadly diseases and epidemics. Malaria,2009. Yoes Prijatna Dachlan,2010

Abs CD8+ T cell Hepatic stage Sporozoite Abs Merozoite LSA SALSA Sporozoite CSP TRAP STARP Abs Merozoite AMA-1 EBA175 Pf RH1/2/3/4 MSP1/2/3 RAP1/2 GLURP Ring trophozoite RESA NK and CD4+ T cell ~Species specific immunity ~Stage specific immunity ~Antigenic diversity ~Geographic origin ~Polyclonal B cell activation Schizonts PfEMP-1 Rifins STEVOR HRP-2 Gametocyte Pfg27 Pfg230 Pfg48/45 (Kinyanjui, 2012) Abs

Pathophysiology 1 – “Knobs” Deformation of pRBCs resulting in “knobs” on the RBC surface Plasmodium falciparum Expressed Membrane Protein (PfEMP1) Endothelial cell ligands CD36 ICAM-1 VCAM-1 P-selectin Chondroitin sulfate A (Yoes Prijatna Dachlan, 2014) 16

PfEMP1 on knob structure (Yoes Prijatna Dachlan, 2014)

Pathophysiology 1: Microvascular cytoadherence/sequestration and microvascular obstruction (Yoes Prijatna Dachlan, 2014)

Pathophysiology 2: dysregulated inflammatory response GPI , Lymphotoxin (Yoes Prijatna Dachlan, 2014)