Imunitas dan Patogen Parasit Yoes Prijatna Dachlan Fakultas Kedokteran Universitas Wijaya Kusuma Surabaya Juni 2014

Unicellular protozoans Eukaryotic pathogens Unicellular protozoans ~sebagian protozoa replikasi secara ekstraseluler ~sebagian lainnya replikasi secara intraseluler Multicellular helminth worms ~Helminth worms reproduksi dalam tubuh host ~atau diluar tubuh host disuatu lokasi dimana parasit mudah mengaksess host ~Pertumbuhan dan maturasi cacing terjadi didalam tubuh host → severe and long- term damage to tissues and organs Parasites Umumnya, cell-mediated immunity dan humoral immunity dimobilisasi untuk menaklukan parasit (Yoes Prijatna Dachlan, 2014)

Most parasites represent complex life cycles Part of which occurs in humans (or other vertebrates) Part of which occurs in intermediate hosts (flies, ticks, snails) Most parasites represent complex life cycles There is a considerable problem from a public health point of view, since a parasite that continually changes form and/or makes use of an invertebrate or animal vector is much harder to control than a pathogen that infects human only (Yoes Prijatna Dachlan, 2014)

Protozoan infections (Kaufmann, 2011) (Yoes Prijatna) Dachlan, 2014)

Platyhelminths Nematodes Trematoda •Schistosoma spp. hati, intestine, bladder, paru → fibrosis •Opistorchis spp. → liver cancer (O. viverrini) •Fasciola hepatica → liver Cestoda •Echinococcus spp. hati dan jaringan lainnya •Taenia solium → otak Platyhelminths s Nematodes Filariae •Brugia malayi lymphatics → elephantiasis •Wuchereria bancrofti lymphatics → elephantiasis •Onchocerca volvulus → kulit, mata Soil transmitted nematodes •Ancylostoma duodenale → intestin (anemia) •Necator americanus → intestin (anemia) •Trichuris trichiura → intestin •Strongyloides stercoralis → intestin •Ascaris lumbricoides → intestin (Kaufmann, 2011) (Yoes Prijatna Dachlan, 2014)

Umumnya infeksi menjadi khronis karena : Lemahnya Innate Immunity Kemampuan parasit menghindar atau bertahan terhadap daya eliminasi Adaptive Immune Response Individu yang tinggal di daerah endemis seringkali mendapat paparan (terus menerus), sehingga memerlukan kemoterapi yang berulang  mahal Vaksin yang efektif belum berhasil ditemukan. Vaksin malaria sangat dibutuhkan sehubungan dengan meluasnya resistensi parasit didunia terhadap obat antimalaria. (Yoes Prijatna Dachlan, 2014)

Respons imun terhadap struktur antigenik yang kompleks mempunyai manifestasi yang bervariasi dan tidak selalu mewujudkan kekebalan yang mampu melindungi hospes dengan sempurna (complete protective immunity) Respons imun seringkali pada kasus-kasus penyakit infeksi menghasilkan penyakitnya menjadi lebih serius dibandingkan dengan yang diakibatkan oleh parasit itu sendiri Beberapa parasit mampu menghindar dari respons imun dengan menggunakan mekanisme yang bervariasi Kemampuan parasit beradaptasi dengan lingkungan hospesnya menyebabkan parasit tetap berhasil mempertahankan hidupnya (Yoes Prijatna Dachlan, 2014)

Persistence, Chronicity and Evasion Most parasitic infections are chronic in nature Chronicity is evidence that the immune response has failed to eradicate the infection and implies that the immune responses to most parasites are to some extent ineffectual A consequence of chronicity is the presence of regulatory mechanisms that develop to modulate immunologically mediated tissue damage associated with infection (Yoes Prijatna) Dachlan, 2014)

Parasit mengembangkan suatu perlawanan terhadap respos imun dengan menghindar dari respons imun (melalui antigenic variation atau mekanisme lainnya) Parasit mengembangkan suatu perlawanan terhadap respos imun atau, mencegah berkembangnya mekanisme efektor kedua strategi diatas dipakai Host merespons kuat hanya terhadap antigen yang diekspresikan pada stadium itu saja Setiap stadium parasit mengekspresikan gen yang spesifik terhadap stadium respons terhadap antigen tersebut tidak efektip untuk melawan stadium parasit → infeksi menjadi khronis (Yoes Prijatna) Dachlan, 2014) (Kaufmann, 2011)

+ √Although parasitism implies mutual coexistence of host and infectious agent, the immune response plays a critical role in the establishment and maintenance of this balance √Traditionally, the control of parasitic infections was thought to be the exclusive domain of the acquired immune system and typical innate functions ~Complement components ADAPTIVE TRADITIONAL CONCEPT + PARASITES Typical Innate (Hunter & Sher, 2011) ~Phagocytes ~Complemen components Primitive vector mechanisms (Yoes Prijatna Dachlan, 2014)

+ √Since the start of the 1990s, it has been recognized that the early interactions between the host innate system and pathogens shape subsequent adaptive responses and the outcome of infection CONCEPT of 1990s Host Innate System ADAPTIVE Outcome of Infection + PARASITES RESOLUTION LATENCY DISEASE (Yoes Prijatna Dachlan, 2014)

Innate Immunity to Parasitic Infections Humoral mechanisms Cellular mechanisms In Determining the Nature of Adaptive Immunity Molecular Basis for Innate Recognition Activation of Complement Mediated by Phagocytes PAMPs & PRRs (eg. TLR) Involve sharply divergent T-cell effector outcomes • Th1/Th2 • a balanced immune response • Tregs Development of IFN-γ Granulocyte populations (Eo, mastocytes) (Kaufmann, 2011) (Hunter CA; Sher A) (Yoes Prijatna Dachlan, 2014)

Adaptive Immunity to Parasitic Infections Intracellular Parasites of Phagocytic Cells (Leishmania, T.gondii, T. cruzi) Initiation of immunity TLR → DCs → cytokine IL-12 T-cell dependent Control Activation of MØ and DCs The key cytokines important for resolution is IFN-γ (Kaufmann, 2011) (Scott P., Riley EM) (Yoes Prijatna Dachlan, 2014)

Mechanic and Innate immune Adaptive immune chemical barrier system Neu B1 B cells Tγδ cells NK Innate immune system DC MØ Tαβ cells Tαβ cells B2 B cells Adaptive immune system (Yoes Prijatna Dachlan,2013)