THE IMMUNE RESPONSE TO PARASITES

Pulendran B, Artis D (2012) Science 337: Multicellular parasite infections trigger Th2 type adaptive immune response

The elicited Th2 response leads to the production of IgE/IgG antibodies The role of dendritic cells is critical in the initiation phase of anti-parasitic Th2 responses. The main sources of the Th2 polarizing cytokine IL-4: 1. DCs 2. Basophils 3. Eosinophils 4. NKT cells Gause WC et al. (2013) Nat Rev Immunol 13:

Unicellular protozoa Plasmodium (malaria) Leishmania Toxoplasma THE IMMUNE RESPONSE TO PARASITES

The life cycle of Plasmodium Inoue SI et al. (2013) Front Immunol 4:258.

Main components of the immune response to Plasmodium macrophages „clearance” role of the spleen!

Dead parazites IL-12 TNF IL-2 Th1 Th2 IL-2IL-10 IL-4 IFNγ Leishmania major MACROPHAGE NO, O 2 -,H 2 O 2,OH - CR3 CR4 lipophosphoglycane CLEARS THE INFECTION DOES NOT CLEAR THE INFECTION MACROPHAGE Active radicals Immune response to the single cell parasite Leishmania

credit: credit: DJP Feruson/University of Oxford Toxoplasma gondii, the „brain-hacker” parasite Global prevalence: 30% (seropositivity in human populations) Rarely causes clinical symptoms in healthy adults; the endangered members of the population are children, elderly people, Immunosuppressed individuals, etc. The genome of T. gondii encodes two aromatic hydroxylases that allow the parasite to synthesize dopamine. This may influence the behavior of seropositive indviduals (e.g. increased risk-taking). Recently, T. gondii infections have been correlated with many neuropsychiatric diseases: - schizophrenia (38 large cohort studies, strong positive correlation); - epilepsy; - OCD (7 large cohort studies, positive correlation); - Bipolar disorder (the correlation has been unclear);

Hunter CA & Sibley LD (2012) Nat Rev Microbiol 10: Sauer A et al. (2013) Int J Parasitol 43: Main characteristics of the immune response to Toxoplasma:

Multicellular parasites Helminths Diphyllobothrium latum Trichinella spiralis

THE IMMUNE RESPONSE TO MULTICELLULAR WORMS Can not be ingested by phagocytes C3a, C5a Monocyte Neutrophil Eosinophil Mast cell IL-3 IL-4 Plasma cell IgE mediators B B Th2 IL-4, IL-5 LYMPH NODE IgE IgG BLOOD Schistosoma mansoni Activated eosinophils bind to IgE-coated parasites via the high affinity FcεRII and release their toxic contents onto the worm Other effector cells bind to IgG-coated parasites Permeability 

Mast cells

Eosinophil granulocytes

IgE – MEDIATED CELLULAR CYTOTOXICITY (ADCC) Shistosoma Eosinophil granulocyte IgE FcεRI Death of worm Granules

DEFENSE MECHANISMS AGAINST HELMINTHS IgE – mediated protection IgE-mediated antibody dependent cellular cytotoxicity ADCC EFFECTOR CELLS: mast cells, basophils, and eosinophils  inflammatory mediators  vasodilation  recruitment of inflammatory cells  fluid outflow  smooth muscle cell contraction  mechanical removal HOST ENVIRONMENT is accepted, resistant to complement and phagocytes BIG – no phagocytosis RESISTANT – to reactive radicals and enzymes of macrophages and neutrophils Schistosoma mansoniDelayed Type Hypersensitivity - DTH Fibrosis around the eggs in the liver Chronic inflammation – Fibrotic connective tissue Inhibits the venous circulation of the liver

ESCAPE MECHANISMS OF PARASITES Poor antigenicity Variations in surface structure – gene conversion Alternating expression Trypanosoma Privileged sites isolated from the immune system (cyst) Intracellular Leishmania, Toxoplasma Inhibition of phagosome and lysosome fusion Toxoplasma Antigen masking by bound self proteins Complement (DAF) like structures