1. Unicelllular protozoa Leishmania major Plasmodium – malaria Trypanosoma (sleeping disease, Chagas disease) SPREADING BY BITES THE IMMUNE RESPONSE TO PARASITES Multicellular invertebrates Helminths –Intestinal worms Ascaris, Cestoda (gut), Trichinella (muscle), Filaria (lymph) Tape worm Diphyllobothrium latum 9m in length, lives in small intestine B12 deficiency (magaloblastic anaemia) Blood, liver, lung flukes COMPLEX LIFE CYCLE

2. THE IMMUNE RESPONSE TO THE SINGLE CELL PARAZITE LEISHMANIA 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

3. IL-3 GM-CSF IL-2 Increased production of neutrophils and monocytes in the bone marrow IFNγ TNFβ Chemokines RECRUITMENT OF CELLS ACTIVATION OF CELLS Activation of macrophages, increased release of inflammatory mediators Local tissue destruction Increased expression of adhesion molecules on local blood vessels MECHANISMS OF DELAYED TYPE HYPERSENSITIVITY

4. 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

5. IgE – MEDIATED CELLULAR CYTOTOXICITY Shistosoma Eosinophil granulocyte IgE FcεRI Death of worm Granules

6. 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 

7. ESCAPE MECHANISMS OF PARASITES Poor antigenicity Variations in surface structure – gene conversion Alternating expression Trypanosoma Priviledged 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

8. THE IMMUNE RESPONSE TO VIRUSES

9. © Media Graphics International LCMV Mouse healthy Mouse dyes No thymus T T T LCMV LCMV INFECTION WITH LYMPHOCYTE CHORIOMENINGITIS VIRUS (LCMV) Mouse dyes

10. THE IMMUNE RESPONSE TO VIRUSES VIRUSES – obligatory parasites ENTRY TO HOST CELL – receptor – mediated internalization LIFE CYCLE – Acute, latent, chronic, slow infection PROTECTION INNATE IMMUNITY – Type I interferons – inhibition of virus replication – NK cells ADAPTIVE IMMUNITY Antibodies – neutralization – opsonisation Cytotoxic reactions– complement – mediated lysis – NK cell – ADCC – virus – specific CD8+ effectors

11. Virus Replication New viral particles Translation Transcrition+ Antibodies VIRUSES REPLICATE WITHIN HOST CELLS AND ARE HIDDEN FROM ANTIBODIESDNA Viral proteins Antibodies

12. THE IMMUNE RESPONSE TO VIRUSES IgA Mucosal surface Neutralization Killing of infected cells by cytotoxic reactions Complement-mediated lysis NK cell-mediated antibody- dependent cytotoxicity (ADCC) Killing by virus-specific cytotoxic T cells IFNαβ Inhibition of viral spread neutralization Phagocytosis opsonization NK cellTc cell KILLING

13. KINETICS OF VARIOUS ANTI-VIRAL MECHANISMS Complement AntibodyCytotoxic T cellsNK cells IFNα/β, IL-12 days level/activity VIRUS TITER

14. RECOGNITION OF TARGET CELLS BY NATURAL KILLER CELLS Antibody-mediated NK-cell killing Ag Fc  RIII CD16 Target NK KAR KIR Target MHC- KAR KIR KIR – Killer Inhibitory Receptor Recognition of MHC class I KAR – Killer Activatory Receptor NK Target MHC+ MHC class I

15. LINKED RECOGNITION OF VIRAL ANTIGENS BY CD4+ AND CD8+ T LYMPHOCYTES INDIRECT ANTIGEN PRESENTATION

16. THE ROLE OF CD4+ AND CD8+ T CELLS IN VIRAL INFECTIONS CD8 –Killing potential Perforin, granzymes Acts before virus progeny –Anti-viral cyto- & chemokines TNF- , IFN-  HBV MIP-1 , , RANTES HIV Blocks virus progeny CD4 –APC conditioning CD40-CD40L (pathogens) IL-12  Th1 IL-15  CTL memory –Anti-viral cytokines TNF- , IFN-  –Growth factors IL-2 –Negative regulation AICD, Fas-FasL

17. ESCAPE MECHANISMS OF VIRUSES  High variability of surface antigens  Integration to the host cell genome  Infection of „privileged” locations  Inhibition of antigen presentation (HSV – TAP, HCMV- MHC-I)  Production of cytokin receptor homologes (HCMV- chemokine, poxvírus- IFN)  Immunosupresszive cytokine production (EBV - IL-10 homológ)  Infection of immunocompetent cells

18. Certain etiologic agents such as viruses are more likely to lead to chronic inflammation, as seen here in the lung of a patient with influenza A. Note also that the inflammatory infiltrates of chronic inflammation are more likely to be interstitial (within tissues) rather than exudative (above surfaces or in spaces) like acute inflammation. CHRONIC INFLAMMATION Chronic inflammation is more difficult to understand, because it is so variable. Seen here is chronic endometritis with lymphocytes and plasma cells in the endometrial stroma. In general, the inflammatory infiltrate of chronic inflammation consists mainly of mononuclear cells: lymphocytes, plasma cells, and macrophages.