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THE IMMUNE RESPONSE TO PARASITES Unicelllular protozoa Leishmania major Plasmodium – malaria Trypanosoma (sleeping disease, Chagas disease) SPREADING BY BITES 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 THE IMMUNE RESPONSE TO THE SINGLE CELL PARAZITE LEISHMANIA Dead parazites NO, IL-12 O2-,H2O2,OH- IL-2 TNF Active radicals CLEARS THE INFECTION Th1 MACROPHAGE IFNγ lipophosphoglycane IL-2 IL-10 Leishmania major CR4 CR3 IL-4 DOES NOT CLEAR THE INFECTION Th2 MACROPHAGE MECHANISMS OF DELAYED TYPE HYPERSENSITIVITY ACTIVATION OF CELLS RECRUITMENT OF CELLS Activation of macrophages, increased release of inflammatory mediators IL-2 IFNγ TH 1 IL-3 GM-CSF TNFβ Local tissue destruction Increased expression of adhesion molecules on local blood vessels Chemokines Increased production of neutrophils and monocytes in the bone marrow DEFENSE MECHANISMS AGAINST HELMINTHS HOST ENVIRONMENT is accepted, resistant to complement and phagocytes BIG – no phagocytosis RESISTANT – to reactive radicals and enzymes of macrophages and neutrophils 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 Schistosoma mansoni Delayed Type Hypersensitivity - DTH Fibrosis around the eggs in the liver Chronic inflammation – Fibrotic connective tissue Inhibits the venous circulation of the liver IgE – MEDIATED CELLULAR CYTOTOXICITY Death of worm Shistosoma IgE FcεRI Granules Eosinophil granulocyte THE IMMUNE RESPONSE TO MULTICELLULAR WORMS Can not be ingested by phagocytes Plasma cell IgE IL-3 IL-4 mediators Th2 ECF NCF Mast cell Permeability Eosinophil B B IL-4, IL-5 BLOOD IgE Neutrophil IgG Th2 C' LYMPH NODE C3a, C5a Monocyte 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 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 THE IMMUNE RESPONSE TO VIRUSES INFECTION WITH LYMPHOCYTE CHORIOMENINGITIS VIRUS (LCMV) LCMV LCMV T T T Mouse dyes Mouse healthy No thymus LCMV Mouse dyes 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 VIRUSES REPLICATE WITHIN HOST CELLS AND ARE HIDDEN FROM ANTIBODIES Virus Antibodies DNA Replication Viral proteins Transcrition + Translation New viral particles Antibodies THE IMMUNE RESPONSE TO VIRUSES neutralization Inhibition of viral spread Phagocytosis IFNαβ Neutralization IgA opsonization KILLING Mucosal surface Killing of infected cells by cytotoxic reactions Complement-mediated lysis C' Killing by virus-specific cytotoxic T cells Tc cell NK cell-mediated antibodydependent cytotoxicity (ADCC) NK cell KINETICS OF VARIOUS ANTI-VIRAL MECHANISMS IFNα/β, IL-12 Cytotoxic T cells Antibody level/activity NK cells Complement vírustiter VIRUS TITER 1 2 3 4 5 6 7 8 9 10 11 12 13 na pok days RECOGNITION OF TARGET CELLS BY NATURAL KILLER CELLS Target MHC+ Target MHC- Target Ag MHC class I KAR KIR KAR NK KIR – Killer Inhibitory Receptor Recognition of MHC class I KAR – Killer Activatory Receptor FcRIII CD16 KIR NK NK Antibody-mediated NK-cell killing LINKED RECOGNITION OF VIRAL ANTIGENS BY CD4+ AND CD8+ T LYMPHOCYTES TNF IFN CD40 CD40L CD40 APC Apoptotic cell CD4+ TH1 CD40L MHCII IL-12 M H CI Ag B Survival IL2 IL4 IFN CD8+ Tc INDIRECT ANTIGEN PRESENTATION THE ROLE OF CD4+ AND CD8+ T CELLS IN VIRAL INFECTIONS • CD4 • CD8 – Killing potential • Perforin, granzymes • Acts before virus progeny – Anti-viral cyto- & chemokines HBV MIP-1,, RANTES HIV • TNF-, IFN- • • Blocks virus progeny – 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 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 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. 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.
