Non-Specific Immunity Innate (natural, native, non-specific) immunity •Always present, ready to recognise and eliminate microbes. Does nor react to nonmicrobial substances. •Frequently eliminates microbes before the specific immunity becomes active. •Receptors are encoded in the germline, are not a product of recombination of genes. Differences between the Innate and Acquired Immunity •Innate Immunity • –Universal –Rapid –Lacks memory • •Acquired Immunity • –Not universal –‘Slow’ to develop –Memory –Specific but…. –‘Plays to the tune of the Innate immune system’ S0241X-002-f001 Downloaded from: StudentConsult (on 19 July 2006 06:34 AM) © 2005 Elsevier top_logo Differences between inntae and specific immunity Basic components of non-specific defence •Non Specific barriers –Anatomical/Physiological •Acute phase reactants and Inflammation –Complement/Interferons/CRP •Innate cells –PMN/Macrophages/NK cells • • PAMPS – patogen-associated molecular patterns (Endotoxin, mannose, double-stranded RNA, unmelylated CpG nucleotides) PRR- Pattern recognition receptors - recognize PAMPS. TOLL-like receptors –surface or intracellular receptors recognizing various PAMPS. Expressed on dendritic cells, macrophages, granulocytes, epitelial cells…. They induce activation of these cells. S0241X-002-f008 Downloaded from: StudentConsult (on 19 July 2006 06:34 AM) © 2005 Elsevier top_logo Activation by Toll-like Receptors and by Cytokine Receptors The Complement System General features of the Complement System Activation •Inactive, preformed protein is activated by the proteolytic cleavage. •It is cleft into the smaller part (called a) and a bigger part (called b). •Usually the bigger part has also proteolytic activity, while the smaller part has various other biological activities (chemotactic, anaphylatoxic). •Component C6-C9 are activated without cleavage, they just „attach“ to the complex of the other complement components. Cesty aktivace komplementu Activation of the complement sytsem Funkce komplementu Complement system activation •Classical pathway: –Complexes IgG-antigen, IgM-antigen, –C-reactive protein •Alternative pathwas –Lipopolysaccharide of G- bacteria –Cell wall of some bacteria –Cell wall of the yeasts (zymozan) –Aggregated IgA •Lectin pathway: –Mannose and other sacharides S0241X-002-f011 Downloaded from: StudentConsult (on 19 July 2006 06:34 AM) © 2005 Elsevier top_logo The Complement System Komplementový systém C9 Alternativní cesta Biological effects of activated complement system •C9 - cytolytic effect •C3b - opsonisation •C3a, C5a – anaphylatoxins, liberation of histamine •C5a - chemotaxin Phagocytosis Phagocytic cells •Polymorphonuclear granulocytes •Monocytes + macrophages •Dendritic cells mainly non-activated cells. After activation they loose most of their phagocytic activity. S0241X-002-f003 Downloaded from: StudentConsult (on 19 July 2006 06:34 AM) © 2005 Elsevier top_logo Polymorphonuclear granulocyte Normal blood count (in adults) •Erythrocytes: 4-5 x 1012/l •Thrombocytes: 150-300 x 109/l •Leukocytes: 4-9 x 109/l –Granulocytes: 55-70% –Eosinophils: 1-4% –Basophils: 0-1% –Lymphocytes: 24-40% –Monocytes: 3-8% • Macrophages •Derived from blood monocytes. •Connective tissue macrophages –Kupffer cells (liver) –Alveolar macrophages (lungs) –Microglia (CNS) –Osteoclasts (bone) –Peritoneal macrophages – S0241X-002-f004 Downloaded from: StudentConsult (on 19 July 2006 06:34 AM) © 2005 Elsevier top_logo Development of macrophages S0241X-002-f005 Downloaded from: StudentConsult (on 19 July 2006 06:34 AM) © 2005 Elsevier top_logo Extravasation of leukocytes Chemotaxins •Attract phagocytic cells •Products of destroyed cells •C5a •IL-7, IL-1 •Leukotriens Opsonins •Substances enhancing phagocytic process by improving attachment of the particle to the phagocytic cell. •Specific: IgG, (IgM only indirectly by activation of the complement system) •Non- specific: C3b, fibronectin…. S0241X-002-f007 Downloaded from: StudentConsult (on 19 July 2006 06:34 AM) © 2005 Elsevier top_logo Steps of phagocytosis phagocytosis Killing mechanisms of phagocytic cells •Reactive metabolites of oxygen (H2O2, hydroxyl radical (.OH), superoxide aniont (O2-), singletted oxygen (.O2) •Reactive nitrogem intermediates (NO, NO2) •Hydrolases: protease, lipases, DNAses •Low pH •Lysozyme •Lactoferin •Defensins – antimicrobial polypeptides • Lysozyme •Cleaves cell walls of G+ bacteria •Present in granules of neutrophil granulocytes, in plasma, secretions. Natural killers (NK cells) •Originate in non-T non-B lymphocyte lineage. •Morphologically: large granulated lymphocytes (LGL). •Recognition of target cells in antigen non-specific. •Virus infected and tumor cells are killed. •Target cells are characterised namely by decreased HLA-I expression. •Cytotoxic mechanisms are similar to Tc cells: perforin and induction of apoptosis. NK buňka II Large granulated lymphocyte interferon2 The action of interferon (IFN) Inflammation •A rapid response to wounding and infection •An important consequence of innate immunity •Cardinal features –rubor (redness), calor (heat), tumor (swelling), dolor (pain) •Local consequences of inflammation –Increased blood flow to affected area –Recruitment of phagocytes to affected area, particularly neutrophils and macrophages –Alteration of vascular permeability leading to entry of soluble molecules from the plasma General symptoms and signs of inflammation •Orchestrated mainly by IL-1, IL-6, TNF-a •Fever •Fatigue, somnolence •Loss of appetite •Laboratory signs: leukocytosis, increased ESR, increase in accute phase proteins, decreased levels of iron and zinc in serum. S0241X-002-f012a Downloaded from: StudentConsult (on 19 July 2006 06:34 AM) © 2005 Elsevier top_logo Initiation of inflammation Accute-phase proteins •Serum levels are increased during inflammation •Produced by the liver after stimulation by IL-1, IL-6, TNF-a •Best known: C-reactive protein •Others: Complement components, A1-AT, fibronectin.. Accute phase response inflammation people.eku.edu/ritchisong/301notes4b.html Initiation of inflammatory process Drugs modulating inflammatory process •Glucocorticoids •Non-steroidal anti-rheumatic (anti-phlogistic) drugs (acidosalicylic acid, paracetamole,…) •Antimalarics •Gold •Monoclonal antibodies against inflammatory cytokines and adhesion molecules