Phagocytosis endocytosis defense role profesional phagocytes

elimination - clearing - Phagocytosis activation other cells secretion enzymes, cytokines presentation Ag killing regulation Inflammation

Phagocytosis Professional Effective phagocytosis and secretion: »macrophages »neutrophil granulocytes Non- Professional Secretion »eosinophils »basophils »mast cells

Professional phagocytes macrophages (monocytes), neutrophils elimination of microbs, partiles membrane receptors –complement R: CR1, CR2 –receptors for Ab: Fc receptors

Mechanism 1) adhesion - endotel 2) diapedesis 3) chemotaxis 4) adhesion – bacteria,... (+ opsonisation) 5) ingestion 6) digestion (killing and degradation)

Adhesion endothelium - neutrophils NeutrophilEndothelial cellFunction Le x (CD15) sialyl-Lewis x antigen P-selectin (CD62P) rolling Integrins: CD11a (LFA-1) CD18 ICAM-1, 2 (CD54, CD102) adhézia CD11b (Mac-1) CD18 ICAM-1 adhézia

Adhesion endothelium - monocytes MonocytesEndothelial cell Function Integrins  1 (CD29)VCAM-1rolling CD11a (LFA-1) CD18 ICAM-1, 2 (CD54, CD102) adhézia CD11b (Mac-1) CD18 ICAM-1adhézia

Diapedesis and chemotaxis Diapedesis Chemotaxis - chemotaxins –exogenous: bacterial oligopeptides (FMLP), LPS, lipids –endogenous: C5a, Ba, fibrinopeptides, kalikrein, plasminogen activator, metabolites of arachidonic acid (LTB 4,...) Stimulation of chemotexis, but also adherence, endocytosis and sekretion of lysosomal enzymes.

Adhesion 1) surface molecules of particle 2) opsonins

Opsonins – immune phagocytosis Opsonisation: –opsonins (specific molecules) –facilitation of adhesion –principle – opsonins represent ligands for receptors of phagocytes

Phagocytosis Immune opsonins Non-immune

Opsonins – immune phagocytosis ReceptorOpsonin (ligand) Cells CR1C3b, C4bneutrophils, monocytes, B cells, some T cells CR2C3bneutrophils, monocytes, macrophages, B cells FcRAb: IgG, IgM monocytes, macrophages, neutrophils

Opsonins C3b Ab Phagocytes - receptors Bactetia + opsonins CR3 FcR

Ingestion - digestion Ingestion >>> pseudopodia – phagozómu. Digestion >>> lysosom –phagolyzozóm. Lysosoms >>> enzymes Role > killing and destruction.

Microbicidal mechanisms 1) Oxygen dependent 2) Oxygen independent

Microbicidal mechanisms Oxygen dependent Myeloperoxidase independent - hydrogenperoxide - superoxide anion - hydroxyl radical - singlet oxygen 2)Myeloperoxidase (MPO) dependent - MPO + hydrogenperoxide + I - - MPO + hydrogenperoxide + Cl -

Respiratory burst Antimicrobial molecules Process: - stimulation of phagocytes (mikroorganizmy, C5a, Ag+Ab,...) - oxygen consuption - anaerob. metabolism - superoxide

Respiratory burst

MPO mechanisms

Oxygen independent mechanism - low pH in phagolysosome - cationic proteins - defensines - bactericidal proteins - lysozyme - neutral proteinases - lactoferin - phospholipase A2 - histones (leukin)

Deficiences 1.Low number of phagocytes a. Kostmann syndrom – inherited agranulocytosis –infections of skin and mucosa b. Cyklic neutropenia – every 3rd week Failure of function 2. Failure of function a. CGD (Chronic granulomatous disease) - defect of NADPH-oxidase - X chromosome – linked decreased bactericidal activity - recurent pyogenic infections staphylococcal infections - pneumonia

Deficiences b. LAD (Leukocyte Adhesion Deficiency) - failure of adhesins on phagocyte - ↓ expresion of β2 subunit of integrins (CD18) Phagocytes: - do not adhere to endothelial cells - absent in the site of inflammation - recurent skin infections - wound healing - candidiasis