Abdul Ghaffar Microbiology and Immunology

"When the mind is ready,a teacher appears.“ Chinese Proverb

Development of the Immune System ery pl mye neu mφmφ lym nk thy CD8 + CD4 + CTL TH2 TH1

Cells of the Immune System Basophils Neutrophils Eosinophils Granulocytic Langerhans & Macrophages Kupffer cells Dendritic cells? Monocytic Cytotoxic Helper Suppressor T-cells Plasma cells B-cells Dendritic cells? lymphoid cells Myeloid cells

Components of the Immune System Humoral Cellular Humoral Cellular Specific Nonspecific complement, interferon, TNF etc. macrophages, neutrophils T cells; other effectors cells antibodies

Balance between Infection and Immunity infection immunity Bolus of infection x virulence immunity Disease =

Response to Infection infection x disease Innate immunity no disease recovery adaptive immunity re-infection no disease x

u Beneficial: u Protection from Invaders u Elimination of Altered Self u Detrimental: u Discomfort (inflammation) u Damage to self (autoimmunity) u Beneficial: u Protection from Invaders u Elimination of Altered Self u Detrimental: u Discomfort (inflammation) u Damage to self (autoimmunity) Significance of the Immune System

Innate Immunity Adaptive Immunity Characteristics of Innate and Adaptive Immunity No Immunologic memory Antigen independent No time lag Not antigen specific Antigen dependent A lag period Antigen specific Development of memory

Innate Immunity Adaptive Immunity Components of Innate and Adaptive Immunity skin, gut Villi, lung cilia,etc many protein and non-protein secretions phagocytes, NK cell eosinophils, K cells physical barriers soluble factors cells non e Immunoglobulins (antibody) T and B lymphocytes

Physical Barriers to Resistance

SiteComponentFunctions Effector mechanisms in Innate Immunity -1 Peristalsis, low pH bile salts, fatty acids columnar cells GI tract Skin squamous cells sweat desquamation flushing, fatty acids tracheal cilia Lung mucociliary elevator surfactants

SiteComponentFunctions Effector mechanisms in Innate Immunity -2 Nasopharynx and eye mucus, saliva, tearsflushing, lysozyme Phagocytes Blood and Lymphiod organs phagocytosis and intracellular killing K, NK & LAK cells direct and antibody dependent cytolysis

SiteComponentFunctions Effector mechanisms in Innate Immunity -3 Serum and other serous fluids lactoferrin, transferrin iron deprivation interferons, TNF-  antiviral proteins phagocyte activation lysozyme peptidoglycan hydrolysis Fibronectin & complement opsonization, enhanced phagocytosis, inflammation

Phagocytes are the Most Important Cells Influenced by the work of Eli Metchnikoff, George Bernard Shaw wrote: “There is at bottom only one genuine treatment for all diseases,…to stimulate the phagocytes. Drugs are a delusion. …(when) the phagocytes are stimulated; they devour the disease…”

All phagocytes eat, digest and extrude

Phagocytes: Neutrophils  phagocytosis, intracellular killing, inflammation and tissue damage  characteristic nucleus, cytoplasm  granules and CD66 membrane marker.

Phagocytes: Macrophages  phagocytosis, intracellular and extra- cellular killing, tissue repair, antigen presentation for specific immune response  characteristic nucleus and CD14 membrane marker.

Characteristics of Neutrophil Granules primary granules contain cationic proteins, lysozyme, defensins, proteases and myeloperoxidase secondary granules contain lysozyme, NADPH oxidase, lactoferrin and B12- binding protein azurophilic; characteristic of young neutrophils; specific for mature neutrophils

Phagocyte Response to Infection uThe SOS Signals –N-formyl methionine –Clotting system peptides –Complement products uPhagocyte response –Vascular adherence –Diapedesis –Chemotaxis –Activation –Phagocytosis and killing uThe SOS Signals –N-formyl methionine –Clotting system peptides –Complement products uPhagocyte response –Vascular adherence –Diapedesis –Chemotaxis –Activation –Phagocytosis and killing

Initiation of Phagocytosis Attachment via IgG FcR ScavengerR CR Toll-like R

Respiratory Burst Oxygen Dependent Myeloperoxidase Independent Reactions 2O H 2 O 2.OH + OH O 2 Glucose +NADP + G-6-P-dehydrogenase Pentose-P + NADPH NADPH + O 2 Cytochrome b558 NADP + + O 2 - 2O H + Superoxide dismutase H 2 O O 2

Respiratory Burst Oxygen Dependent Myeloperoxidase dependent reactions H 2 O 2 + O 2 - 2O H + Superoxide dismutase H 2 O 2 + Cl - myeloperoxidase OCl - + H 2 O H 2 O + O H 2 O 2 catalase 2OCL - + H 2 O 1 O Cl - + H 2 O

Pathways of Intracellular Killing

Effector MoleculeFunction Mediators of Oxygen Independent Killing in the Phago-lysosome Cationic proteins (cathepsin)Damage to microbial membranes Lysozyme Hydrolyses mucopeptides in the cell wall Lactoferrin Deprives pathogens of iron Hydrolytic enzymes (proteases)Digests killed organisms

Nitric Oxide Dependent Killing IFNγ  TNF Nitric Oxide

Non-specific Killer Cells NK and LAK cells ADCC (K) cell Activated macrophages Eosinophils NK and LAK cells ADCC (K) cell Activated macrophages Eosinophils They all kill foreign and altered self targets

Natural Killer (NK) cells ualso known as large granular lymphocytes (LGL) ukill infected and malignant cells uare identified by the presence of CD56 & CD16 and absence of CD3 uactivated by IL2 and IFN-γ to become LAK cells ualso known as large granular lymphocytes (LGL) ukill infected and malignant cells uare identified by the presence of CD56 & CD16 and absence of CD3 uactivated by IL2 and IFN-γ to become LAK cells

Lymphokine Activated Killer (LAK) cell IL2 IFN IL2 kills malignant cells kills transformed and malignant cells

Regulation of NK Cell Function

K Cells umorphologically undefined uhave IgG Fc receptor urecognize antibody coated targets ucould be NK cells (IgG), macrophages (IgG), eosinophils (IgE) or other cells (IgG) umorphologically undefined uhave IgG Fc receptor urecognize antibody coated targets ucould be NK cells (IgG), macrophages (IgG), eosinophils (IgE) or other cells (IgG)

Macrophages uphagocytose & kill intracellularly uidentified by CD14 uadherent of plastic and glass surfaces uactivated by cytokines ukill both intracellular organisms ukill malignant and altered self targets uphagocytose & kill intracellularly uidentified by CD14 uadherent of plastic and glass surfaces uactivated by cytokines ukill both intracellular organisms ukill malignant and altered self targets

Elements of Nonspecific Immunity Summary uPhysical Barriers uskin, muco-ciliary escalator, secretions, peristaltic movement, etc. uSerous Proteins uAcute phase proteins, Interferon(s), lysozyme, lactoferrin, cationic proteins, etc. uPhysical Barriers uskin, muco-ciliary escalator, secretions, peristaltic movement, etc. uSerous Proteins uAcute phase proteins, Interferon(s), lysozyme, lactoferrin, cationic proteins, etc.

Elements of Nonspecific Immunity Summary uCells upagocytes uOxygen-independent killing uO2-dependent - MPO independent killing uO2-dependent - MPO dependent killing uNitric Oxide mediated killing ucytotoxic cells uNK, LAK, K (ADCC) uCells upagocytes uOxygen-independent killing uO2-dependent - MPO independent killing uO2-dependent - MPO dependent killing uNitric Oxide mediated killing ucytotoxic cells uNK, LAK, K (ADCC)