Immunology

ImmunologyNonspecific Host Defenses

Dr, HudaHbrahim Lec. no. 2


PartⅡ Cells participating in innate immunity Natural killer cells (NK) Mononulear phagocytes Neutrophils Other cells participating in innate immunity


Ⅰ. Natural killer (NK)cell Also called large granular lymphocytes (LGL)Kill various infected and malignant cells spontaneously, without stimulation of antigen and MHC restriction(MHC molecules class 1are proteins expressed on all nucleated cells in every individuals) Identified by the presence of CD56,CD16Activated by IL-12 and produce IFN -γ

Recognition mechanism of NK cells

FcγRⅢ: recognize antibody covered cell antibody dependent cell cytotoxicity ------ADCCKiller activating receptor (recognize cell surface molecules expressed on host cells infected with viruses)

NK cells also express killer inhibitory receptors that recognze normal cells.NK cells is tolerant to self-antigen:Only virus infected cells and tumor cells could be killed by NK cells, not the normal tissue cells.Virus infected cells or tumor cells  MHC-I  inhibitory signal  Killed by NK cells。


Effector of NK cellsCytotoxicity: -ADCC-mediated by FcγRⅢ(CD16) -Granules like CTLs: Perforin: creates pores in target cell membranes Granzymes : enzymes which enter through perforin pores and induce apoptosis of target cells.

However, upon exposureto IL-2 and IFN-γ,the NK cells become lymphokine activated killer (LAK) cells, which are capable of killingmalignant cells. Continued exposure to IL-2 and IFN-γ enables the LAK cells to kill transformed as well as malignant cells. LAK cells

K Cells

morphologically undefined have IgG Fc receptor recognize antibody coated targets could be NK cells (IgG), macrophages (IgG), eosinophils (IgE) or other cells (IgG)

Phagocytes: Neutrophils

phagocytosis, intracellular killing, inflammation and tissue damage characteristic nucleus, cytoplasm granules and CD66 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


Sequence of events in migration of leukocytes to site of infection*Macrophages that have encountered microbes produce TNF & IL-1 that activate the endothelial cells to produce selectins , integrins & chemokines.These mediators lead to rolling , adhesion , & neutrophils migration respectively.

Phagocytes:Macrophages

Phagocytosis & killings, tissue repair, antigen presentation for specific immune response characteristic nucleus and CD14 membrane marker.

Macrophages

Contain numerous lysosomes, activated by cytokines kill malignant and altered self targets


Phagocytosis: Phagocytosis is carried out by white blood cells: macrophages, neutrophils, and occasionally eosinophils. Neutrophils predominate early in infection. Wandering macrophages: Originate from monocytes that leave blood and enter infected tissue, and develop into phagocytic cells. Fixed Macrophages (Histiocytes): Located in liver, nervous system, lungs, lymph nodes, bone marrow, and several other tissues.

Recognizing and excluding pathogens

Recognizing Ingestion Digestion Exclusion
recognizing
digestion
ingestion
exclusion

The receptor associated with antigen-recognition of macrophage

Pattern recognition receptor (PRR) or non-opsonic receptor------Mannose receptor(MR) Scavenger receptor(SR) Toll like receptor(TLR)Opsonic receptor------FcγR and C3b R/

Activated macrophage secrets

Interleukin-1 (IL-1)
Tumor necrosis factor-1(TNF-) Interleukin-6 (IL-6)
Interleukin-12 (IL-12)
Interleukin-8 (IL-8) (chemokines, CXCL8)

IL-1, TNF-, and IL-6 have systematic functions 1. Acute phase response

IL-1, TNF-, IL-6 Liver
Blood circulation
Acute phase proteins
C-reactive protein
Mannose-binding lectin
Complement activation Facilitate phagocytosis

Phagocyte Response to Infection

The Signals N-formyl methionine Clotting system peptides Complement products Phagocyte Chemotaxis Vascular adherence Phagocytosis and killing


Stages of Phagocytosis 1. Chemotaxis: Phagocytes are chemically attracted to site of infection. 2. Adherence: Phagocyte plasma membrane attaches to surface of pathogen or foreign material. Adherence can be inhibited by capsules (S. pneumoniae) or M protein (S. pyogenes). Opsonization: Coating process with opsonins that facilitates attachment. Opsonins include antibodies and complement proteins.

Phagocytes are Attracted to Site of Infection by Chemotaxis

Stages of Phagocytosis (Continued) 3. Ingestion: Plasma membrane of phagocytes extends projections (pseudopods) which engulf the microbe. Microbe is enclosed in a sac called phagosome. 4. Digestion: Inside the cell, phagosome fuses with lysosome to form a phagolysosome. Lysosomal enzymes kill most bacteria within 30 minutes and include: Lysozyme: Destroys cell wall peptidoglycan Lipases and Proteases RNAses and DNAses After digestion, residual body with undigestable material is discharged.



Receptors on Macrophages:Fcγ receptorsComplement receptorsToll-like receptors(TLRs) Scavenger receptors(SRs)LPS receptor(CD14) Macrophages phagocytose and degrade foreign particles, bacteria and dead (and dying) host cells.

Pathways of Intracellular Killing

Respiratory Burst
Oxygen Dependent Myeloperoxidase Independent Reactions
2O2- + H2O2
.OH + OH- + 1O2
Glucose +NADP+ G-6-P-dehydrogenase
Pentose-P + NADPH
NADPH + O2 Cytochrome b558
NADP++ O2-
2O2- + 2H+ Superoxide dismutase
H2O2 + 1O2

Respiratory Burst

Oxygen Dependent Myeloperoxidase dependent reactions


H2O2 + O2-
2O2- + 2H+ Superoxide dismutase
H2 O2 + Cl- myeloperoxidase
OCl- + H2O
H2O + O2-
2 H2 O2 catalase
2OCL- + H2O
1O2-+ Cl-+ H2O

Nitric oxide dependent killing

Binding of bacteria to macrophages, particularly binding via Toll-like receptors results in the production of TNF-α, which acts in an autocrine manner to induce the expression of the inducible nitric oxide synthetase gene (i-nos ) resulting in the production of nitric oxide (NO)..

If the cell is also exposed to interferon gamma (IFN-γ) additional nitric oxide will be produced. Nitric oxide released by the cell is toxic and can kill microorganism in the vicinity of the macrophage

Nitric Oxide Dependent Killing

IFNγ TNF
TNF
Nitric Oxide
Nitric Oxide

Process of Phagocytosis