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Immune system protects body against pathogen External barriers prevent microorganism entry to the body Immune system performs immune response resulted in immunity Classification
Innate immune response Adaptive immune response

Innate immunity
Immediate Short protection Non specific Elimination: phagocytosis & killing activity Cells: granulocyt, macrophage, NK cell (natural killer) Humoral: complement

Adaptive immunity
Induced immune response Long term protection Memory Specific Cells: lymphocyte (B and T) Humoral: antibody

Non-Specific or natural Immune system Immediate response (0-4 hours) Function: provide the initial defense against infections: Prevent infections Eliminate microbes : depends on the presence of cells that recognize and kill pathogens and foreign materials directly

Consists of: Cellular

Phagocytes NK cell

Humoral
Acute phase protein Complement

Other Immune responses:

Fever Response Inflammatory Response, Interferon Response

Epithelial barriers Phagocytes:

Recognition of foreign particle Rapid destruction of an infectious organism phagocytic cells

Localized protective response (inflammation) Cytokine reactions Extracellular killing

Intact epithelial form physical barriers Produces peptides that have antimicrobial properties
Defensins (epithel/paneth cell, neutrophil, NK cells, Tcytotoxic,) direct toxicity to microbes Cathelicidins (neutrophil, skin, GI mucosal cells, respiratory mucosal cells) direct toxicity

Intraepithelial T lymphocytes, B-1 lymphocytes Mast cell in lamina propria

Function: identify, ingest, destroy microbes Members:

Granulocytes Macrophages DC

Steps:
Recruitment to sites of infection Recognition of pathogens Ingestion of microbes Destruction

Other: produce cytokine

Chemokine as a chemo-attractant Selectin

P-selectin & E-selectin: express by endothelial cells L-selectin: express by leucocytes Selectin-selectin receptor affinity is low rolling

Integrin stabilize adhesion of leucocyte to endothelium Cytoskeleton alter the shape of cells Extracellular matrix

The innate immune system distinguishes infectious microbes from self cells by recognizing molecular structures which expressed by microbes Pathogen has non-self structures : PathogenAssociated Molecular Patterns (PAMPs) Part of the innate immune cells which bind to PAMPs known as Pattern-recognition receptors

Certain sugar residue Certain sugar residue

Anionic polymers Broad spectrum of ligands LPS (in gram negative bacteria)

Mannose binding lectin Macrophage mannose receptor Scavenger receptor Toll-like receptor (TLRs)

PAMPS in pathogens

PRR in phagocytes

Activate phagocyte Release of cytokine & chemokine Inflammatory process

Phagocytic receptor : stimulate ingestion of pathogen Chemotactic receptor : binds to special peptide on bacteria

O2 dependent degradation (ROS) O2-independent degradation (ex: NO) Opsonins: protein that coat pathogen easy to be ingested
Antibodies Complements Lectins

Other mechanism

CRP Mannose binding protein Serum amyloid P component 1 acid glycoprotein, etc

Opsonization Inhibits bacterial protease Increase complement function

Substance that interfere with viral replication 14 class of IFN Infected cell secretes IFN to the extracelullar fluid bind to uninfected cell cordon of uninfected cell around site of infection inhibits viral reproduction between cells

Some mediator resets thermal setpoints in the hypothalamus induce heat formation fever Mediator = pyrogen Can be endogenous ( PG, IL-1) or exogenous (bacterial toxin, etc)

Inflamare: to set on fire Complex biological response of vascular & tissues to harmful stimuli Objection: to remove the injurious stimuli initiate the healing process for the tissue Terminology:
Organ + -itis

Deliver additional effectors molecule and cells to sites of infection augment killing of invading microorganism Induce blood clotting physical barrier to the spread of infection in blood stream Promote the repair of injured tissue

Increase in vascular diameter increase local blood flow increase the metabolic rate heat and redness

Endothelial cells lining the blood vessels are activated to express cell-adhesion molecules promote binding of circulating leukocytes

Increase in vascular permeability exit of fluid and protein from blood accumulate in the tissue swelling and pain

Clotting in microvessels in the site of infection prevents the spread of pathogen via the blood

Macrophage activation by pathogen lead to cytokine; chemokine release & local mediators Various cytokine can lead to fever & interferon response Various chemokine attract other cell to come to site of infection Local mediators make blood vessels dilate & increase vascular permeability redness & heat

Leukocyte in blood circulation has receptor for chemokine come to blood vessel near the site of infection Blood vessel express cell adhesion molecule bind leucocyte
Margination Rolling adhesion Tight adhesion Diapedesis Migration

Leucocyte migration/extravasation together with fluid & protein increase interstitial volume swelling Accumulation can activate free nerve endings pain Inflammatory mediators can also induce pain sensation More accumulation loss of function

Lymphocytes derived from lymphoid progenitor. Circulate in the blood Contain cytolytic granules Important in the defense from certain lymphoid tumor cell lines and from virally infected cells. Innate immune response Act without prior activation

NK cells' activity is increased when they are exposed to:

IFN- IFN IL-12

NK cell has 2 receptors: killing receptors & inhibiting receptors allow NK cells to kill infected cells, while sparring uninfected cells.

Activation of NK cell is regulated by a balance between signal from activating receptor and inhibitory receptors Activating receptor recognize
stressed cell Virus infected cell Malignant cell

Inhibitory receptor recognize:

Normal cell that expressed MHC class I

 Activation

release of cytotoxic granule contents production of the cytokines IFN- and TNF-

of NK cells results in:

NK

cells are activated through Killer Activating Receptors (KARs). Ex: NKp46, NKp30, NKp44 of these receptors contain a (+) charge in their transmembrane domain associated with adaptor to internalize external signals stimulates granule release

Each

Structures of various KARs, including their associations with adaptor molecules.

Figure 1 Moretta A., et al. Surface Receptors Delivering Opposite Signals Regulate the Function of Human NK Cells. Seminars in Immunology. Vol 12, 2000: pg. 129138.

Perforin or cytolysin can insert into cell targets membrane Polymerize form transmembrane pore Release of granzymes through transmembrane pore Granzymes consists of serine protease activate apoptosis reaction cell target death NK cell contain Fas Ligand bind with receptor (Fas) apoptosis

Infected cells can inhibit the synthesis of all proteins decreases the amount of MHC-I produced. Viruses can also selectively prevent the export of MHC-I molecule number of MHC class I molecules on the cell surface is decreased Decreased MHC-I expression decrease in the number of KIR/MHC-I interactions reduces inhibition signaling killing activity of NK cell

Macrophage produces cytokine IL-12 activates NK cell NK cell produces cytokine IFN- activates macrophage

Complement : heat-labile component of normal plasma that augments the opsonization and killing of bacteria by antibodies. Complement= the ability to assist or complement the antimicrobial activity of antibodies The complement system may be activated by microbes in the absence of antibody as part of innate immune response to infection, and by antibodies attached to microbes

Signal needed to induce adaptive immune response:

Antigen : presented by APC Molecules induced by innate response Cytokine signal

Adjuvants : substances that need to be administered to elicit maximal immune response