Innate Immune Response

Goals of Innate Immune Response:

• ID pathogen to destroy by recognizing PAMPs on pathogen (PRRs recognize PAMPs)

• Phagocytosis to destroy pathogen (activating adaptive) and present antigen (protein, lipid, carbohydrate) to T & B cells

• Recognition factor

• Antimicrobial peptides destroy bacteria

PAMPs:

• exclusive and pathogens

• Lipids

• Proteins

• Carbohydrate

• Recognized by PRRs

• Receptor to phagocytes = Ph

Opsonins (opsonization):

• tags a pathogen for destruction

• Activating complement system

Innate Immune response overview:

1) recognition by PRR and PAMPs

2) leads to phagocytosis

3) antimicrobial peptides destroy

4) Opsonization: codes pathogen so phagocyte can recognize pathogen

Simpler way:

1) breach of Barrie’s (physical) skin

2) cellular response

3) activate adaptive immune response

Anatomical barriers:

• Pathogen has to pass through barriers:

• skin = slaty

• Acidic

• AMPs

• Flora (good bacteria ; natural microbiome):

• Mucosa

• Proteases: enzymes degrade protein

• Cilia

• No bacteria in lower respiratory tract/ kidney / blood and can’t get past stomach

• Lysozyme degrades cell wall

• Respiratory linings: superfactant protein (targets cell wall)

What is on your skin that helps defeat a pathogen?

• low pH

• Enzymes and binding proteins

• AMP & proteases

Inflammation characteristics:

• heat, pain, swelling & redness due to:

• Vasodilation

• Vascular permeability

• Leukocyte migration which:

• Blood vessels are dilating

• Increase of blood flow

• Increase of leukocytes to site

• Epithelial cells release cytokines

Damage cells release:

• cytokines: chemical messengers that promote inflammation (pro-inflammatory cytokines) and recruit leukocytes

• Neutrophils/ DC (immune cells) recognize bacteria and release cytokines

• Phagocytosis

What are the 4 types of CAMs in the initiation of Extravasation?

• Integrans

• ICAM

• E-selection

• Musin

What is rolling and extravasation?

• immune cells out of blood vessel into site of infection

• CAMs (cell adhesion molecules) on surface of leukocytes and epithelial cells

• Musin attaches to e-selection

• Neutrophil/ DC/ damaged cell releases cytokines and causes a confirmation change when Integran binds/ attaches to ICAM

• Cytokines must be present in order to attach/ bind to

Rolling and Extravasion steps:

1) Rolling

2) activation

3) arrest/adhesion

4) transendothelial migration

What are the 3 main soluble molecules?

• proinflammatory cytokines

• Antimicrobial peptides

• Acute phase response (APR) and acute phase response proteins

What are the Proinflammatory cytokines?

• IL-1

• TNF alpha

  Cytokines:

• Chemokines: specifically attract leukocytes

• Chemoattractants

IL-1 (interlukin-1):

• family of 11 members promote:

• Vasodialation

• Adhesion

• Regulate hypothalamus which increase metabolic rate, increase temperature and stop microbial growth

Which cells release IL-1?

• DC

• Macrophages

• Damaged epithelial cells

What are the APR (acute phase response) proteins/ opsonins that recognize pathogens?

• complement proteins

• MBL (mannose binding lectin): found in microbial cell walls; trigger phagocytosis by DC, macrophages, Th, NK cells

• CRP (c-reactive protein)

TNF alpha:

promotes:

• Adhesion

• Permeability

• Develop macrophages

• Increase phagocytosis

What cells release TNF alpha?

• DC

• Macrophages

• Th-helper cells

• NK cells

AMPs:

• short stretches of amino acids

• Fast acting (quick response)

• Destroying cell wall and membrane

Complement Proteins:

• increase during innate

• Opsonins trigger phagocytosis

• Activate complement system

Mannose binding lectin (MBL):

• Recognizes mannose (excluding to cell wall)

• Triggers phagocytosis

C-reactive protein (CRP):

• opsonin triggers phagocytosis

• Recognizes LPS to trigger phagocytosis

Receptors detecting infection (PAMPs and PRRs):

• PRRs bind to PAMPs (ligands)

• Toxins are released by microbes

• Intracellular receptor important for viral pathogens

• Ligand + receptor

Signal Transduction:

• Ligand binds to receptor

• Conformational change inside the cell happens

• Activates signal transduction

• Activating transcription factors

• To turn on/ express genes: AMPs, cytokines, signaling/ adhesion molecules and make more leukocytes

• A second protein is able to bind due to ligand already attached and w/o ligand= no 2nd protein.

Membrane bound PRRs:

• Can be signaling/ endocytic

• Toll- like receptors (TLR)

• C-type lectin receptors (CLR)

• scavenger receptors (SRs)

• Lipopolysaccharide receptor (LPR)

Cytoplasmic (inside the cell) PRRs:

• NOD-like receptors (NLR)

Secreted PRRs:

• Mannose-binding lectin (MBL)

• Complement receptors

• C-reactive protein (CRP)

• LPS-binding protein (LBP)

Bacteria cell (E. Coli):

• has 2 cell membranes + peptidoglycan layer + outer membrane w/in there is LPS

• When gram (-) cells die they release endotoxins (lipid A) = ends in fever

• Considered a PAMP:

• Exclusive to pathogens and can be recognized by membrane bound

Toll-like Receptors:

• membrane bound/ phagocytes intracellular

• Triggers phagocytosis and signaling