Lecture 3 Barriers and Innate Immunity Flashcards
What are Neutrophils and what weapons does it use?
Phagocytic cells recruited by immune response
Can use
- Lysozyme - digests bacterial peptidoglycan
- Defensin - Lyses prokaryotic membranes
- ROS - reactive oxygen species
- NETs - Neutrophil extracellular trap. Uses DNA to make mucous trap. Kills neutrophil
What are Basophils and MAST cells?
They produce inflammation
-Basophils circulate in blood and MAST cells in tissue
Release Inflammatory cytokines
- Histamines
- Interleukins
What effect does histamine have in the inflammatory response?
Vasoactive chemical that acts on blood vessels
-Vasodilation and increase vascular permeability
What are eosinophils?
Anti-parasite response
What are monocytes and macrophages?
Monocytes leave blood, enter cell, and become macrophages
- phagocytic cells
- releases inflammatory cytokines
What are dendritic cells?
a subset of macrophages
- also phagocytes
- take piece of pathogen and present antigen to Tcells
What are the types Lymphocytes?
T Helper Cells
Cytotoxic T cells
Natural Killer Cells
B cells
What do T helper cells do?
- Produce chemokines
- communicates with every other cell
- Activates other WBC’s
What do Cytotoxic T cells do?
- Specific. Adaptive Response.
- Recognize antigen presented by DCs
- Kill cells with intracellular pathogens
What do Natural Killer Cells do?
- Nonspecific. Innate Response.
- Recognize antigen presented by DCs
- Kill cells with intracellular pathogens
What do B cells do?
differentiate into plasma cells that produce antibodies
How do Cytotoxic T cells and Natural Killer cells induce apoptosis?
Perforin
-perforates the cell wall
Granzymes
-induce apoptosis
Through what mechanisms do Cytokines communicate?
Endocrine - cytokine enters circulation to act on distant cell
Paracrine - Cytokine acts on nearby cell
Autocrine - Cytokine acts on cell that released it
-used in positive feedback like to induce mitosis
How do the innate and adaptive immune systems communicate?
DCs capture antigens
- migrate to secondary lymphoid tissues
- presents antigens to T cells
Goal is to activate B and T cells through antigen presentation
-T cells will know if microbe is intra/extracellular
What are secondary lymphoid tissues?
Lymph nodes, spleen, MALT
How are intracellular pathogens dealt with?
Usually viruses which invade host cell
The endogenous protein antigens are presented using MHC I molecules on the exterior of infected cell
Activated Cytotoxic T cells target and kill virus infected cells by recognizing the antigen presented with MHC I
-Natural Killer Cells can work too
How are extracellular pathogens deal with?
Bacteria in circulation are phagocytosed by APC cell
The exogenous protein antigens are presented using MHC II molecules on exterior of APC Cell
Activated Helper T Cells recognize antigen and produce cytokines that stimulate B cells and macrophages like neutrophils
Activated B cells differentiate into Plasma cells which produce antibodies. How do antiodies bind antigens and inactivate them?
Neutralization
- Block viral binding sites
- Wait to be phagocytosed
Agglutination
- Clump them together
- Wait to be phagocytosed
Precipitation of dissolved antigens
-Wait to be phagocytosed
Activation of complement
-Leads to cell lysis
What are the types of 1st line natural barriers?
Physical
-limit access. eg. skin
Mechanical
-removal and expulsion. eg. sneeze, tears, mucus
Chemical
-growth inhibition and death. eg. acid mantle, stomach
Biological
-competition with normal microbes who live in body
How does the skin act as a first line barrier?
The skin is a hypertonic, has a pH of 5
The epidermis contains langerhans cells
The dermis contains innate cells
-Macrophages, Mast cells, dendritic cells
DCs phagocytose pathogens and travel through lymphatic system to activate adaptive response
How does the respiratory tract act as a first line barrier?
Beneath the epithelial layer of cells are
- DCs
- Macrophages
- Mast Cells
- Plasma Cells
On the Epithelial layer are
- IgA, special antibody secreted by plasma cells
- Defensins
How does cystic fibrosis frequently lead to pneumonia?
Overactive production of thick mucus
- can’t be mechanically cleared
- buildup of bacteria
How does the digestive tract act as a first line barrier?
Macrophages, mucosal Mast cells, Plasma cells and DCs are present beneath epithelium
Plasma cells produce IgA
Peristalsis keeps everything moving
Normal flora bacteria create competition
What is the role of innate and adaptive immunity?
Innate
- stimulates and regulative adaptive immunity
- what type of microbe is attacking
Adaptive
- utilizes effector mechanisms of innate immunity to eliminate microbes
- what the appropriate response is for that microbe
How is the innate immune system stimulated?
PAMPs
- pathogen associated molecular patterns
- unique, conserved microbial components
DAMPs
- damage associated molecular patterns
- signals of cell damage
How do innate immune cells recognize PAMPs?
When it binds to PRR
-Pathogen Recognition Receptor
Results in intracellular signal to gene expression to secretion of cytokines, chemokines, antimicrobials
these innate cells can serve as link between type of pathogen and adaptive response
- PRRs recognize different PAMPs
- intracellular response will recruit lymphocytes
- DCs will present antigens to activate T cells
What are TLRs?
Toll-Like Receptors
-type of PRR
Three domains
- Ligand binding domain - made of extracellular Leucine Rich Receptors, LRR
- These are exterior and dimerize to bind microbe - Transmembrane Domain - goes through membrane
- TIR Domain - executes intracellular signalling
What is an endosome?
Intracellular vessicle which contains TLRs to recognize PAMPs within the cell
How does intracellular signalling occur?
- Ligand binding at cell membrane or endosomal TLR
- Kinases phosphorylate transcription factors
- Transcription factor proteins access nucleus to increase gene expression
Walk through the inflammatory response.
- Tissue damage and bacteria cause mast cells release inflamatory cytokines like histamine and chemokines
- Permeable capillaries allow influx of exudate, fluid, and cells
- Chemotaxis attracts neutrophils and other phagocytes
- Phagocytes and antibacterial substances destroy bacteria
What is the purpose of inflammation?
Vasodilation and increase vascular permeability
- allows exudate containing antimicrobial proteins
- recruit phagocytes like neutrophils
What are the types of antimicrobial proteins?
Defensins - attracted to prokaryote phospholipid bilayers and open up their membranes
Lysozyme - digests bacterial cell walls
Lactoferrin - sequester iron, important for microbial growth
How does opsonization help with phagocytosis?
Proteins called opsonins, like C3b, bind to and coat the microbial surface in a process call opsonization
Phagocytes have receptors, like CR1, for opsonins that increase binding and ingestion of microbes
Allows phagocytes to only need one receptor instead of multiple for different types of microbes
How does dendritic cell PRR signaling influence Helper T cell response?
The DC TLR that is activated determines the type of T cell that is activated
-like cytotoxic T cel or NK or
What are the three steps of the Complement system?
- Initiation
- complement binds to cell surface - Amplification
- cascade - Termination
- complement proteins impact microbial clearance
What is the initation step of the complement system?
The first step of the complement cascade
- Three ways to initiate
- CLASSICAL, LECTIN, and ALTERNATIVE pathways
CLASSICAL pathway - antibodies bind to antigens on microbial surface; C1q binds to antibodies; initiates the formation of C3 CONVERTASE (C4b2a)
LECTIN pathway - MBL (mannose binding lectin) binds to carbohydrates on microbial surface; initiates the formation of C3 CONVERTASE (C4b2a)
ALTERNATIVE pathway - spontaneous hydrolysis of C3 at microbial surface; initiates formation of ALTERNATIVE C3 CONVERTASE (C3bBb)
All three pathways lead to the formation of the C3 CONVERTASE, an enzyme that hydrolyzes C3 into C3a and C3b
What is the Amplification step of the complement system?
Complement proteins are activated by enzymes (also complement proteins that were previously activated by initiation) called CONVERTASES.
-Positive feedback loop causes a rapid increase in complement activation and convertase formation.
C3 CONVERTASE (C4b2a or C3bBb) hydrolyzes C3 into C3a and C3b
C3b helps form the C3bBb alternative C3 CONVERTASE that help convert more C3 into C3a and C3b (positive feedback)
C3b helps form the C5 CONVERTASE (C3bBbC3b) to hydrolyze C5 into C5a and C5b (important components of termination)
What is the Termination step of the complement system?
Where the final activated complement proteins act on the microbes directly or just help your immune system do its job better.
C3a, C4a, and C5a (all the “a” products of convertases) are invovled in stimulating and enhancing INFLAMMATION (including chemotaxis of neutrophils)
C3b is involved in OPSONIZATION of microbes to enhance adherence to PHAGOCYTES (neutrophils, macrophages, and DCs have receptors for C3b)
C5b is involved in the formation of the MEMBRANE-ATTACK COMPLEX (MAC) - see figure 6-10 - that creates pores in the microbial membrane and leads to cellular LYSIS
What are Type I Interferons?
(also known as interferon-alpha and beta, or IFN-α and IFN-β) are part of innate anti-viral response.
When cell is infected with a virus, it expresses and secretes type I interferons which bind to IFN-receptors on nearby uninfected cells.
Induces anti-viral response from these cells so when virus multiplies in first cell and tries to spread to the nearby cells, those cells will already be primed with the IFN response
-degrade viral RNA and inhibit viral protein synthesis.
This slows down viral multiplication and the spread of the virus to other host cells.
-can trigger apoptosis in infected cells and help with the activation of immune cells.
By themselves will not get rid of all virus from the host. But will help slow the virus enough to let NK cells, cytotoxic T cells, and antibodies do their job more effectively.
