Lecture 6: Inflamation and Innate Immunity Flashcards
Goal of the Immune System
Recognition of the Pathogen
Respond to the Pathogen and remove it
Remember the Pathogen
Defense is achieved by the concerted actions of the innate and adaptive immunity
Innate Immune System
Provides physical and chemical barriers (tight junctions, paneth cells and keratinocites)
Non Clonnaly derived cells
Immediate, early response
Does not require prior exposure to pathogens
Germ line encoded receptors
Recognition of PAMPs
Adaptive Immune System
Clonally derriced effector cells that are specific to a particular antigen
Requires time
Requires prior exposure to the pathogen - memory
Receptors arise from gene rearrangment and somatic mutation
Recognition of processed papthogen derived peptides (foriegn peptide in the context of a MHC receptor)
Surface and Chemical Barriers
First Line of Defense
Mechanical - Tight junctions, air or fluid flow, and movemnt of mucus by cilia and flagella
Chemical - Secrtuin if defensins, low pH conditions, and other enzymes that make the environment inhospitable to foreign particles
Leukocytes
Second line of deffense
Neutrophils
Macrophages
Mast Cells
Eosinophils
Basophils
NK Cells
Phagocytes of the Innate Immune System
Neutrophils
- Arise from a common myeloid progenitor from the bone marrow
- Most abundant leukocyte in circulation
- Short lived, forming nets after a respiratory burst
- Rarely founf in healthy tissue
- Kill pathogens through ohagocytosis the the release of enzymes, defensins, and NADPH oxidase release
- If a patient in deficent in neutrophils, the neutrophils can be simulated with injections of GCSF and GMCSF
Macrophages
- Mature form of monocytes
- Found in resident tissues everywhere
- Long lived
- Highly efficent at phagocytosis and inflamatory cytokine production (TLR>MyD88>NFkB>IL1)
- Facilitate adaptive immunity through antigen presentation (MHC 2) and Co stimulatory molecule expression
Innate Lymphocytes
Natural Killer Cells
Arrise from a common lymphoid progenitor in the bone marrow
Can kill virally infected cells and tumor cells
Use inhibitory/ activating receptors to decide whether or not to kill - A healthy cell presentsan aposing signal that sends a inhibitory signal to the NK cell, preventing the NK cell from killing the healthy cell
Virally infected cells downregulate MHC clas 1 receptors, which is recognized as missing self receptors by NK cells and the NK cell kills the infected cell
Abundant in tonsils
ADCC
Antibody Dependent Cell Mediated Cytotoxicity
Neutrophils, eosinophils, NK cells, and macrophages have Fc Receptors
If an FC receptor binds an antibody that is bound to an antigen the cells will release cytotoxic granules to kill the target cell
NK Cells are the most efficent ADCC
Inflamation
The local accumulation of fluid, plasma, and leukocytes initiated by physical injury, infection, or local immune response
Fundementally protective, intendend to create a hostile environment for the pathogen and destroy the patogen
Initiator of tissue repair
Destructive if prolonged
Cells Involved in Inflamation
Endothelial Cells
Cells lining blood vessels become activated during inflamation and release mediators and modify surface receptors to signal for other cells to come into the area
Platlets
Circulating anuclear cells that attach at the site of tissue injury. Activation causes degranulation and release of pro inflammatory and clotting mediators
Also involves mast cells which release histamine and tissue macrophages
Major Events in Inflamation
Alteration in blood flow
Increased vascular permeability - allowing the wbc to get out of the blood vessles and into the tissue
Activation and infiltration of leukocytes
Alteration in Blood Flow
In a cappillary bed of inflamed organ there is an opening of increased blood flow and periability of the endothelial cells lining the inflamed organ
Increased Vascular Permeability
Occurs from direct trauma to the endothelium or contraction of the endothelium
Increased vascular permiability allows for leakage of antibodies, leakage of compliment, and migration of pphagocytes to the inflamed area
Activation and Infiltration of leukocytes
Begins in minutes, lasts for days
Infiltration order
- Neutrophils
- Monocytes that become macrophages
- If necessary adaptive immunune cells are recruited and lymphocytes (T cells, B Cells, and NK Cells) arrive
Requires activation of the endothelium, allowing cells to recognize the location of the probelm
Cytokines produced at the sites of inflamation by leukocytes that promote the inflammatory response
IL1
TNFa
IL6
IL8
IL1
Activates vascular endothelium
Activates lymphocytes
Local tissue destruction increasess access of effector cells
IL1 can travell to the hypothalamus to increase body teperature
TNFa
Activates vascular endothelium and increases vascular permiablility
Increased entry of IgG complement, and cells to tissues and increased fluid drainage to lymph nodes
IL6
Lymphocyte activation and increased antibody production
IL8
Acts as a chemokine that brings in other cells (neutrophils, basophilsm and t cells) to the site of infection
Will be on the endothelium of inflamed tissue
Halmarks of inflamation
- Calor - heat
- Dalor - pain due to the compression of perihrial nerves from swelling
- Rubor - redness due to increased blood flow
- Tumor - swelling
3 Main Steps in Phagocytosis
- Particle/Pathogen Recognition
- Internalization
- Killing
Particle/Pathogen Recognition
Several different types of receptors allow for recognition
PAMPS activate TLRs
MAnnose Receptor
Glucan Receptor
Fc Receptor
Coating a particle with antibody or complement enhances binding
Internalization and Killing
Phagocytosis
- Pathogen attaches to the membrane
- Membrane forms a phagazome and the particle is engulfed
- The phagazome fuses with lysosomes and lysosomal enzymes digest the captured material - NADPH oxidase causes the release of these molecules resulting in a respiratory burst
- Digested products are presented on the cell surface in the context of a MHC class 2 receptor or extruded from the cell
Binding of bacterial product to macrophages activates cytokine and chemokine gene expression
LPS binds to a receptor on a phagocytic cell
The complex recruits TLR4, which coalleces with the LPS activated recepter
The activated TLR4 releases Myd88 which stimulates NFkB translocation into the nucleus where a cytokine response is transcribed and translated
*in this case IL1 is activated (activation also occurs through the inflamasome)
Macrophage Derived Cytokines
IL1
TNFa
IL6
IL8 (CXCL8)
IL12
Macrophage Derived IL1
Activation of vascular endothelium
Activates lymphocytes
Local tissue destruction increases the access of effector cells
Results in Fever and the production of IL6
Macrophage Derived TNFa
Activates vascular endothelium and increases vascular periability which leads to incread entry of IG complement and cell to tissues and increased fluid drainage to lymph nodes
Can cause fever and high levels can result in systematic shock
Macrophage Derived IL6
Lymphocyte activation increased antibody production
Results in fecer and induces acute phase protein production
Macrophage Derived IL8
Chemokine that recruits neutraphils, basophils, and some T cells to the site of infection
Helps neutrophils pas through the endothelial barrier in concert with other proteins
Macrophage Derived IL12
Activates NK cells and induces the maturation of CD4 cells to Th1 cells
BCL - CXCL13
Produced by stromal cells
Imortant for directing B cells to the follicle of lymph nodes
Movement of Neutrophils through the endothelial cell layer
- S-LeX on the surface of neutrophils will recognize E selectin on the endothelial cell surface
- Receptors for IL8 on the neutrophil bind to IL8 on the endothelial surface - the endothelial surface is inflamed
- LFA-1 on the surface of neutrophils binds to ICAM-1 on the endothelial cells allowing for diapedisis of the neutrophil into the tissue
How is the movement of neutrophils from the blood into the tissue diffrent from T cell and B cell entry into tissue?
Chronic Inflamation
Chronic inflamation can lead to autoimmunity, persistant infection, granuloma formation, fibrosis, and tissue destruction
Hashimoto Disease
A disease in which an individual recognizes the thymus as foreing and eventually destroys the thymus.
The individual mus be suplimented with thyroid hormones for T cell development/education and activation of B cells
Areas that look like lymph nodes will form in tissues the individual is immune to.
Complement
A system of 30 plasma and membrane proteins that react with one another to coat pathogens and induce a series of inflamitory responses that help fight infection
When activated by Ag/Ab complexes or bacteria, these components interact in a highly regulated fashion to generate products that can help clear pathogens or promote certain aspects of the inflamitory response
Complement Activation
Activation occurs on a surface such as a bacteria or antibody coated particle
Spontaneously activated complement components can also bind to pathogen surfaces
3 Pathways
- Classical complement activation pathway
- Alternative Complement Pathway
- MB Lectin Pathway
All three pathways generate a protease called
C3 convertase
Classical Complement Pathway
Antibody/Antigen complexes activate C1, C2, and C4
to activate C3 Convertase
MB-Lectin Complement Pathway
Manose binding lectin binds the manose on pathogen surfaces activating MBL, MASP, C2, and C4
This activates C3 convertase
Alternative Complement Pathway
Pathogen surfaces activate C3, B, and D to activate C3 convertase
Activation of C3 Convertase
Cleavage of C3 convertase results in 3 actions
- C3a, C5a - peptide mediators of inflamation, phagocytic recruitment
- C3b - binds to complement receptors on pathogens and opsonized the oathogenm recruiting inflamatory cells, and removal of immumne complexes
- C5, C6, C7, C8, C9 - forms a membrane attack comlex (pore formation), and cell lysis ocurs
Consequences of Complement Activation
Lysis
Opsonization
Activation of Inflamatory Response
Clearance of Immune Complexes
Removal of Pathogens from the blood and into tissue
Regulation of the complement system
Controlled by:
Decay Receptors
Regulatory Factors - inhibit initiation of enzymatic cleavage, enzymes within the cascade, and MAC formation
Inflamatory Response Overview
