Lecture 2. Inflammation and Innate Defences Flashcards
What is the timeline of a primary immune response?
- Pre-formed/innate response
- Induced inflammatory response
- Specific adaptive response
What does the induced inflammatory response rely on ?
Recognition of danger
Why does the adaptive immune response occur late ?
Lymphocyets specific for the invading pathogen must first undergo clonal expansion
Where are naive T-lymphocytes found ?
Lymph nodes
What are the general PAMPs ?
- LPS
- dsRNA
- CpG
- DNA
What are the two cell types involved in the innate immunity ?
- Macrophages
- Dendritic cells
What are the pathogen recognition receptors ?
- TLRs
- CLRs
What are some specific antigens involved in the adaptive immunity ?
- PHA
- Ovalbumin
What are the cells involved in the adaptive immunity ?
- T cells
- B cells
What does the innate immunity form ?
One of the earliest responses to infection
What does the innate immune system do ?
Distinguish self from non-self
What does the innate immune system activate ?
Adaptive immune syste - if pathogen bypasses innate host defences
What function does the innate immunity carry out ?
A delaying function
What is the delaying function of the innate immune system ?
Keeping pathogen numbers in check while adaptive immune system gears up
What is the innate immune system mediated by ?
- Innate immune cells
- Soluble effector proteins
What are the three things involved in the innate immunity ?
- Physio-chemical barriers
- Humoral components
- Cellular components
What does the induced inflammatory response do ?
Delivers cells and plasma proteins to infection sites
What is the insult of the induced inflammatory response ?
Infection or damage
What are the resident cells of the induced inflammatory response ?
- Macrophages
- Dendritic cells
- Epithelial cells
What are the messengers involved in the induced inflammatory response ?
- Cytokines - IL1, TNF
- Chemokines - CXCL8
- Prostaglandins
What is an epithelial cell ?
Local cell
What are cytokines ?
Driver of inflammation
What are the recruited cells in the induced inflammatory response ?
- Monocytes - macrophages and dendritic cells
- Neutrophils
What is the first thing found at the site of infection ?
Neutrophils
What is the second thing found at an infection site ?
Mononucletide
What does CsF1 determine ?
Difference in macrophage an mononucleoties
What do neutrophils do ?
Have a short life, degranulate, netosis and expel nucleus
What are the effector mechanisms involves in the induced inflammatory response ?
- Immune signalling
- Cytokine production
- Phagocytosis
- Antigen presentation
When does the induced inflammatory response have an adaptive response ?
In the presence of specific antigens
What happens as a result of effector mechanisms and addaptive responses ?
Resolution of inflammation
What are the routes of infection ?
- Inhalation
- Direct contact
- Invasion
- Ingestion
What is infection ?
The invasion and multiplication of a pathogen in a susceptible host
What is invasion facilitated by ?
- Toxins
- Factors encoded by pathogens or immunosupression
- Susceptibility in the host
When does infectious disease manifest ?
When infection results in clinical pathology or tissue damage
What are the epithelial surfaces involved in barriers to infection ?
- Skin
- Mucous membrane
What are the features of the epidermis ?
- Multiple layers of cells
- Lipid rich - therefore a tight water barrier
- Glands which produce anti microbial molecules and patrolling immune cells
What are the features of the mucosal surface ?
- One cell layer thick
- Covered with mucus and often cilia
- Significant immune cell infiltrate beneath
What do tight junction proteins do ?
Maintain epithelial integrity
What is included in tight junction proteins ?
- Claudins
- Occludins
- JAMs
- Tricellulins
What do pathogens target for invasion ?
Tight junction proteins
What are the mechanical barriers to infection ?
- Skin
- Gut
- Lungs
- Eyes/nose/oral cavity
What are the chemical barriers to infection ?
- Lysozymes in tears
- Mucus lining in trachea
- Rapid pH cchange in gut
- Flushing of urinary tract
- Intact skin, fatty acids, commensals
- Digestive enzymes
- Vaginal acids
What is lysozymes specific to ?
Bacteria only
What does lysozyme do ?
Host enzyme targets bacterial cell wall
What type of bacteria is lysozyme more effective against ?
Gram positive bacteria
What antimicrobial peptides are made by epithelial cells ?
- TH17
- IL17
What do antimicrobial peptides made by epithelial cells act on ?
Mucosal fluid
What do anti-microbial peptides cause ?
Target cell lysis
What are the three evolutionary conserved families of anti-microbial peptides ?
- Defensins
- Cathelicidins
- Lecticidins
What do anti-microbial pepides cause ?
- Pore formation
- Target cell lysis
What do antimicrobial peptides have ?
A cationic portion and a hydrophobic core
What do antimicrobial peptides repel ?
Eukaryotic membranes - neutral cationic
What do anti-microbial peptides do ?
Insert into bacterial membranes which are anionic- hyrophobic
What do commensals have ?
Many mutualistic relationships
What is dysbiosis ?
Abnormal ratio of beneficial and agressive bacterial species
What is a key characteristic of IBD ?
Dysbiosis
What do commensal microbiota need to avoid ?
luminal expression of toll like receptors on epithelial cells for example mucin
What is sensed and induced by commensal microbiota ?
A protective response example defensis
A tolerant response example regulatory T cells
What are pre existing innate defences ?
Chemicals with anti microbial properties found in body in anticipation of infection
What do pre existing innate defences not require ?
Induced inflammatory response to be made
What is there some level of in pre existing innate defences ?
Pattern recognition
What are some examples of anti-microbial enzymes ?
- Lysozymes
- Amylase
- Phospholipase A2
What are some examples of anti-microbial peptides ?
- Defensins
2.
What are pre existing blood and tissues that require activation/pattern recognition for full anti-microbial function ?
- Complement
- Coagulation proteins
What are the stages of complement action ?
- Pattern recognition trigger
- Protease cascade amplification/C3 convertase
- Inflammation
- Pagocytosis
- Membrane attack
What is the complement system ?
Collection of soluble proteins found in blood and other bodily fluids
Where is the complement system mainly synthesised ?
- liver
- Immune cells
What happens once the complement system is activated ?
Important host defense and anti microbial function
How does the complement system activate proteins ?
A cascade system of proteins through proteolytic cleavage
What complex promotes cascasde (C1q) ?
AB-Ag complex
What binds CHO on pathogen in complement ?
Mannose binding lectin or ficolins
What is the alternative binding on a pathogen ?
C3 serum protein by spontaneous hydrolysis to C3b
What do all complement pathways generate ?
A c3 convertase
What does c3 convertase do ?
Cleaves C3 leaving C3b bound to the microbial surface and releasing C3a
What does activation in the complement system lead to ?
- Phagocytosis of microbes
- Cell lysis
- Inflammation
What are the effector pathways from C3 cleavage ?
- C3b
- C3a
What does C3b do ?
- Binds pathogen or Ag:Ab complex
- Attaches to C3 receptor on phagocytic cells and induces phagocytosis
- Interacts with C5 complexes and forms membrane attack complex causing lysis
What does C3a do ?
- Associates with c5a
- Promotes inflammation through binding to mast cells
- Promoting degranulation
- Vasodilation
- Activate mast cells
What does C5b do ?
Binds C6 and C7
What do c5b67 complexes do ?
Bind to membrane via C7
What does c8 do ?
Binds to the C5b67 complex and inserts into the cell membrane
What does c9 do ?
Bind to the complex and polymerise
How does a pore form in the membrane ?
10-16 molecules of C9 bind to complex
What does c3b have an affinity for ?
Microbial surfaces due to thioester bond
What is the antibody recognised by ?
Fc receptor on phagocytes
What is the complement c3b recognised by ?
CR1
What are the cardinal features of inflammation ?
- Redness
- Pain
- Heat
- Swelling
- Loss of function
How are the cardinal features alleviated ?
Vasculature and action of clotting proteins
What is the route for recruitment of new immune cells ?
Blood vessels
What do blood vessels do ?
Delivers proteins, complement, anti-microbial peptides and clotting factors
What inflammatory mediators cause vasodilation ?
- Bradykinin C5a
- Histamine 5HT
- Nitric oxide
- Substance O
Where is bradykinin found ?
Blood
What is the specific function of bradykinin C5a ?
Protease cascade
Where is histamine 5HT found ?
Mast cells and platlets
What is the specific function of histamine 5HT ?
Degranulation
Where is nitric oxide found ?
Endothelial cells
What is nitric oxide induced by ?
Cytokines
Where is substance P found ?
Neurons
What is the clotting activation signal ?
Thrombin activation
What is the clotting intrinsic pathway caused by ?
Vascular injury - contact clotting factors
What is the extrinsic clotting pathway ?
Tissue damage - tissue factor
When are clots degraded ?
When tissue repair occurs
What promotes tissue repair ?
Fibrinolytic proteins (plasminogen)