Immunological Response to Injury Sepsis Flashcards
Name the types of dysfunctional inflammation (un-controlled):
Acute
Chronic
Contributory
Name some anti-inflammation foods:
Tomatoes Fruits Nuts Olive Oil Leafy greens Fatty fish
What is inflammation?
A protective tissue response to tissue damage or microbes, which serve to destroy, dilute, or wall-off both the injurious agent and the injured tissues.
What pathways can develop from acute inflammation?
- Resolution - Infection clearance and tissue homeostasis
- Persistance
- chronic inflammation
- chronic inflammatory diseases
- pre-cancer and cancer
Cardinal signs of inflammation are:
- Heat
- Redness
- Swelling
- Pain
- Loss of function
Explain the cycle process when there’s a new damage, involving both innate and adaptive response:
- Stimulus cause sentinel activation
- Vascular - dilation, increased blood flow/permeability
- Leukocyte migration
- Cellular - antimicrobial, phagocytosis, antigen presentation
- Induction phase - Antigen presenting, clonal expansion and maturation
- Leukocyte migration
- Effect phase - lymphocyte recruitment, cellular/tissue activation
What happens vessels during acute inflammation?
- vascular changes
- neutrophil recruitment
- mediators
What happens in vessels during resolution?
- clearance of injurious stimuli
- clearance of mediators and acute inflammatory cells
- replacement of injured cells
- normal function
what is abscess?
pus formation
If acute inflammation progresses, it becomes chronic inflammation. What happens in vessels during chronic inflammation?
- angiogenesis
- mononuclear cell infiltrate
- fibrosis (scar)
What was used in the Wheal and Flair reaction (Lewis triple response)?
- Bradykinin
- Histamine
- Capsaicin (Ralgex)
What are some inflammatory mediators for heat and redness (increases blood flow)?
- Histamine
- PGE2/PGI2
- 5-hydroxytryptamine
- Platelet activating factor
- nitric oxide
- bradykinin
What are some inflammatory mediators for swelling (increases vascular permeability/cellular infiltration)?
- anaphylatoxins
- C3a/C5a
- LTB4/PGE2/VEGF
- TNFalpha/IL-1/IL-8
- Platelet activating factor
- Bradykinin
What are some inflammatory mediators for pain?
- Substance P
- Calcitonin gene-related peptide
- Bradykinin
What are some inflammatory mediators for loss of function)?
- Lipases
- Proteases
- Free Radicals
What are some inflammatory mediators for spasm of bronchial muscle?
- Bradykinin
- LTD4/LTC4
- Histamine
Name the cellular components of inflammation:
- Mast cells
- Neutrophils
- Eosinophils
- Macrophages
- Lymphocytes
- Neurons
- Platelets
Which are the first cells to migrate during inflammation?
Neutrophils
How do you distinguish between neutrophils and eosinophils?
Eosinophils have more granules
Which cell released during inflammation have antigen presenting feature?
macrophages
What are the divisions and subdivisions of lymphocytes?
B and T cells
subdivided to CD4+ and CD8+ cells
What is PRR?
Pattern Recognition Receptors
What are the pattern recognition receptors? (PRR)
Signalling:
- TLR (Toll-like)
- NOD-like receptors/NLR
Endocytic:
- Pentaxins
- CLR (c-type lectin)
- Complement receptors
- Scavenger receptors
- N-formyl met-leu-phe receptors
- RIG-like receptors
Name the cascades in PRR?
Kinins cascade
Coagulation cascade
What are the stimulus in PRR?
DAMPs (damage-associated molecular patterns)
PAMPs (pathogen-associated)
Where can Toll-like receptors be found on?
- Macrophages
- Neutrophils
- Dendritic cells
Name an antagonist for acute and chronic inflammation:
TLR-2, 4
Name an agonist for asthma:
TLR-9
Name a component involved in the coagulation cascade:
Thrombin
Name a component involved in the Kinin cascade:
Kallikrein
Name a component involved in the complement cascade:
C3
Name a component involved in the fibrinolytic cascade
Plasmin
What are the 3 pathways that stimulate complement pathways?
- Classical
- Lectin
- Alternative
How is the classical pathway stimulated?
antigen-antibody complexes fix C1
How is the alternative pathway stimulated?
contact with bacterial polysaccharide or other cell wall component
How is the lectin-mannose pathway stimulated?
plasma lectin binds mannose component in a microbe
Explain the processes of the 3 complement pathways:
- All 3 pathways lead to formation C3 convertase that plays a central role in complement effects
- C3 convertase cleaves to C3a and C3b
- C3b deposits on surgace of microbe - binds C3 convertase and forms C5 convertase
- C5 convertase cleaves C5 to C5a and C5b
- Assembly of C6-C9 - membrane attack complex
How does one develop angioedema?
- Drug induced
- Hereditary
What could lead to increased systemic levels of C3?
- Adiposity
- Inflammation
- Immune activation
- Insulin resistance
- hypetriglyceridaemia
- hyperglycaemia
What are the potent vasodilator mediators in microcirculation?
- prostaglandins, nitric oxide (from endothelial/inflammatory cells)
- neuropeptides (from sensory nerves)
What are the oedema producing mediators that increases microvascular permeability?
Direct-acting:
- histamine
- bradykinin
- leukotrienes
- PAF
- Substance P
- VEGF
Neutrophil dependent:
- agents that stimulate neutrophil activation
Where is histadine found?
- mast cells
- basophils
- histaminergic neurons
Histadine is released by?
- IgE
- C5a, C3a
- Substance P, VIP
Histadine metabolism includes the following 3:
- oxidation
- n-methylation
- acetylation
What does an increase in cAMP do to histamine?
- inhibits histamine release
What are cytokines?
Simple polypetides or glycoproteins with a molecular weight <30kD
Explain the general cytokine production:
- regulated by including stimuli at the level of transcription and translation
- transient and action of radius is usually short
Explain the general cytokine action:
- act by binding to high-affinity cell-surface receptors
- actions are attributed to altered gene expression in the target cells
Name the steps of leukocyte emigration:
- Rolling
- Activation
- Tight Adhesion
- Transmigration
Name an inflammatory mediator that is an omega-6 polyunsaturated fatty acid
AA (free arachidonic acid)
Name an ANTI-inflammatory mediator that is an omega-6 polyunsaturated fatty acid
DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid)
What are the antigen presenting cells?
- Dendritic cells
- Macrophages
- B cells
What do the antibody domains consist of?
beta-pleated sheet ‘sandwich” with hydrophobic centre
Describe the Class I MHC antigens:
- Glycoproteins of ~43kDa
- On surface of all nucleated somatic cells
- Has a peptide binding groove
- Recognised by Tc cells - major function to aid Tc cells recognise infected self cells and elimination
Describe the Class II MHC antigens:
- 2 chains of 35kDa and 28kDa
- On surface of antigen-presenting cells
- Also has peptide binding groove
- Recognised principally by Th cell receptors - essential for APC presenting Ag to Th cell
What are some differences between MHC I and MHC II?
- MHC I is ubiquitous and found on ALL cells (recognised by CD8+ t cells)
- MHC II only found on APC’s so that the immune system can efficiently and quickly activate CD4+ helper t cells
State what is involved in the 3 signals involving T-cells and APC:
Signal 1: - TCR, MHC class II and Ag
Signal 2:
- CD28, CD80/CD86
Signal 3:
- cytokines
What are the outcomes of signal 1?
- apoptosis
- energy
What are the outcomes of signal 2?
- Proliferation
- Differentiation
- Effector function
What are the outcomes of signal 3?
Cell-cycle arrest
What are some physical triggers of immune response?
- infections
- toxins
- food peptides
- allergens
- medications
- auto-antigens
What are some t-cell subsets?
- Th17 (IL-17/21/22)
- Th1 (IL-2, IFN-gamma, TNF-alpha)
- Th2 (IL-4/5/6/10/13)
- Treg (TGF-beta, IL-35/10)
- APC
- Th0
Name the functions of macrophages:
- Antigen presenting (dendritic cells)
- Atherogenesis
- Wound healing/regeneration
- Inflammation resolution
- Microbe killing
- granuloma formation
- angiogenesis
- neurodegenerative disease
- tumour biology
What are the types of macrophage-derived products:
- enzymes
- pro-inflammatory cytokines
- immuno-modulatory cytokines
- chemokines
- growth factors
- angiogenic factors
- adhesion, matrix molecules
- complement proteins
- bioactive lipids
- reactive oxygen intermediates
- reactive nitrogen intermediates
Describe the M1 macrophages:
- classical activation by Th1
- stimulated by IFN-gamma or LPS
- high levels of pro-inflammatory cytokines
- antigen-presenting
- produce NO
- kills microbes
Describe the M2 macrophages:
- alternative activation by Th2
- stimulated by IL-4/13, immune complexes, LPS, glucocorticoids, etc
- low levels of pro-inflammatory cytokines
- NOT antigen-presenting
- doesn’t produce NO
- builds ECM
Describe the M1 macrophage activation:
- TLR receptor present on surface
- LPS attach to IFN-gamma receptor
- microbial trigger by LPS
- Proinflammatory cytokines released
- NO and respiratory burst
- Microbicidal tissue damage, cellular immunity, DTH
What occurs during sepsis and multiple organ failure?
- microbial initiation leading to systemic inflammatory response
- drop in blood pressure
- haematologic dysfunction
- acute respiratory distress
- kidney, liver dysfunction
- decrease in cellular oxidative phosphorylation
What is sepsis categorised by?
Profound metabolic derangements
What serves as diagnostic/prognostic biomarkers for sepsis patients?
- metabolic changes
- lactate
What is metainflammation?
cold inflammation, low grade
Describe metainflammation involvement:
- associated with metabolic disease
- high levels of C-reactive protein (CRP - general marker of inflammation)
- adipose tissue release of inflammatory cytokine - invasion of macrophages
