Immunological Response To Sepsis, Injury And Inflammation Flashcards
Overview of inflammation
1) noxious agent stimulate the innate immune system
2) mast cells and macrophages sense the stimuli (innate immune response- leukocytes) and vascular dilation and increased permeability occurs (stimulated by inflammatory mediators ie. bradykinin), leukocytes (ie. neutrophils) can roll along endothelium forming loose interactions via selectins. Chemokines then activate leukocytes (can be released by macrophages) and tight adhesions between leukocyte and endothelium occur, mediated by integrins. Leukocyte flattens and transmigrates into the site of inflammation via integrins
3) leukocyte migration: macrophages release cytokines (which are pro-inflammatory) and chemokines by detecting PAMP via PRR, which recruits neutrophils (in aforementioned process) which stimulates neutrophil degranulation and become apoptotic. Macrophages can then engulf these apoptotic neutrophils
4) phagocytosis can then occur by macrophages, also start antigen presenting via MHCII to T helper cells (key link between innate and adaptive immunity)
5) induction of adaptive immunity: macrophages/dendritic cells present antigen and bind to T helper cells on TCR (could also be via CD28 on TH: CD80/86, or CTLA4: CD80/86), which can cause differentiation to cytotoxic CD8+ via IL2 (virus), or B cell via IL4, IgE, which can produce antibodies which can attract the complement cascade
6) resolution or chronic inflammation
Principles of robust inflammation
- needs to be responsive, appropriate and redundant
- robust: have a cascade of inflammation mediators
Inflammatory mediators
- heat and redness (vasodilation): histamine (problem in rosacea, should avoid histidine containing foods), bradykinin, nitric oxide
- swelling (increased vascular permeability): anaphylotoxins, VEGF, IL8, bradykinin
- pain: substance P, bradykinin
- loss of function: lipases, proteases, free radicals
TLR4 signalling: activates leukocytes and increases inflammatory mediators
- found on macrophages, neutrophils
- TLR4 is a pattern recognition receptor (PRR) activated when bound to a pathogen associated molecular pattern (PAMP)= LPS (liposaccharide endotoxin)
- if LPS binds on plasma membrane: activates MYD88 via TIRAP which leads to cascade of IRAP-> TRAF-> TAK1 which increases the transcription factor NFkB which is pro-inflammatory
- if LPS binds within endosomes: activates TRIF-> TRAF-> IRF (interferon response factor which increases interferons)
The complement cascade
- classical pathway is activated by antibodies, lectin pathway is activated my CHO, alternative pathway is activated by C3b-microbe
- leads to activation of C3 convertase which produces C3a (amphylotoxin increasing inflammation) and C3b (for opsonisation)
- C5 convertase is then activated which forms the membrane attack complex which is responsible for killing microbes
Complement cascade regulation
- prevents inappropriate complement response
- factor 1 cofactor activity
- decay-accelerating of C3 convertase
- inhibition of lysis
- cleavage of anaphylotoxins
Inflammatory mediators: histamine
- causes: vascular permeability, vasodilation and pain
- produced from: histidine
- found: in basophils
- Production: IgE binds to FceR1 on mast cells causing increase in Ca and degranulation of histamine
- removed by oxidation, methylation and acetylation by gut flora. DAO and HMT are enzymes responsible for breakdown
- implicated in Rosacea: recommend to avoid foods high in histidine, such as smoked meats and red wine
Inflammatory mediators: lipid mediators
- phospholipase A2 liberates aracadonic acid from phospholipids
- via the cyclic-endoperoxide pathway can produce pro-inflammatory prostaglandins and thromboxins
- can also form leukotrienes (pro-inflammatory too)
- omega 6 contributes to these pro-inflammatory pathways
- omega 3 (EPA/DHA) also enters arachidonic pathways but produces resolvins instead which are anti-inflammatory
Macrophages: functions and phenotypes
- heterogeneous and plastic in nature
- function: leukocyte linker between innate and adaptive immunity. Forms dendritic cells (APC), granuloma formation (ROS), microbe killing (complement recruitment), wound healing, angiogenesis (VEGF), chemokine production to recruit more leukocytes, pro-inflammatory cytokine production
- M1: proinflammatory and uses intermediates from the TCA cycle to produce proinflammatory cytokines
- M2: (resting state) uses TCA cycle to produce anti-inflammatory components. Important for wound healing
T cell subsets
- TH0: naive T helper
- TH1: differentiation via IL2, used for inflammation
- TH2: differentiation via IL4 and 2. Used for antibody mediated immunity
- Treg: differentiation via TGFb and IL12. Used for immune tolerance
- TH17: differentiation via TGFb and IL6. Used for extracellular bacteria
Metabolic pathways and inflammation: gout, sepsis, cachexia, obesity and metainflammation
- gout: PPP produces purines which can crystallise to form monosodiumurate crystals in joints
- sepsis: characterised by low BP and multi-organ failure in response to microbe. Quick deaths causes by over-production of inflammatory response. Longer term deaths may be caused by persistent inflammation/immunosuppression or by intractable inflammation induced organ injury. Derangement in metabolism (ie. high lactate) could be used as a prognostic marker
- cachexia: losing >5% of BW. Accompanied with profound changes in inflammation, TNFa may have a role
- obesity and metainflammation: adipose tissue may lead to low grade inflammation causing increases in CRP, AT releases inflammatory cytokines causing infiltration of macrophages. If have high cholesterol, PPR can bind and cause differentiation to M1 macrophage via IL1B and causes infiltration into AT
- nutrient/energy stress may increase metainflammation
