Inflammation Flashcards
What is inflammation?
A complex response process triggered by infection, tissue injury or irritants enabling specific host cells and interacting chemicals (cytokines) to coordinate and attempt their neutralisation and removal
What is the difference between inflammation and swelling?
Swelling is an abnormal enlargement of a part of the body usually as a result of fluid accumulation
Inflammation and swelling are connected but not the same
What are the types of inflammation?
Acute
Chronic
Describe acute inflammation
Rapid onset (mins, hours)
Short duration (days)
Initiated by non-specific innate immune responses
Refined and prolonged by adaptive immune responses
Describe chronic inflammation
Slow or insidious onset
Long duration (weeks, months)
Initiated by inadequate acute inflammatory responsiveness or host susceptibility
Attempts to repair damaged tissue more likely to cause scarring/fibrosis
What is the outcome of acute inflammation?
Resolution
Fibrosis
Scarring
Persistence
What is the outcome of chronic inflammation?
Tissue destruction
Fibrosis
Scarring
Necrosis
Describe the course of acute inflammation
Non self antigens or damage signals trigger response
Immune cells and mediators are attracted and retained at the initiating site
Immune cells commit by differentiating and activating mechanisms able to kill pathogens, limit the spread of infection and further injury and protect damaged tissue from becoming infected
Infectious agents/dead cells/tissue are deconstructed
Conditions are created for tissue repair e.g. TGF-b
How are PAMPs and DAMPs involved in acute inflammation?
PAMPs/DAMPs are recognised by PRRs on cell surfaces initially involving resident macrophages
PRR activation triggers cell signalling pathways to secrete pro-inflammatory cytokines and type I IFNs
What type of inflammation do PAMPs cause?
Infectious
What type of inflammation do DAMPs cause?
Sterile
What causes releases of DAMPs?
Endogenous cell damage/stress
Describe recruitment in acute inflammation
Resident tissue macrophages and mast cells recognise pathogens and secrete cytokines and histamine
Cytokine activate integrins, capturing neutrophils attracted by chemotaxis which then migrate into tissue
Neutrophils capture bacteria then release more vascular permeability and monocyte recruitment mediators
Differentiated monocytes remove bacteria and release cytokines for further recruitment or repair
Describe the response stage of acute inflammation
Short lived neutrophils phagocytose pathogens
Cytokine release
Neutrophils expand and burst, sending out neutrophil extracellular traps (nets) to capture and immobilise other pathogens
Describe the removal and repair stages of acute inflammation
Monocytes initially differentiated into killing M1 convert to resolving M2 macrophage types
M1 has highly phagocytic activated killing and is able to clear the inflammation site
M2 secretes growth factors e.g. TGF-b for repair involving angiogenesis, fibroblast proliferation and collagen synthesis
Describe the course of chronic inflammation
Macrophage activation or direct innate encounters by other leukocytes of non-self antigens or host cell damage signals
Macrophages, neutrophils, T cells, eosinophils and mast cells are recruited
T cell activation feeds back directly to activate macrophages, both secrete pro-inflammatory cytokines and stimulate broader adaptive responses
Persistent pathogens or long term non-specific antigen exposure are not removed, prolonging the response
Tissue repair signalling is compromised (may form granulomas) and can lead to tissue destruction. Cell proliferation needs specialised regulatory cells to resolve
What are the triggers of chronic inflammation?
Failure to activate or resolve acute inflammatory reaction - persistent infections (viruses, Mycobacteria, parasites, fungi)
Misdirected inflammatory reactivity - harmless environmental substances (allergies), self antigens (autoimmune diseases)
Underlying disorders prolong immune activity - cancer, atherosclerosis, Alzheimer’s, T2D
What happens if there is persistent build up of endogenous substances?
Become target crystals of cholesterol and urate
Cholesterol = atherosclerosis
Urate = gout
What can chronic inflammation result in?
Large accumulations of T cells at inflamed sites
e.g. Rheumatoid arthritis
Describe recruitment of T cells in chronic inflammation
Activated naive T cells migrate and become effectors in lymphoid organs
Effector T cells return to inflammatory sites and increase response
Describe recruitment of eosinophils in chronic inflammation
Recruited and activated by parasites and IgE responsiveness
Describe recruitment of mast cells in chronic inflammation
Activated by injury or IgE mediated allergy
Describe recruitment of neutrophils in chronic inflammation
Several diseases influenced by over recruitment of neutrophils
e.g. COPD
Describe the resolution stage of chronic inflammation
Phases of incomplete resolution gradually increase the magnitude of inflammation
What cells are involved in resolution of CI?
Macrophages
Treg cells
Innate lymphoid cells
Myeloid derived suppressor cells (MDSC)
Describe the role of macrophages in resolution of CI
Killing, removal or apoptotic/spent immune cells
Type shift to M2 drives repair
Describe the role of Treg cells in resolution of CI
Derived from CD4 lineages
Use various cytokines (IL-10, TGF-b, IL-17) to deactivate many cell types exhibiting inflammatory cell responses (mast, eosinophils)
Where is lack of Tregs found?
In IBD
Particularly IL-17
Describe the role of innate lymphoid cells in resolution of CI
e.g. NK cells
Help to reduce activation of proinflammatory cells such as eosinophils (asthma)
Describe the role of MDSCs in resolution of CI
Aid in efferocytosis
Induce Treg cell expansion
Promote IL-10 and TGF-b production
What is chronic granulomatous inflammation?
Granulomas form when the causative agent cannot be eradicated to try and isolate/prevent its spread
What do granulomas comprise of?
Macrophages
Lymphocytes - mostly T cells, some B cells
Fibroblasts and collagen
Necrotic tissue (sometimes)
What are the causes of chronic granulomatous inflammation?
Immune granulomas
Foreign body granulomas
Diseases of unknown aetiology - Sarcoidosis, Crohn’s disease
What are immune granulomas associated with?
Persistent T cell activation due to specialist chronic infectious agents
- M.tb
- M.leprae
- Treponema pallidum
- Schistosoma sp.
What are foreign body granulomas associated with?
Inert materials but no T cell activation
- talc
- sutures
- fibres
- silica
Describe the course of chronic granulomatous inflammation
Macrophages take up agent but initial killing is ineffective
T cell activation begins helping to activate macrophages
Activated macrophages still do not kill agents
Macrophages become epitheloid with large cytoplasms
Macrophages fuse into giant multinucleate cells
Inflammation is persistent and granulomas are formed
Often causes significant tissue destruction
What are the outcomes of M. tb granulomatous inflammation?
MTB is eradicated
MTB becomes latent
What does eradication of MTB lead to?
Tissue healing but with scarring/fibrosis and tissue damage
Calcium deposits associate with scars and can be seen on xray
What happens when MTB becomes latent?
Leads to ‘walling off’ by fibrous tissue
TB kept from dissemination by persistent T cell activation and surrounding activated macrophages
However once immunity wanes (age/HIV) MTB reactivates
What does too little inflammation lead to?
Opportunistic or persistent infections
e.g. Cryptococcus fungal infection in HIV
What does excessive inflammation cause?
Can produce fatal tissue damage
e.g. excessive neutrophil activity associated with COVID-19 acute respiratory distress syndrome
What does undirected inflammation do?
Can drive chronic inflammation
e.g. gut mucosal granulomas of unknown aetiology arising from chronic inflammatory dysregulation
What are the mediators of inflammation?
Vasoactive amines
Lipid-derived mediators
Complement
Inflammatory cytokines
Chemokines
Name some vasoactive amines
Histamine
Seratonin
Name some lipid-derived mediators
Prostaglandins; COX-1/2
Leukotriens; lipoxygenases
Lipoxins are anti-inflammatory
What are the complement inflammation mediators?
C3a
C5a
What are some other inflammation mediators?
Kinins (bradikinin)
Neuropeptides
What is a cytokine?
A molecule inter-signalling between cells of the immune system
What is a chemokine?
A chemotactic (attractant) cytokine
What are the cytokine families?
Il-1 family
Class 1
Class 2
IL-17 family
TNF family
TGF family
Chemokines
Describe the IL-1 family
Pro-inflammatory
Includes IL-1 (alpha and beta), IL-18 and IL-33
Describe class 1 cytokines
Cell proliferation, differentiation and Ab secretion
Includes IL-2, 3, 4, 5, 6, 7, 12, GM-CSF
Describe class 2 cytokines
Response to viruses, macrophage activation
Includes type I IFN (alpha and beta) and type II IFN (gamma), IL-10
Describe IL-17 family
Pro-inflammatory
Includes IL-17-A, B, C, D, F
Describe the TNF family
Induce differentiation, survival, proliferation, apoptosis
Includes TNF alpha and beta
Describe the TGF family
Inflammatory regulators
Includes TGF-B
Describe chemokines
Chemoattractants
Includes CXCL8, CCL2, MCP-1
How are chemokines given their names?
Based on the number and location of N-terminal cysteine residues
What are the types of chemokines?
Type CC - expressed by monocytes and eosinophils
Type CXC - expressed by neutrophils, Th1 cells and macrophages
What are the roles of chemokines?
Recruiting immune cells to infection sites
Regulating traffic/recirculation through lymphoid organs
Regulating DC migration from infection sites to lymph node
Attracting effector T cells to specific sites of infection
Migrating memory T cells
What are some additional roles of chemokines?
Regulating angiogenesis and tissue healing (fibrosis)
Driving development of lymphoid organs
Activating cell proliferation
Regulating susceptibility to apoptosis
Driving development of non-lymphoid organs (heart and cerebellum)
What do chemokines bind to?
7TM-spanning G-protein-coupled receptors on leucocytes AND GAGs (glycosaminoglycans) on epithelial cells
What are decoy chemokine receptors?
Non-signalling chemokine receptors used to dampen or scavenge chemokine responses and fine tune inflammatory reactions
What cells secrete IL-1b?
Monocytes/macrophages
DCs
Neutrophils
Epithelial cells
Endothelial cells
What induced IL-1b release?
PAMPs and DAMPs
What are systemic effects of IL-1b?
Pyrogen (fever)
What are immune effects of IL-1b?
Activated endothelial cells with TGF-b
Induces Th17 differentiation
What cells secrete TNF-alpha?
Macrophages
DCs
Th1 cells
What induces TNF-a release?
PAMPs and DAMPs
What are systemic effects of TNF-a?
Pyrogen (fever)
Acute phase protein release from hepatocytes
Catabolism of muscle and fat
What are immune effects of TNF-a?
Activates neutrophils
Induces apoptosis in some cells
Activates endothelial cells
What cells secrete IL-6?
Macrophages
Endothelial cells
Fibroblasts
What induces IL-6 release?
PAMPs
IL-1b
TNF-a
What are systemic effects of IL-6?
Acute phase protein release from hepatocytes
Catabolism of muscle and fat
What are immune effects of IL-6?
Increases neutrophil production
Proliferates B cells
With TGF-b induces Th17 differentiation
What cells secrete type 1 IFNs?
Macrophages
DCs
Virally infected cells
What induces release of type 1 IFNs?
PAMPs
IL-1b
TNF-a
TLR3
TLR7
TLR9
What are the effects of type 1 IFNs?
Inhibit viral replication
Induce MHC 1 expression/presentation
Promotes Th1 differentiation
What cells secrete IGN gamma?
NK cells
Th1 cells
CD8+ T cells
What induces release of IFN-g?
IL-12
IL-18
T cell activation to Th1/CD8+
What are the effects of IFN-g?
Activates macrophages
Induces MHC 1 and 2 expression/presentation
Promotes Th1 differentiation and inhibits Th2
Controls Ab switching (promotes IgG2a, inhibits IgE and IgG1)
