Inflammation Flashcards
Define inflammation and differentiate it from swelling
A complex response process triggered by infection, tissue injury or irritants enabling specific host cells and interacting chemicals (cytokines) to co-ordinate and attempt their neutralisation and removal
Swelling : an abnormal enlargement of a part of the body, usually triggered due to the result of accumulation of fluid.
Comparison acute vs. chronic inflammation
Describe the course of acute inflammation
Recognition - non-self antigens or damage signals trigger response
Recruitment - immune cells & mediators are attracted and retained at the initiating site
Response - immune cells commit by differentiating and activating mechanisms able to kill pathogens, limit spread of infection and further injury and protect damaged tissue from becoming infected
Removal-infectious agents/dead cells/tissue are deconstructed
Resolution - conditions are created for tissue repair (e.g. TGF-)
In the absence of inflammation there will be no tissue repair
What are the Recognition triggers in acute inflammation?
PAMPs ( Infectious inflammation )/ DAMPs ( Sterile inflammation ) are recognised by Pattern Recognition Receptors (PRR) on cell surfaces
initially involving RESIDENT Macrophages
PRR activation triggers cell signalling pathways to secrete pro-inflammatory Cytokines & Type I Interferons (IFN)
Describe recruitment in acute inflammation
Resident tissue macrophages and mast cells recognise pathogens and secrete mediators
(cytokines, histamine)
The activation of vascular endothelium by TNFa or IL-1 causes chemokine production and adhesion molecules to be expressed on the endothelial surface.
Once an immune reaction has developed in tissue, leukocytes generate their own cytokines
and promote further leukocyte migration.
Cytokines ‘inside-out’ activate integrins capturing neutrophils attracted by chemotaxis that then migrate into tissue
Neutrophils capture bacteria then release more vascular permeability and monocyte recruitment mediators. Generally leukocytes migrate through the junctions between cells
Differentiated monocytes remove bacteria and release cytokines for further recruitment or repair
Describe the importance of E-selectin in acute inflammation recruitment.
When tissue is damaged, TNFa or IL-1, induce synthesis and expression of E-selectin on endothelium. Both E-selectin and P-selectin can slow circulating platelets or leukocytes
at sites of inflammation, E-selectin and P-selectin, bind to the sialyl Lewis-X carbohydrate associated with CD15, present
on many leukocytes
Describe the pattern of leukocyte migration
- Step-1 leukocytes are slowed as they pass through a venule and roll on the surface of the endothelium before being halted – this is mediated primarily by adhesion molecules called selectins interacting with carbohydrates on glycoproteins;
- Step-2 the slowed leukocytes now have the opportunity to respond to signaling molecules held at the endothelial surface – particularly important is the large group of cytokines called chemokines, which activate particular populations of leukocytes expressing the appropriate chemokine receptors;
- Step-3 activation upregulates the affinity of the
leukocytes’ integrins, which now engage the cellular adhesion molecules on the endothelium to cause firm adhesion and initiate a program of migration.
Describe the response in acute inflammation
Short lived neutrophils phagocytose pathogens
releasing cytokines then expanding and bursting to throw out neutrophil extracellular traps (nets) to capture and immobilise other pathogens
Describe removal and repair in acute inflammation
Monocytes initially differentiated into killing M1 convert to resolving M2 macrophage types
M1 : highly phagocytic activated killing, able to
clear inflammation site
M2 : weakly microbicidal secrete growth factors (eg TGF-β) for REPAIR involving angiogenesis, fibroblast proliferation and collagen synthesis
Plus anti-inflammatory cytokines eg IL-10
Activity such as efferocytosis (M1 macrophages engulfing spent neutrophils ) or increased levels of IL-4 / IL-13 in the inflammatory environment promotes polarisation from M1 into M2 macrophages
Describe the course of chronic inflammation
Recognition - Macrophage activation or direct innate encounters by other leukocytes of non-self antigens or host cell damage signals
Recruitment - Macrophages, Neutrophils, T-cells, Eosinophils, Mast cells
Response - T-cell activation feeds back directly to activate macrophages, both secrete pro-inflammatory cytokines and stimulate broader adaptive responses
Removal - Persistent pathogens or long term non-specific antigen exposure are not removed prolonging the response
Resolution - 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 Recognition triggers in chronic inflammation?
Recruitment involving Macrophages, Neutrophils and T-cells occurs similarly to acute inflammation
T cells
Pathogens escaping or resisting innate immune responses can still be presented by APC
Activated naïve T-cells migrate and become effectors in lymphoid organs. Effector T-cells return to inflammatory sites and increase response
Chronic inflammation can result in large accumulations of T-cells at inflamed sites eg Rheumatoid arthritis
Describe recruitment in chronic inflammation
Eosinophils can be recruited and activated
by parasites and IgE responsiveness
Mast cells (connective & mucosal) can be
activated by injury or IgE mediated allergy
Several diseases influenced by over recruitment of neutrophils e.g.s Chronic Obstructive Pulmonary Disease (e.g. through smoking) and COVID-19 related severe acute respiratory syndrome
Describe the resolution in acute inflammation
Cells involved
Macrophages – killing, removal of apototic/spent immune cells – type shift to M2 drives repair
Regulatory T-cells – derived from CD4 lineages
use various cytokines (IL-10, TGF-ß, IL-17) to
deactivate many cell types exhibiting inflammatory cell responses (Mast, Eosinophils)
Lack of Tregs (particulary IL-17) found in IBD
Innate lymphoid cells eg NK cells help reduce
activation of proinflammatory cells such as
eosinophils (asthma)
Myeloid derived suppressor cells (MDSC) aide in
efferocytosis, induce Treg cell expansion, promote IL-10 and TGF-ß production.
What is Chronic granulomatous inflammation?
Granulomas form when the causative agent can’t be eradicated to try and isolate/prevent its
spread
which cannot produce reactive oxygen
intermediates suffer from repeated bacterial infections.
Granulomas comprise of Macrophages
Lymphocytes (mostly T cells and some B cells)
Fibroblasts & Collagen Necrotic tissue (sometimes)
Describe the cause Chronic granulomatous inflammation?
- Immune granulomas:
Associated with persistent T cell activation due to specialist chronic infectious agents
Mycobacterium tuberculosis
Mycobacterium leprae
Treponema pallidum
Schistosoma sp. - Foreign body granulomas:
Associated with inert materials but no T-cell activation:
talc
sutures
fibres
silica - Diseases of unknown aetiology:
Sarcoidosis, Crohn’s Disease (granulomas with no visible bacteria)
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
Describe Mycobacterium tuberculosis granulomatous inflammation
TNF and lymphotoxin-a are essential for granuloma formation during mycobacterial
infections.
Divergent Outcomes
1. MTB is eradicated
Leads to tissue healing but with scarring/fibrosis and tissue damage. Calcium deposits associate with scars and can be seen on X-ray
- MTB becomes ‘Latent’ (non-dividing)
Leads to ‘walling off’ by fibrous tissue
TB kept from dissemination by persistent T cell activation and surrounding activated macrophages
BUT
Once immunity wanes (steroids/HIV/age) …
MTB recrudesces
What are the consequences of uncontrolled inflammation?
Too little inflammation can lead to opportunistic
or persistent infections
e.g. Cryptococcus fungal infection in HIV
Undirected inflammation can drive chronic inflammatory disease
e.g. Gut mucosal granulomas of unknown aetiology arising from chronic inflammatory
dysregulation
Excessive inflammation can produce fatal tissue damage
e.g. Excessive neutrophil activity associated with
COVID-19 acute respiratory distress syndrome
List the mediators of inflammation
- Vasoactive amines: histamine, serotonin
- Lipid-derived mediators (from arachidonic acid)
- prostaglandins (PGE2, PGD2, prostacyclin, thromboxane); COX-1/2
- leukotriens (LTC4, LTD4, LTE4); lipoxygenases
- lipoxins are anti-inflammatory (lipoxygenase pathway) - Complement (C3a, C5a)
- Inflammatory cytokines: IL-1, IL-6, TNF-a
- Chemokines: CXCL8 (IL-8)
- Other: kinins (bradikinin), neuropeptides
define cytokines and chemokines
Cytokine
A molecule inter-signalling between cells of the
immune system (Interleukin - Interferon)
Chemokine
A chemotactic (attractant) cytokine
List the Cytokine families involved in inflammation their roles and examples
- IL-1 family
pro-inflammatory
includes IL-1 (α & β), IL-18 and IL33 - Class 1
cell proliferation, differentiation, Ab secretion
includes IL-2, 3, 4, 5, 6, 7, 12, GM-CSF - Class 2
response to viruses, macrophage activation
includes type I IFN (α & β) and type II IFN (λ), IL-10 - IL-17 family
pro-inflammatory
includes IL17-A, B, C, D, F - TNF family
induce differentiation, survival proliferation, apoptosis
includes Tumor Necrosis Factor TNF (α & β) - TGF family
inflammatory regulators
includes TGF-β - Chemokines
chemoattractants
includes CXCL8, CCL2, MCP-1
Describe chemokines
Small 8-10 KDa proteins
A large group of cytokines falling into four
families, of which the main families are the CC and the CXC group.
Type CC expressed by Monocytes (CCL2) and Eosinophils (CCL11)
Type CXC expressed by Neutrophils (CXCL1/2/3), Th1 cells (CXCL9/10/11), Macrophages (CXCL1, CXCL8)
Conditionally expressed in response to inflammatory cytokines, recognition of microbes, cell activation
They act on G protein-linked, seven-transmembrane pass receptors on leukocytes and GAGs (glycosaminoglycans) on Epithelial cells
What are the roles of Chemokines?
Recruiting immune cells to infection sites
Regulating traffic/recirculation through lymphoid organs
- skin homing: CCL17:CCR4; CCL27:CCR10
- gut homing: CCL25:CCR9
Attracting effector T cells to specific sites of infection
Regulating DC migration from infection sites to lymph node
Migrating memory T cells
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
List the receptors for chemokines
Many chemokine receptors can bind multiple chemokines
10 receptors for CC chemokines: CCR1-CCR10
6 receptors for CXC chemokines: CXCR1-CXCR6
1 receptor for C (also named XC chemokine): XCR1
1 receptor for CX3C chemokine: CX3CR1
Describe Decoy Chemokine receptors
Decoy Chemokine receptors
‘Non-signalling’ (‘silent’) chemokine receptors
Used to dampen or scavenge chemokine responses and fine tune inflammatory reactions
Some pathogens (viruses, parasites) express
mimic soluble receptors able to capture IL-1β, TNF-α and IFN-γ confusing leucocyte recruitment mimic chemokines able to interfere with leucocyte recruitment Th2 and Treg activities
Describe the roles of cytokines
- Innate cytokines
IL-1β, TNF-a, IL-6 = Pro- inflammatory
IL-10 = Anti-inflammatory
IL-12, type I IFNs = T cell stimulation
IFN-y = Cell activation
CXCL8, MCP-1 = Cell recruitment - Adaptive cytokines
IL-4 = Promotes Th2, blocks Th1 and Th17
IL-5 = Activates eosinophils and B cells
TGF-β = Inhibits macrophage activation, influences T regs
Key innate pro-inflammatory cytokines: TNF-a
secreted by?
induced by?
systemic effects?
immune effects?
Secreted by:
-monocytes/macrophages,
-dendritic cells,
-neutrophils,
-epithelial cells,
-endothelial cells
Induced by:
-PAMPs and DAMPs
Systemic effects:
-pyrogen (fever)
-Acute phase protein (SAP, MBL, CRP, Fibrinogen) release from hepatocytes
-catabolism of muscle and fat
Immune effects:
-activates neutrophils, induces apoptosis in some cells
-activates endothelial cells (E-selectin, ICAM/VCAM-1)
Key innate pro-inflammatory cytokines: IL-6
secreted by?
induced by?
systemic effects?
immune effects?
Secreted by:
-macrophages
-endothelial cells
-fibroblasts
Induced by
-PAMPs, IL-1b,TNF-a
Systemic effects:
-Acute phase protein (SAP, MBL, CRP, Fibrinogen) release from hepatocytes
-catabolism of muscle and fat
Immune effects:
-increases neutrophil production (bone marrow)
proliferates B cells
with TGF-a (IL-21 & IL-23) induces Th17 differentiation
Innate cytokines: Type I interferons
secreted by?
induced by?
systemic effects?
immune effects?
examples?
(IFN-a, IFN-b, IFN-e, IFN-k, IFN-w)
Secreted by:
-macrophages
-dendritic cells
-virally infected cells
Induced by:
-PAMPs, IL-1b,TNF-a, TLR3 (ds.viralRNA),
-TLR7 (ssviral RNA), TLR9 (unmethylated CpG DNA)
Effects:
-inhibits viral replication
-induces MHC I expression/presentation
-promotes Th1 differentiation
Innate cytokines: Type II interferon
secreted by?
induced by?
systemic effects?
immune effects?
examples?
(IFN-y)
Secreted by:
-NK cells
-Th1 cells
-CD8+ T cells
Induced by
-IL-12, IL-18 + T cell activation to Th1/CD8+
Effects:
-activates macrophages
-induces MHC I & II expression/presentation
-promotes Th1 differentiation and inhibits Th2
-controls Ab switching (promotes IgG2a : inhibits IgE & IgG1)
