Chronic Inflammation Flashcards
How does chronic inflammation differ from acute inflammation?
- Greater tissue destruction
- Inflammatory infiltrate is a mixture of macrophages, lymphocytes and plasma cells (neutrophils may be present)
- The reaction is more productive than exudative (i.e. production of new fibrous tissue rather than exudation of fluid)
- Chronic inflammation/healing often proceed in unison
What are the 3 main classes of chronic inflammation?
- Non-specific
- Specific
- Granulomatous (subset of specific)
What is non-specific chronic inflammation?
- Failure to resolve acute inflammation (need more armoury at site of infection)
- Persistent bouts of acute inflammation
What is specific chronic inflammation?
- Arises de novo (starts from the beginning) - something initiates immune response - goes straight to acute then straight to chronic
- Persistent exposure to antigen
What is granulomatous chronic inflammation?
- Subset of specific chronic inflammation characterised by presence of granulomas - seen in number of diseases such as Crohns’s disease
When does chronic inflammation occur?
When the acute inflammation response is not adequate to resolve completely
Describe the process of non-specific chronic inflammation?
- Infiltrate is dominated by tissue macrophages, T cells and B cells
- Non specific chronic inflammation is characterised by a dynamic between tissue destruction and repair
- Disease pathogenesis may include repeated acute phases and chronic phases with ongoing repair
What are the subsets of specific chronic inflammation?
Can be granulomatous or non-granulomatous
What is specific chronic inflammation characterised by?
Excessively activated macrophages - driving force between acute and chronic inflammation
What non-immunological factors is specific chronic inflammation induced by?
- Foreign body reactions
- Inert noxious material(non-moving poisonous material) (e.g. silica and asbestos)
What immunological factors is non-specific chronic inflammation induced by?
- Infective organisms that grow in cells (viruses, mycobacteria)
- Hypersensitive reactions
- Autoimmune reactions
- Infection by fungi, protozoa or parasites
What are the 2 subsets of macrophages?
Macrophages are central figures in chronic inflammation
- M1: cause tissue destruction - they are great at fighting disease and produce lots of different molecules that can also cause tissue damage so have to be carefully regulated
- M2: Produce a lot of molecules that can switch off M1 - also molecules that drive tissue repair
All about balance - want immune system to eradicate pathogen but then needs to switch to repairing damage caused to tissues
What can activated macrophage products result in?
- Tissue injury
- Fibrosis
Activated macrophage products can result in tissue injury, by using what?
- Toxic oxygen metabolites
- Proteases
- Neutrophil chemotactic factors
- Coagulation factors
- AA metabolites
- Nitric oxide
Activated macrophage products can result in fibrosis, by using what?
- Growth factors
- Fibrogenic cytokines
- Angiogenesis factors
- Remodelling collagenases
How does chronic granulomatous inflammation differ from normal chronic inflammation?
As the predominant cell types are modified activated macrophages:
- epithelioid macrophages
- Giant cells (multi-nucleated: formed from fused epithelioid macrophages)
What are the causes of chronic granulomatous inflammation?
Immunological
- Invading pathogens which cannot be cleared (can avoid host immune system and persist in tissue) e.g. TB
Non-immunological
- Foreign body in tissue e.g. asbestos particles
Unknown
- Chronic inflammatory diseases such as Chron’s and sarcoidosis (no causes have been effectively proven)
What is the process of granuloma formation?
- Macrophages present antigen to lymphocytes
- T cells (lymphocytes) recognise antigen and produce cytokines
- Induces the formation of epithelioid macrophages
- Epithelioid macrophages fuse together to form giant cells
- Giant cells - macrophages engulf foreign material
What is oral Chron’s/orofacial granulomatosis?
Granulomas in soft tissues of oral cavity and swelling
Chron’s is an autoimmune reaction to commensal organisms in the GIT
What is intestinal Chron’s called?
Oral Chron’s
What is non-intestinal Chron’s called?
Orofacial granulomatosis
What are the inciting causes and pathogenesis of oral Chron’s?
Relatively unknown
What is an effective treatment for paediatric patients with orofacial granulomatosis?
- Dietary restriction
2 common things patients with Chron’s may have hypersensitivity to is cinnamaldehyde and benzoates (benzoate found in fizzy drinks)
What is an autoimmune disease?
- Unwanted response to body’s own cells and tissues or commensal bacteria
- Loss of tolerance to self antigens or commensal bacteria
What in our body usually prevents autoimmunity?
- Multiple mechanisms of tolerance
- Autoimmunity develops if these safeguards are overcome
What does the sustained immune response do?
Generates cells and molecules that destroy tissues
What is the disease mechanism and consequence of Psoriasis?
- Psoriasis is one of the most common autoimmune diseases
Disease mechanism
- Autoreactive T cells against skin-associated antigens
Consequence
- Inflammation of skin with formation of scaly patches or plaques
What is the disease mechanism and consequence of Sjogren’s syndrome?
This is an orally relevant autoimmune disease (of unknown cause)
Disease mechanism
- *Autoantibodies and autoreactive T cells against ‘self’ ribonucleoprotein antigens
Consequence
- Lymphocyte infiltration of exocrine glands, leading to dry eyes and/or dry mouth; other organs may be involved, leading to systemic disease
Chronic inflammation associated with glands
- T cell infiltration ( greater than 75% of cells)
- B cells
- Auto-antibodies as above *
What is the disease mechanism and consequence for Type 1 diabetes?
This is a chronic immune disease
Disease mechanism
- Autoreactive T cells against pancreatic islet cell antigens
Consequence
- Destruction of pancreatic islet beta cells leading to nonproduction of insulin
Periodontal disease is a form of chronic inflammation and tissue destruction. What are the characteristics of this?
- Soft tissue destruction
- Alveolar bone loss (hard tissue destruction) - losing the supporting structures of the teeth
What is extracellular matrix?
A complex structure that supports cells
What is extracellular matrix made of?
Protein fibres - mainly collagen
What is extracellular matrix re-modelled by?
Matrix Metalloproteinases
Why is extracellular matrix remodelled?
If cells need to move they need to make their way through the ECM they will break the fibres - so MMP’s in the ECM will help to repair this
How are matrix metalloproteinases activated?
- Start life as pro-MMP which is an active enzyme with a block on it
- Cytokines can drive the production of these enzymes
- Enzyme produced in safe form - plasmin can remove safety device to produce the active enzyme
- Increased production of pro-MMP’s and plasmin results in loads of active MMP’s when you don’t really want them, however we do have molecules that can switch off MMP’s (TIMPS) - but, cytokines can switch off the production of TIMPS
Matrix metalloproteinases are associated with tissue destruction in many pathologies. Name 3 of these pathologies?
- Arthritis
- Caries
- Periodontal disease
MMP’s are not the only factor that causes self-harm. What else does?
Numerous other proteins and chemical produced by host can cause ‘collateral damage’ if not regulated
Dysregulation of the host response promotes excessive production of what mediators?
- Constantly activated cell signalling pathways
- Recruitment/activation/ differentiation of immune cell subtypes
What does ROS stand for?
Reactive oxygen species
What does NOS stand for?
Reactive nitrogen species
What is the term used for ‘bone formation’?
Osteoblastogenesis
What is the term used for ‘bone resorption’?
Osteoclastogenesis
Bone is constantly remodelled during adult life. How many years does it take to form a completely new skeleton?
Around every 10 years
Why is there no net loss of bone in bone remodelling?
In general formation and resorption of bone are couples so there is a balance between osteoblastogenesis and osteoclastogenesis
What is the process of osteoclastogenesis?
- Activation of Receptor Activator of Nuclear Factor Kappa-B (RANK) by its ligand (RANKL)
- RANKLY expressed by numerous immune cells (including macrophages)
- If expression of RANKL not controlled then increased alveolar bone loss
What is the process of osteoblastogenesis?
- Osteoblasts secrete Osteoprotogerin (OPG)
- OPG inhibits RANKL therefore bone resorption
In bone remodelling what is an excessive immune response associated with?
An increase in the RANKL/OPG ratio and ‘tips the balance’ towards bone loss
