Chronic inflammation Flashcards
What is chronic inflammation?
Chronic inflammation is referred to as slow, long-term inflammation lasting for prolonged periods of several months to years.
Histological features of chronic inflammation
Hard (indurated), red (erythematous) swelling
Mononuclear cell infiltrate
Little oedema
Angiogenesis (neovascularisation)
Collagen deposition (with time)
How is chronic inflammation sustained/ caused?
WBC in tissue produce inflammatory cytokines, growth factors, enzymes and hence contributing to the progression of tissue damage
Secondary repair including fibrosis and granuloma formation.
Give examples of one infectious and one non-infectious cause of chronic inflammation.
Infectious: Tuberculosis
Non-infectious: Gout/silicosis
What is the nature of the giant cells?
Langhans cells (in TB) are formed from the fusion of macrophages infected with TB
What is the most likely cause for the formation of the granuloma (TB)?
Immune system was overcome by the TB infection - could not eliminate infection and so granuloma was formed to contain the infection
Macrophages are the major source of the cytokine TNF alpha
True
Neutrophil recruitment is a key feature of chronic inflammation
False, (probably) composition of the white blood cells changes and macrophages and lymphocytes begin to replace short-lived neutrophils.
(TNF alpha contributes to the weight loss (cachexia) seen in chronic infection
True
Role of cytokines in chronic inflammation
Induce the injury-site-endothelial cells to release Selectins and Integrins which stimulate chemotaxis and diapedesis of the circulating leukocytes.
Role of neutrophils in the early stages of inflammation
Contain granules rich with lysozyme, matrix metalloproteinases, myeloperoxidase which are released on the foreign or self-antigen leading to its destruction.
Role of macrophages and DCs in chronic inflammation
Release cytokines such as IL-1 and TNF-α
Clear the antigen by phagocytosis and serve as antigen-presenting-cells to lymphocytes.
Role of platelets in chronic inflammation
Platelet aggregation, thrombus formation and degranulation releasing chemokines and inflammatory mediators.
Chronic osteomyelitis is associated with infection with…
Chronic inflammatory process of the bone secondary to infection with pyogenic organisms: Staphylococcus aureus and occasionally Enterobacter or Streptococcus species
Silicosis is caused by
Simple chronic silicosis results from long-term exposure (more than 20 years) to low amounts of silica dust. Nodules of chronic inflammation and scarring provoked by the silica dust form in the lungs and chest lymph nodes.
What is the response to inhaled silica particles
Particles phagocytosed by alveolar macrophages and induce breakdown of lysosomes - activates NALP3 inflammasome - macrophages die and release cytokines (IL1Beta, TNF) - further macrophage recruitment and fibroblast proliferation - collagen deposits and fibrosis around the silica particles - nodules of inflammation and scarring form in lung and chest lymph nodules.
Describe a silicosis nodule
Nodules characterised by concentric onion skin arrangement with collagen fibres, central hyalinization and cellular peripheral zone.
When does TB primary infection often occur?
Childhood
What is a Ghon focus?
Infection develops in periphery of lung, primary lesion seen on an x-ray
What is a primary complex?
Ghon focus and lymph node involvement
What are the two main sequelae of primary TB infection?
Most infections heal without clinical disease
Small proportion of infected individuals cannot contain infection, this leads to widespread dissemination (primary disease)
Why may lead to secondary TB?
Re-activation of Tb infection is seen in drug addicts and alcoholics, HIV-infected individuals, patients treated with anti TNF-alpha drugs
What does HIV positive individuals being at a higher secondary infection risk tell us about granuloma?
Importance of CD4+ T cells in contain Tb within granulomata
What does risk of anti-TNF alpha in TB patients tell us about TNF alphas role in TB?
TNF-alpha important in host suppression of Tb infection
Histology of TB
Abundant Macrophages
Many lymphocytes
Fibroblasts
Collagen deposition
What is the role of TB chronic inflammation?
Asymptomatic containment of TB bacterium in tubercles
What happens when MTB is phagocytosed by macrophages?
Antigen presentation to CD4+ T cells
Cytokine release
What does MTB do inside the phagocyte?
Prevents maturation of the phagosome at an early stage
LAM (TB surface lipid)
What cytokines are released from MTB macrophage, what does each one stimulate?
IL-12 - Th1 cells induced and produce IFN gamma
TNF-alpha - recruits monocytes, recruits CD4+ T cells to produce granulomas
Osteopontin - promotes adhesion and recruitment
What does IFN gamma do to stimulate macrophages?
Activates macrophages to produce, defensins (toxic antimicrobial peptide), iNOS (NO creates reactive nitrogen species to kill mycobacteria
Produce TNF-alpha
What tissue supports granuloma formation (not blood)?
Other cytokines needed for granuloma formation produced by respiratory tract epithelial cells and immune cells (e.g. CCL12 binds CCR2 Receptor leads to early recruitment of macrophages).
What is a granuloma?
A granuloma is a group of epithelioid macrophages surrounded by a lymphocyte cuff.
Granulomata can contain macrophage giant cells (MGCs) which are the result of macrophage fusion (e.g Langhans cells in Tb granuloma).
TB granulomata can be accompanied by extensive necrotic cell death = Caseating necrosis
What drives macrophage fusion?
IFN gamma
What are giant cells and their role?
Langhans multinucleated giant cell Horseshoe arrangement of nuclei.
Non-phagocytic for Mtb - contributed to blunting bacterial killing.
How do granulomas necrose, why is this a ‘good’ thing?
Fibrous cuff around granuloma prevents blood vessel reaching centre - hypoxic centre and bacterial replication and dissemination reduces - dormant bacteria - necrosis and fibrosis
What is the role of foam cells in granulomas?
Foam cells contain lipid bodies (LBs)
Bacteria in phagosomes associated with LBs. Bacteria utilise host derived LDLs/cholesterol in LBs for their metabolism.
What is the mantoux test?
Inject tuberculin or PPD into skin
A person who has been exposed to the bacteria is expected to mount an immune response in the skin containing the bacterial proteins.
The response is a classical example of delayed-type hypersensitivity reaction (DTH), a type IV of hypersensitivities
What can cause cirrhosis?
Congenital biliary obstruction
Alcohol abuse
Obesity
Viral hepatitis
Which inflammatory cytokine is released following inflammasome activation of Caspase 1?
IL-1beta
Which of the following cytokines stimulates collagen deposition by fibroblasts and is associated with fibrosis?
TGF-beta
