31.3 Chronic Inflammation Flashcards
What is the time-fram for chronic inflammation?
Weeks to years
*far longer than is appropriate or necessary.
What are the three main stimuli for chronic inflammation?
-Prolonged exposure to toxic agents (exogenous or endogenous)
-Hypersensitivity from innate immune cells
-Persistent infections leading to adaptive immune triggered chronic inflammation
What can chronic inflammation lead to?
poor wound resolution, pain and increased likelihood of damage in the future.
What cells are typically present in chronic inflammation?
*Mononuclear cell infiltrate. i.e. macrophages (possibly giant and epithelioid cells) and lymphocytes
What is absent in chronic inflammation that is seen in acute inflammation?
PMNs (infiltration) and pus.
*However, PMNs are present in repeated and long-standing acute inflammation
Is oedema present in chronic inflammation?
Very little
Do normal repair processes still happen in chronic inflammation?
Yes, there is vascularisation/ angiogenesis and collagen deposition (which can be excessive).
What are the 2 different possible pathologies of chronic inflammation?
*Toxic and innate immune-triggered
*Adaptive-immune triggered
Give an example of toxic and innate-immune triggered chronic inflamation.
*Silica dust particles are deposited in the alveoli
*Macrophages phagocytose silica and phagosome fuses with lysosomes
*Silica is unable to be broken down so lysosome bursts and the enzymes are released which kills the macrophages
*Upon death, macrophages release cytokines such as IL-1 and growth factors which recruit further macrophages and fibroblasts
*Fibroblasts secrete collagen resulting in lung fibrosis and loss of tissue function.
*Macrophages continue to repair the surrounding tissue
What are the general steps that take place during toxic and innate immune-triggered chronic inflamation?
*Toxic, non-antigenic particle activation and killing of macrophages.
*Stimulation of further recruitment and death of macrophages.
*Release of mediators by macrophages to cause persistent repair reaction. Resultant fibrosis + loss of function.
What can repeated bouts of acute inflammation result in?
Fibrosis and scarring.
E.g. cholecystitis
Give an example of long-standing acute inflammation.
Chronic Osteomyelitis (presence of foreign body causing constant inflammatory response)
*Infection of the bone which results in sequestrum formation (dead bone tissue)
What are some examples of adaptive immune-triggered chronic inflammation?
Tuberculosis (granuloma formation), rheumatoid arthritis, cirrhosis.
What is the role of macrophages in adaptive immune-triggered chronic inflammation?
Secretory cells that cause tissue damage.
What do macrophages secrete which aids in sustaining chronic inflammation?
Secrete IL-1 and TNF-α which attract lymphocytes to the area of inflammation
What is adaptive immune-triggered chronic inflammation?
CD4+ T-cell mediated immune response to persistent antigens.
List the the different subsets of T cells involved in propagating chronic inflammation. How do they do this?
TH1: Secrete IFN-gamma which activates macrophages and stimulates killing
TH2: Secrete IL-4, IL-5 and IL-13 which recruit eosinophils (TH2 cells are important for parasite infection and allergic inflammation)
TH17: Secrete IL-17 which recruits PMNS
Name a pathogen which can result in chronic granulomatous inflammation
M. Tuberculosis
(persists and activates T cells which recruit macrophages)
Describe how a granuloma is formed
- Phagocytosis of Mtb by alveolar macrophages
*TLR-2 recognition of Mtb lipids
*Secretion of TNF-α - Recruitment into the airway of circulating phagocytes (by CKs)
*Mainly monocytes
*Differentiation into airway macrophages - Vascular supply /Structuring of cells around infection/ Appearance of foamy macrophages/ Recruitment of lymphocytes
*Mainly CD4 T cells → secrete IFN-γ
*Vascular supply ↑ by VEGF response
*Site where there is both innate and adaptive response limiting replication + dissemination of bacteria.
*Foamy macrophages → contain membrane bound lipid bodies.- Bacteria in phagosome associated w/ LBs
- Bacteria utilise LDLs/ Cholesterol in LBs for metabolism
- Formation of fibrous cuff → ↓ vascularisation/bacterial numbers
*Infected area becomes hypoxic → bacterial replication ↓ (possibly as a consequence) → enter persistent/ dormant stage- Mechanisms not fully understood. 5. Bacterial Development of Ghon focus/ granuloma
*Langhans multinucleated giant cell → horseshoe arrangement of nuclei fusion of macrophages driven by IFN-γ. Non-phagocytic - Immune response blunts bacterial killing.
*Caseous material - Derived from LDLs
- Possibly from foamy macrophages
- Mechanisms not fully understood. 5. Bacterial Development of Ghon focus/ granuloma
How do granulomas evolve?
Fibroblasts are recruited and synthesise collagen around the primary lesion
Describe the structure of a granuloma
How do macrophages and T cells have a bidirectional relationship?
Macrophages present antigens on MHC class II molecules to T cells and express costimulators (B7) for activation
T cells secrete IFN-gamma needed for macrophage activation and ROS generation and transcription of lysosome enzymes
How does the Mantoux test work?
A standard dose of PDD tuberculin (a protein derived from bacterial analogues of Mycobacterium tuberculosis) is injected intradermally
Delayed hypersensitivity to infected individuals results in a local inflammatory response 24-48 hours later as memory B and T cells are recruited to the site of protein
What does a positive Mantoux test result look like? Why?
Hard, palpable red raised surface due to mononuclear cell infiltration and CD4+ memory T cell recruitment resulting in a local inflammatory response within 24 hours
What is the purpose of granuloma formation?
Cellular attempt to contain and offending agent that is difficult to eradicate (TB)
What is Rheumatoid arthritis (RA)?
A chronic inflammatory disorder of autoimmune origin that principally attacks the joints producing inflammatory synovitis
What drives the pathogenesis of RA?
CD4+ T cells displaying self antigens resulting in serum antibodies against citrullinated peptides (peptidyl arginine residue is converted to citrulline) and type II collagen
Inflammation triggers activation of fibroblasts and chondrocytes resulting in destruction of bone and cartilage
What has be used to treat RA?
Corticosteroids (immunosupressive)
TNF antagonists (stop recruitment of immune cells) but this can increase the risk of TB infection
What is the general result of chronic inflammation?
Fibrosis
Tissue scarring
Loss of function
