31.3 Chronic Inflammation

Question 1

What is the time-fram for chronic inflammation?

Answer 1

Weeks to years
*far longer than is appropriate or necessary.

Question 2

What are the three main stimuli for chronic inflammation?

Answer 2

-Prolonged exposure to toxic agents (exogenous or endogenous)
-Hypersensitivity from innate immune cells
-Persistent infections leading to adaptive immune triggered chronic inflammation

Question 3

What can chronic inflammation lead to?

Answer 3

poor wound resolution, pain and increased likelihood of damage in the future.

Question 4

What cells are typically present in chronic inflammation?

Answer 4

*Mononuclear cell infiltrate. i.e. macrophages (possibly giant and epithelioid cells) and lymphocytes

Question 5

What is absent in chronic inflammation that is seen in acute inflammation?

Answer 5

PMNs (infiltration) and pus.
*However, PMNs are present in repeated and long-standing acute inflammation

Question 6

Is oedema present in chronic inflammation?

Answer 6

Very little

Question 7

Do normal repair processes still happen in chronic inflammation?

Answer 7

Yes, there is vascularisation/ angiogenesis and collagen deposition (which can be excessive).

Question 8

What are the 2 different possible pathologies of chronic inflammation?

Answer 8

*Toxic and innate immune-triggered
*Adaptive-immune triggered

Question 9

Give an example of toxic and innate-immune triggered chronic inflamation.

Answer 9

*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

Question 10

What are the general steps that take place during toxic and innate immune-triggered chronic inflamation?

Answer 10

*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.

Question 11

What can repeated bouts of acute inflammation result in?

Answer 11

Fibrosis and scarring.
E.g. cholecystitis

Question 12

Give an example of long-standing acute inflammation.

Answer 12

Chronic Osteomyelitis (presence of foreign body causing constant inflammatory response)
*Infection of the bone which results in sequestrum formation (dead bone tissue)

Question 13

What are some examples of adaptive immune-triggered chronic inflammation?

Answer 13

Tuberculosis (granuloma formation), rheumatoid arthritis, cirrhosis.

Question 14

What is the role of macrophages in adaptive immune-triggered chronic inflammation?

Answer 14

Secretory cells that cause tissue damage.

Question 15

What do macrophages secrete which aids in sustaining chronic inflammation?

Answer 15

Secrete IL-1 and TNF-α which attract lymphocytes to the area of inflammation

Question 16

What is adaptive immune-triggered chronic inflammation?

Answer 16

CD4+ T-cell mediated immune response to persistent antigens.

Question 17

List the the different subsets of T cells involved in propagating chronic inflammation. How do they do this?

Answer 17

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

Question 18

Name a pathogen which can result in chronic granulomatous inflammation

Answer 18

M. Tuberculosis
(persists and activates T cells which recruit macrophages)

Question 19

Describe how a granuloma is formed

Answer 19

1. Phagocytosis of Mtb by alveolar macrophages
   *TLR-2 recognition of Mtb lipids
   *Secretion of TNF-α
2. Recruitment into the airway of circulating phagocytes (by CKs)
   *Mainly monocytes
   *Differentiation into airway macrophages
3. 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
4. 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

Question 20

How do granulomas evolve?

Answer 20

Fibroblasts are recruited and synthesise collagen around the primary lesion

Question 21

Describe the structure of a granuloma

Answer 21

Question 22

How do macrophages and T cells have a bidirectional relationship?

Answer 22

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

Question 23

How does the Mantoux test work?

Answer 23

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

Question 24

What does a positive Mantoux test result look like? Why?

Answer 24

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

Question 25

What is the purpose of granuloma formation?

Answer 25

Cellular attempt to contain and offending agent that is difficult to eradicate (TB)

Question 26

What is Rheumatoid arthritis (RA)?

Answer 26

A chronic inflammatory disorder of autoimmune origin that principally attacks the joints producing inflammatory synovitis

Question 27

What drives the pathogenesis of RA?

Answer 27

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

Question 28

What has be used to treat RA?

Answer 28

Corticosteroids (immunosupressive)
TNF antagonists (stop recruitment of immune cells) but this can increase the risk of TB infection

Question 29

What is the general result of chronic inflammation?

Answer 29

Fibrosis
Tissue scarring
Loss of function