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Medsci 203 > Chronic Inflammation > Flashcards

Chronic Inflammation Flashcards

1
Q

Chronic inflammation arises when

A

acute inflammation fails to resolve, or distinctive properties of chronic inflammation are present from the outset

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2
Q

Acute inflmmation is mediated by cells of the _____ immune system

A

innate

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3
Q

Chronic inflammation involves both the innate and the _____ immune system

A

adaptive

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4
Q

Macrophages link innate and adaptive immunity/chronic inflammation by acting as _________ cells

A

antigen-presenting cells

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5
Q

What are the functions of antigen-presenting cells? (3)

A
  1. Engulfment of microbes or macromolecules
  2. Processing of microbes/macromolecules into fragements
  3. Presenting fragments to lymphocytes
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6
Q

Lymphocytes have a vast repertoire of receptors that recognise specific molecular shapes known as _____

A

epitopes

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7
Q

Immune reponses are generated when epitopes are recognised as ____

A

foreign

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8
Q

T lymphocytes include helper cell (Th) populations - these cells secrete _____ that regulate innate and adaptive immunity

A

cytokines

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9
Q

What is the function of the cytokine interferon-γ (IFNγ) secreted by Th1 cells? What does an abnormal response mediate?

A

Stimulates Th1 development and macrophage responses to intracellular pathogens - abnormal responses mediates autoimmunity

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10
Q

What is the function of the cytokine IL-4 secreted by Th2 cells? What does an abnormal response mediate?

A

Stimulates Th2 development and eosinophil responses to helminths (worms). Abnormal responses mediate allergy.

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11
Q

What is the function of cytokines IL-17 and IL-21 secreted by Th17 cells? What does an abnormal response mediate?

A

Stimulates Th17 development and epithelial responses to microbes (secretion of anti-microbial peptides, AMP, such as defensins, and GM-CSF that recruits neutrophils).

Abnormal responses mediate autoimmunity.

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12
Q

What is the function of the cytokine TGFβ secreted by Treg cells? What does deficient Treg function lead to?

A

TGFβ stimulates Tred development and suppresses inflammation (as a “fire extinguishes of other Th cell activities)

Deficient Treg function leads to excessive inflammation. and loss of tolerance

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13
Q

Name the cytokine(s) produced by Th1 cells, the cells they affect, their role in immunity and their pathology

A

IFNγ - macrophages - against intracellular pathogens - autoimmunity

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14
Q

Name the cytokine(s) produced by Th2 cells, the cells they affect, their role in immunity and their pathology

A

IL-4 - eosinophil - against helminths (worms) - allergy

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15
Q

Name the cytokine(s) produced by Th17 cells, the cells they affect, their role in immunity and their pathology

A

IL-17, IL-21 - epithelia, neutrophils - against extracellular pathogens - autoimmunity

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16
Q

Name the cytokine(s) produced by Treg cells, their role in immunity and their pathology

A

TGFβ, IL-10 - “fire-extinguishers”, tolerance - loss of tolerance

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17
Q

B lymphocytes differentiate into _____ cells

A

plasma

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18
Q

Plasma cells produce _______

A

antibodies

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19
Q

What are antibodies?

A

Proteins that bind to particular epitopes on target molecules (antigens)

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20
Q

List 5 kinds of environemental influences on chronic inflmmation

A
  1. Psychological stress
  2. Exercise
  3. Diet
  4. Obesity
  5. Commensal microbes
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21
Q

Describe how phsychological stress influences chronic inflammation

A

Psychological stress can act throug hthe sympathetic nervous system via noradrenaline to induce inflammatory cytokines
- TNF, IL-1β, IL-6

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22
Q

Describe how exercise influences chronic inflammation

A

Exercise suppresses inflammatory cytokines and reduces the risk of chronic metaboic and cardiovascular diseases.

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23
Q

Describe how diet influences chronic inflammation - in particular, how short-chain fatty acids and Omega-3-fatty acids play a role

A

short-chain fatty acids (SCFAs, such as butyrate) are produced in the colon by permentation of plant fibre, and activate GPR41/43 receptors. Omega-3-fatty acids bind GPR120.

These suppress inflammation.

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24
Q

Describe how obesity influences chronic inflammation

A

Hypertrophic adipose tissue releases:

  • TNF, IL-1β, and IL-6
  • SFAs which stimulate TLRs, ROS (from malfunctioning mitochondria) and DAMPs (from necrotic adipocytes)

These recruit inflammatory macrophages and Th1 cells

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25
Q

Describe how commensal microbes influence chronic inflammation

A

Increased hygiene, enriched diets and antibiotics affect the composition of commensal microbes in the body.

Symbionts - beneficial; promote Treg activity
Pathobionts - harmful

26
Q

List four inflammatory conditions, and whether they are increasing/decreasing in frequency.

A
  1. Chronic oesophagitis - increasing
  2. Chronic gastritis - decreasing
  3. Inflammatory bowel diseases - increasing
  4. Chronic hepatitis - increasing
27
Q

Describe the mechanism behind chronic oesophagitis

A

Chronic oesophagitis arises from reflux of gastric fluid, containing acid, digestive proteases (pepsin), bile acids (ROS ->NF-κB -> IL-6) and RNS (from dietary nitrate that is metabolised by microbes)

  • Proinflammatory cytokines such as IL-6 promote epithelial cell proliferation and inhibit apoptosis
  • Inflammation may lead to squamous-to-intestinal metaplasia (Barett’s oesophagus) and oesophageal adenocarcinoma
28
Q

Describe the mechanism behind chronic gastritis

A

Chronic gastritis is caused by the bacterium Helicobacter pylori, which lives on gastric epithelial cells and injects a toxin (CagA) into them. The resulting chronic inflammation produces gastric ulcers, atrophic gastritis, gastric-to-intestinal metaplasia, and (in <1% of infected people) gastric adenocarcinoma

29
Q

Describe the mechanism behind inflammatory bowel diseases

A

Inflammatory bowel diseases may reflect altered relationships with commensal bacteria, from beneficial symbiosis to harmful dysbiosis - possibly due to altered diet, inadequate innate immune defences or loss of barrier funciton

  • Ulcerative colitis - ocurs in the large colon and causes mucosal ulceration
  • Crohn’s disease - occurs throughout the gut (commonly in the terminal ileum) and leads to mucosal ulceration and transmural damage (fibrosis, fissures, fistulas)
30
Q

Describe the mechanism behind chronic hepatitis

A

Chronic hepatitis follows liver damage from viruses such as HBV and HCV as well as toxins (aflatoxins, alcohol), but is reaching epidemic proportions in parallel with metabolic syndrome/insulin resistance/type 2 diabetes.

31
Q

Describe the progression of fatty liver disease phases (2)

A
  1. Steatosis - triglyceride accumulation in hepatocytes
  2. Non-alcoholic steatohepatitis (NASH) - with cycles of cell death, inflammation and later on, deposition of scar tissue
  3. Cirrhosis - in which regenerating hepatocytes are reduced to nodules surrounded by sheets (septa) of scar tissue
    - long term consequences include portal hypertension (high blood pressure), liver failure (with loss of blood proteins and increased nitrogenous catabolites that cause encephalopathy), and liver cancer
32
Q

Liver damage leading to fibrosis may result from: (5)

A
  1. Viral infections (HBV, HCV)
  2. Alcohol abuse, diet induced metabolic disease
  3. Fungal aflatoxin B1 in poorly stored food
  4. Conditions that prevent the flow of bile (cholestasis)
  5. Genetic change with abnormal iron storage (haemochromatosis)
33
Q

Non-alcoholic fatty liver disease (NAFLD) involves _______ accumulation in the liver.

A

triglyceride

34
Q

NAFLD is associated with which diseases?

A

Obesity, type 2 diabetes and heart disease.

35
Q

In the USA, NAFLD may affect __% of the population, and up to __% of children

A

30% of the population, 9% of children

36
Q

What is steatosis and how does it arise?

A

Steatosis is fat accumulation in the liver - benign

Arises from:

  • high fat/fructose diet
  • excessive fatty acid liberation from insulin-resistant adipocytes
  • Increase in fatty acid synthesis in insulin-resistant hepatocytes
37
Q

What is non-alcoholic steatohepatitis (NASH) characterised by? (3)

A
  1. Hepatocyte injury
  2. Inflammation
  3. Fibrosis
38
Q

How does NASH arise?

A

NASH has been suggested to arise from two events, or ‘hits’

  1. Steatosis - non toxic in itself but increases vulnerability of liver cells to damage
  2. Agents such as ROS, pro-inflammatory cytokines and endotoxin from gut bacteria = second toxic hit
39
Q

Actual cell damage in NASH arises from:

A

An excess of FFAs - lipotoxicity

  • Adipocytes: TNF promotes lipolysis and FA release
  • Hepatocytes: TNF and FAs impair mitochondrial respiration = ROS
  • ROS consume SOD, catalase and glutathione
  • oxidative stress generates lipid peroxides and aldehydes = damage
  • increased ratio of saturated to unsaturated FAs disrupts ER environment = ER stress = unfolded protein response due to accumulation of unfolded protein in ER
40
Q

What is fibrosis?

A

Fibrosis is an exaggerated wound-healing process that occurs in many chronic inflammatory diseases. Cells respond to injury and inflammation by laying down fibrillar collagen.

41
Q

Liver-specific pericytes are called:

A

Hepatic stellate cells (HSCs)

42
Q

Where do hepatic stellate cells reside?

A

In the gap between hepatocytes and sinusoidal endothelial cells, known as the space of Disse

43
Q

What are the features of hepatic stellate cells (HSCs)? (3)

A
  1. Store lipids such as vitamin A
  2. Low proliferative activity
  3. Synthesise low amounts of basement membrane-type ECM
44
Q

What happens to hepatic stellate cells (HSCs) following liver damage?

A

They trans-differentiate into myofibroblasts (MFs)

45
Q

What changes as a result of hepatic stellate cells (HSCs) trans-differentiating into myofibroblasts (MFs)? (5)

A
  1. They store less lipids
  2. They are more proliferative
  3. They synthesise fibrillar collagen I and III
  4. They express αSMA and are contractile
  5. They synthesis tissue inhibitors of MMPs (TIMPs), preventing the remvoval of excess fibrous tissue
46
Q

What are other possible sources of myofibroblasts (MFs)? (3)

A
  1. Bone marrow-derived progenitor cells (fibrocytes)
  2. Portal fibroblasts
  3. Epithelial cells that undergo epithelial-to-mesenchymal transition (EMT)
47
Q

What occurs as a result of fibrosis in the liver?

A

Lumen of sinusoid narrowed, causing haemodynamic resistance and portal hypertension

48
Q

How is trans-differentiation of hepatic stellate cells (HSCs) to myofibroblasts (MFs) and fibrogenesis induced?

A

Kupffer cells (liver macrophages) release TGFβ and PDGF when their TLRs bind bacterial products (from leaky gut mucosa) and DAMPs (from oncotic cells)

Myofibroblasts (MFs) produce these factors and TGFβ-inducible connective tissue growth factor (CTGF)

Neutrophils release ROS which is fibrinogenic

Low ratio of Th1 (releasing IFNγ) and Th2 (releasing IL-4) is fibrinogenic

49
Q

Injury-hepatocyte death-repair cycles lead to

A

cirrhosis

50
Q

What is cirrhosis?

A

The loss of liver architecture, with septa (sheets) of fibrous tissue surrounding nodules of hepatocytes

51
Q

What three things can cirrhosis lead to?

A
  1. Portal hypertension
  2. Liver failuer
  3. Liver cancer
52
Q

How does portal hypertension arise with cirrhosis? (3)

A
  1. Ascites (fluid accumulation in abdominal cavity) due to elevated hydrostatic pressure in mesenteric capillaries, decreased concentrations of plasma albumin, sodium and water retention
  2. Varicose veins (varices) in the oesophagus due to increased pressure in the portal veins - varices have weak walls and can rupture and bleed
  3. Renal failure
53
Q

How does liver failure arise with cirrhosis?

A
  1. Hyperbilirubinaemia - excess bilirubin in the blood, with jaundice
  2. Loss of blood proteins (albumin, clotting factors) with oedema and bleeding
  3. Encephalopathy (brain malfunction) from nitrogenous catabolites (such as ammonia( in the blood
    - may be mild (sleep disturbance, irritablity
    - may be severe (coma)
54
Q

Macrophages aggregate to form ______ in response to indigestible substances

A

granulomas

55
Q

List the two types of granulomas and how they arise

A
  1. Foreign body granulomas - from fragments of bone or silica
  2. Immune granulomas - localised inflammatory responses to infectious agents such as mtb and M leprae
56
Q

How does Mtb proliferate within macrophages?

A

Mtb enters the lung in aerosols and is phagocytosed by alveolar macrophages - mtb suppresses the fusion of phagosomes with lysosomes, allowing proliferation intracellularly

57
Q

How can mtb infection of macrophages be eliminated?

A

Infection may be eliminated by innate immunity cells such as neutrophils and natural killer T cells (NKT)

Natural killer T cells produce GM-CSF (Granulocyte-macrophage colony-stimulating factor) which activate macrophages to kill bacteria

58
Q

What does successful infection of Mtb require?

A

Progressive disease in the lung involving airways = coughing transmits infection

Suppression of systemic disease that would cause early death without transmission

59
Q

Describe the process that allows Mtb to be eliminated by Th1 cells.

A

Dendritic cells are antigen presenting cells which take Mtb to the lymph nodes and present Mtb antigens to T cells, generating antigen-specific Th1 adaptive immunity.

Th1 cells reach the lung parenchyma after 18-20 days.

Th1 release IFNγ that enables macrophages to kill Mtb - apoptosis of infected macrophages kills Mtb

60
Q

How can Mtb fashion the lung environment to its advantage?

A
  1. Mtb lipids can inhibit the TLR-dependent activation of macrophages, and promote recruitment of macrophages that are mermissive for Mtb growth - may block access of Th1 cells to infected macrophages
  2. Treg cells may suppress Th1 activity
  3. Mtb may suppress IL-1/PGE2-dependent apoptosis and favour necrosis - which spreads Mtb
61
Q

How could granulomas grant Mtb access to damaged airways?

A

Growing granulomas may undergo liquifactive necrosis, producing cavitation (MMPs) which allow Mtb to access damaged airways

Medsci 203 (10 decks)

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