Organ-specific immunity: LIVER - Physiology & Innate Immunity Flashcards
Anatomy: of what parts does the liver consist?
Major left and right lobes + smaller inferior lobes
What is special about the liver as opposed to any other organ?
Dual blood supply
What is meant with this dual blood supply?
- Nutrient-rich, oxygen-poor blood via portal vein from intestines
- Oxygen-rich blood via hepatic artery
What are the three immunity characteristics of the liver?
- Protection against pathogens and food toxin from the intestine
- Removal of translocated intestinal bacteria and bacterial toxins
- Tolerance to food antigens and commensal bacteria
Why does the liver need a tightly controlled immunity?
Tolerate antigens, but generate immune response against potential threats
Anatomy: What can be said about the structuring of hepatocytes?
Sheets of hepatocytes, centered around a central vain.
How are hepatocytes grouped?
In portal triads
What does this grouping of hepatocytes in portal triads mean for the blood flow? (direction)
Blood flowing from the portal vain towards the central vain
Anatomy: What is collected in the bile duct?
Drainage of hepatocytes
What is important about the blood flow from the portal vain to the central vain? What does that allow for?
Flow of blood is quite slow. Allows for hepatocytes to really come in contact with whatever is in that blood.
Anatomy: What is between the hepatocytes and the blood? What do they form?
Liver sinusoids and T cells that form an impermeable barrier
What is the Space of Disse (perisinusoidal space) and what is its function?
- Space between sinusoids and hepatocytes
- Microvilli of hepatocytes extend into this space, allowing proteins and other plasma components from the sinusoids to be absorbed by the hepatocytes.
Which cells/substances stay in the vessel and which cells/substances can be directly taken up by hepatocytes?
- Vessel: most cells
- Direct uptake: nutrients
Main functions of the liver (3)
- Metabolism
- Detoxification
- Synthesis
For what kind of immunity is the liver important?
Systemic immunity
Name three examples of the metabolizing function of the liver
- Nutrients
- Amino acid metabolism
- Collestral
What is an example of nutrient metabolism in the liver?
Storing of glucose in the form of glycogen
What is an example of amino acid metabolism in the liver?
Deamination to form urea, which is secreted by the kidneys
What is an example of collestral?
Synthesis of phospholipids
Why is the synthesis of biomolecules important?
Proper functioning immune system
What is an important immune function of the liver?
Synthesis of molecules that are involved in co-agulation and complement system (systemic immunity)
What is the difference between PRRs in the liver and on cell membranes?
The liver PRRs are soluble
What can be said about the secretion levels of PRRs and immunological proteins?
They are not always secreted at equally high levels, especially when a threat is being sensed
Which cytokines lead to an increase of immunologically relevant systemic proteins by the liver? In what kind of situations is this induced?
- IL-6, IL-1, TNF-a
- Inflammation
How are systemic proteins produced by the liver called?
Acute-phase proteins
What is C-reactive protein? How is it often used in the clinic?
Acute-phase protein –> PRR that binds to phosphocholine on bacterial surfaces. Used as a marker of inflammation
Which cytokine triggers C-reactive protein?
IL-6
What does C-reactive protein do?
Activates complement system via classical pathway
C-reactive protein: How is it often used in the clinic?
Used as a marker of inflammation in the blood –> diagnostic molecule
Complement system: How is the classical pathway activated?
Antigen::antibody complexes
Complement system: What is an important function of C3b? How does it do that?
Opsonization of the pathogen. Binds to complement receptors on phagocytes.
Complement system: How is the alternative pathway activated? What does it result in?
- Pathogen surfaces
- Continuous C3b deposition on the pathogen surface
How are host cells shielded from this continuous C3b deposition?
They have anti-C3b binding proteins on their surface
Complement system: How is the MB-lectin pathway activated?
Mannose-binding lectin binds mannose on pathogen surfaces
Describe the two-step recognition by MBL
- Recognizes mannose on pathogen cell surface
- Recognizes spacing of the mannoses in the membrane
Why do we need recognition of the spacing of the mannoses in the membrane?
To make a distinction between self- and non-self
Which association can be made between transplantation of a liver with MBL/Ficolin-2/MASP-2 polymorphisms and incidence of bacterial infections?
INCREASED bacterial infections
Which factors are required for LPS-signaling? (2)
Liver produced LBP and CD14
Characteristics of LBP (lipopolysaccharide binding protein) (3)
- Secreted by liver
- Binds LPS in circulation
- Transfers LPS to CD14
Characteristics of soluble CD14 (2)
- Supports binding of LPS to TLR-4 (in absence of membrane bound CD14)
- Inhibits binding of LPS to membrane bound CD14
To what antigens do we need liver tolerance? (2)
- (Endo)toxins
- Food antigens
Unwanted tolerance in the liver is geared towards..? (3)
- HBV/HCV
- Malaria
- Tumor metastases
Against what antigens do we need liver immunity? (3)
- Hepatitis A virus
- Hepatitis B virus
- Many bacterial species
Why are auto-immune reactions often happening in the liver?
Why do tumors often metastasize to the liver? (2)
- Circulation: seef function
- Tolerance in the liver –> base level of tolerance against food antigens and commensals is needed
What is unique for liver transplants? Why?
No HLA match required of the donor/recipient –> liver is a very tolerogenic organ
Liver transplantation confers protection against?
Rejection of other organ grafts from the same donor
True or false: “Liver transplant have a higher incidence of chronic rejection.”
False. Liver transplants have a lower incidence of chronic rejection.
What can be a problem when weening a patient off of their immunosuppressive medication in case of a liver transplantation?
It is hard to determine if and when a patient is suitable to ween off.
What are examples of situations when you ween someone off their immunosuppressive medication? (2)
- They need vaccination
- CMV infection
How is the balance between tolerance and activation maintained?
Liver contains numerous innate immune cells involved in local immunity
Which innate immune cells are present in the liver? (6)
- Kupffer cells
- DCs
- NK cells
- NKT cells
- Hepatic stellate cells
- Liver sinusoidal endothelium (LSEC)
What is the function of hepatic stellate cells?
Vitamin A storage
What are the functions of LSECs? (2)
- Removal of ‘waste products’ and pathogens from circulation
- Antigen presenting
How do LSECs remove waste products and pathogens from the circulation? (2)
- Receptor-mediated endocytosis
- Lysosomal degradation
Which receptors are used by LSECs?
- Scavenger receptors
- Carbohydrate receptors
What does the slow blood flow in the sinusoids facilitate?
Detection and capture of pathogens, proteins and toxins
What are Kupffer cells and what is their function?
Resident liver macrophages. Phagocytosis and degradation of particulate materials from blood
Name examples of ‘particulate materials from blood’ (3)
- Dying cells
- Aged erythrocytes
- Pathogens
What kind of receptors do KCs express? (5)
- Scavenger
- Fcy and Fca
- Complement
- TLR-4
- TLR3,9
Why are Kupffer cells antigen-presenting cells with tolerogenic properties? (4)
- Direct contact with T cells entering liver
- Modest T cell stimulatory capacity
- Suppress T cell activation via IL-10
- Induce expansion of CD4+FoxP3+ Tregs
What is the default mechanism of antigen-presenting DCs when they migrate from the liver to the hepatic lymph nodes?
Tolerance, via IL-10 secretion & IDO upon TLR-stimulation
Tolerogenic mechanisms in the liver act through…(4)
- Secretion of IL-10, TGF-B
- Non-productive activation of CD8+ T cells
- Stimulation of CD4+FoxP3+ Treg differentiation
- Expression of PD-L1
What is the function of PD-L1?
Inhibiting T cell functions
