Immune system and autoimmune disease

Question 1

What is autoimmunity?

Answer 1

An immune response against self-antigens- The failure of hosts immune system to distinguish self from non-self.

Question 2

What is the difference between an immunogen and a tolerogen?

Answer 2

An immunogenicity is a substance that is capable of eliciting an immune response.
Whereas, a tolerogen can’t cause an immune response like an immunogenicity but will cause tolerance- the substance is identifies by the immune system but no response.

Question 3

What is an immune privileged site and an example?

Answer 3

This is an example of segregation of antigens e.g. antigens in the eyes as b and t-cells can’t physically enter the eyes to lead to an immune response so therefore the eyes are an ‘immune privileged site’

Question 4

What are the 2 types of self-tolerance?

Answer 4

• Peripheral tolerance
• Central tolerance

Question 5

What does tolerance mean in immunology?

Answer 5

Tolerance is the prevention of an immune response against a particular antigen

Question 6

Where does central tolerance act?

Answer 6

On the development of immature b and t-cells in the thymus and bone marrow

Question 7

Where does peripheral tolerance act?

Answer 7

On the regulation of b and t-cells in circulation- peripheral tissues and lymph nodes

Question 8

What is negative selection in central tolerance?

Answer 8

Ensures that any lymphocytes developing that could initiate a potent reaction to self-antigens are eliminated via apoptosis to prevent autoimmunity.

Question 9

What are the 4 outcomes of the immature t- lymphocytes in central tolerance and how does it come about?

Answer 9

MHC class proteins on the antigen-presenting cells e.g. Thymus dendritic cells present the self-antigens to the t-cell receptor on the t-lymphocyte.

This leads to either a strong, intermediate, weak or no reaction

Strong reaction - Negative selection = apoptosis
Intermediate- Form regulatory t-cells
Weak reaction- Positive selection
No reaction- Apoptosis

Question 10

What are the 2 outcomes of the immature b-lymphocytes in central tolerance and how does it come about?

Answer 10

The immature b-lymphocytes in the bone marrow are exposed to self-antigens.

High avidity- Can cause receptor editing = expresses a new light chain (antibodies have 2 light chains and 2 heavy chains- if a light chain is changed slightly= a different binding site is created) or if editing fails, apoptosis

Low avidity- Reduce the receptor expression= becomes anergic, meaning it doesn’t really do anything

Avidity = represents the overall strength of the antibody-antigen interaction
Anergy = absence of the normal immune response to a particular antigen or allergen.

Question 11

What is peripheral tolerance?

Answer 11

When the t-cells in the peripheral circulation is exposed to a self-antigen, we don’t want it to become activated. If it does become activated, there are three options:
- Anergy: T-cell has functional unresponsiveness
- Suppression: Regulatory t-cells come and block the activation
- Deletion: The t-cell undergoes apoptosis

When a b-cell is exposed to a self-antigen, it binds to the b-cell receptor, but there is no t-cell activation = no cytokine released by helper t-cells = no antibody is produced against the self antigen

Therefore b-cells, become anergic, apoptosed or regulated by inhibitory receptors.

Question 12

Is b-cell tolerance or t-cell tolerance more important?

Answer 12

Because maintaining t-cell tolerance also enforces b-cell tolerance to the came antigens and therefore t-cell tolerance is more important.
This is due to when a b-cell is exposed the a self- antigen it binds to be the b-cell receptor, but there is no t-cell activation and therefore no cytokines are release from, t-helper cells and there are mo antibodies produces against the self-antigen.

Question 13

What has happened to tolerance if a person develops an autoimmune disease?

Answer 13

Autoimmune diseases occur when multiple layers of self-tolerance have become dysfunctional.
- They are a combination of genetic susceptibility, breakdown of natural tolerance mechanisms, and environmental triggers, infection or inflammation.

Question 14

What is the mechanism of autoimmunity?

Answer 14

Patient often has genetic susceptibility- susceptible genes lead to the failure of self-tolerance and therefore the production of self-reactive lymphocytes.
Additionally, in the presence of infection or inflammation, there is an influx of these self-reactive lymphocytes into tissues. Here, they become activated and tissue injury occurs= Autoimmune disease

Question 15

What does it mean that most autoimmune diseases are polygenic?

Answer 15

That the individuals inherit multiple genes that increase disease susceptibility- not just 1 gene is causative.

Question 16

Is it true that infections can prevent autoimmune conditions aswell as cause them?

Answer 16

Yes- in some cases autoimmune diseases are prevented by infections e.g. multiple sclerosis or T1DM. However, this is rare and the mechanism is unkown.

Question 17

What are the various mechanisms of autoimmune damage?

Answer 17

CIRCULATING AUTOANTIBODIES:
- Complement lysis e.g. haemolytic disease such as SLE : The complement system can cause lysis to bacterial cells via membrane attack complex (MAC) which leads to holes in cells and therefore cell death. Also, Can be caused by deficiencies in early components of the classical complement activation pathway e.g. C1q and c4 are common in patents with systemic lupus erythematosis
- Interaction of autoantibodies with cell surface receptors e.g. Myasthenia Gravis where autoantibodies form against nicotinic acetylcholine (ACh) postsynaptic receptors at the neuromuscular junction (NMJ) of the skeletal muscles, causing muscle weakness and rapid muscle fatigue
- Formation of toxic immune complexes e.g. In SLE - Primarily it leads to activation of both innate and adaptive immunity, which consequently leads to autoreactive B cell activation by T cells and leads to immune complexes deposition in tissues leading to an autoimmune cascade that may be limited to the single organ or can cause a widespread systemic involvement
- Antibody dependent cellular cytotoxicity- this is where cells containing tumour or pathogen antigens on their surface are coated in antibodies to target these cells for destruction by NK cells
- Penetration of circulating autoantibodies into living cells

T-LYMPHOCYTES: (don’t quite understand)
- CD4+ cells are polarised to Th1 cells via cytokines in conditions such as arthritis, MS and T1DM
- CD8+ cells are activated to become cytotoxic t-cells

NON-SPECIFIC:
- The recruitment of inflammatory leukocytes into the autoimmune lesions e.g. in synovitis

Question 18

What is plasmapheresis?

Answer 18

Plasmapheresis (also known as plasma exchange) is the removal of blood from a vein that is then separated via a machine into plasma and then the blood cells (RBCs and WBCs). The cells are transfused back into the body alongside a plasma replacement fluid and the plasma is not. This is because the plasma contains the circulating antibodies in the bloodstream.
- Its only a short-term, treatment

Question 19

What is immunoglobulin?

Answer 19

Is an IV immunoglobulin treatment that contains antibodies from healthy donors.

Question 20

How is a fever generated during infection?

Answer 20

• The bacterium is ingested by macrophages
• When the bacterium is degraded, it releases endotoxins that stimulate the macrophage to produce IL-1
• IL-1 is released into the bloodstream and it travels to the hypothalamus in the brain
• Here it induced the production of prostaglandins
• These prostaglandins, reset the normal body temperature to a high temperature causing a fever
• A fever, increases the survival rates from an infection!

Question 21

What are the symptoms of inflammation?

Answer 21

• Rubour- Redness
• Dolour- Pain
• Calor- Heat, fever
• Tumour- swelling
• Function laesa- loss of function

Question 22

How do the inflammatory cells migrate through the endothelial cell layer to the site of infection?

Answer 22

• Cells such as leukocytes and neutrophils are floating in the blood vessels at a high speed
• Chemoattractants are displayed on the endothelial cell surface (inside the blood vessel) ( the expression of chemoattractants is increased in response to increased cytokine production)
• These chemoattractants capture the leukocytes/neutrophils and cause them to slow down and roll over the endothelial cell layer
• They are then firmly adhered to the endothelial cell layer
• They can then transmigrate through the endothelial cell layer and into the site of inflammation

Question 23

What are some of the roles of cytokines in inflammation?

Answer 23

Cytokines are signaling proteins that help control inflammation (they are chemical messengers):
- They activate the cells in the local environment of the site of inflammation
- They recruit immune cells to the environment to attack the pathogen. They tell them where to go and what to do.
- They stimulate cell growth
- Act as endogenous pyrogens- means are capable of inducing a fever e.g. IL-1, IL-6 and TNF
- Induce acute phase proteins in the liver- these are proteins that increase or decrease their conc in response to inflammation
- Cell differentiation: Cytokines can tell immature cells to develop into a specific type of cell. For example, cytokines can tell an immature cell to mature into a white blood cell capable of fighting infection.

Question 24

What does it mean if a cytokine can act as an endogenous pyrogen?

Answer 24

Means they are are capable of inducing a fever e.g. IL-1, IL-6 and TNF

Question 25

What are acute phase proteins, where are they made, in what concentrations?

Answer 25

APPs are a class of proteins whose concentrations either increase or decrease in response to inflammation (some proteins will increase, some decrease)

Acute phase proteins (APPs) are produced in the liver by hepatocytes in response to inflammation- production is simulated by pro-inflammatory cytokines- IL-1, IL-6 & TNF
- The concentration of APPs fluctuates in response to tissue injury and infection ( can increase or decrease)
If they increase = positive APPs
if they decrease = negative APPs

Examples- C-reacitve protein, Fibrinogen, serum amyloid a

Question 26

list examples of acute-phase proteins and their functions?

Answer 26

• C-reactive protein: Acts as an opsonin- opsonins are molecules that bind to foreign microorganisms or cells making them more susceptible to phagocytosis- highlights them for destruction!
• Fibrinogen- Is a coagulation factor which is needed in order to from clots to close any open wounds.
• Serum amyloid A - Recruitment of immune cells to the site of inflammation. Also, the Induction of enzymes that degrade extracellular matrix- MMPs
• Complement factors- Opsonin (as above), Cell lysis, clumping, chemotaxis e.g. c3a and c5a
• Haptoglobin- Binds hemoglobin, inhibiting microbe iron uptake and prevents kidney damage
  Ferritin- binding iron, inhibits microbe uptake

Question 27

Give some examples pf pro-inflammatory cytokines and their functions

Answer 27

• IL-1- inflammation, induces fever, Induces APP
• TNF-alpha: Inflammation, induction of APP, Induction of apoptosis, neutrophil activation
• IL-6- Induces APP, influences adaptive immunity by b-cells

Question 28

What do chemokines do?

Answer 28

control the migration and positioning of immune cells in tissues
e.g. CXCL8 attracts IL-8
MCP1- monocytes

Question 29

What are adhesion molecules and examples?

Answer 29

Transmembrane receptors that bind to the EC matrix and allow cells to attach to the endothelial layer and move into the cell.
4 classes:
- Igs- VCAM-1, ICAM-1, LFA-2
- Cadherins- E, P, N
- Selectins- E, P, L
- Integrins-

Question 30

What are MMPs?

Answer 30

They degrade and remodel the extracellular matrix.

• Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan

Question 31

What is the function of NF-KB?

Answer 31

is a transcription factor that regulates pro-inflammatory mediators:
cytokines e.g. TNF, IL-1, IL-6
Chemokines e.g. IL-8, CCL23, MEP-1
Adhesion molecules e.g. VCAM-1, ICAM-1,
MMPs
Acute phase proteins

Question 32

How is NFKB activated?

Answer 32

• NFKB is bound to IKB in the cytoplasm- IKB inhibits NFKB from having any activity
• If DNA damage occurs or there is presence of bacteria/virus etc IKB kinase phosphorylates IKB and causes it to be broken down and degraded
• This causes the release of NFKB
• NFKB migrates to the cell nucleus and binds to promoter sequences = drives transcription of certain cytokines, chemokines, APPs
• Therefore, NFKB acts as a transcription factor in the nucleus to drive transcribing of RNA and DNA = enhances inflammatory response by driving production of inflammatory mediators

Question 33

What are the 2 phases of the inflammatory response?

Answer 33

Phase 1 = Pro-inflammatory
Phase 2 = Resolution (anti-inflammatory)

Question 34

What are examples of anti-inflammatory mediators (drive resolution)?

Answer 34

• Cytokines e.g. IL-10, IL-4
• Soluble adhesion molecules- bind to adhesion molecules to prevent other cells from binding- stops more immune cells coming to the area
• TIMPs- inhibit MMPS
• Plasmin activation system- recedes the clots formed in inflammation
• opioid peptides- counteract pain

Question 35

What causes chronic inflammation and inflammatory diseases?

Answer 35

When there is no resolution phase in the inflammatory response = keep releasing cytokines, chemokines etc = tissue destruction, organ failure etc