Lecture23

Question 1

What is tolerance with regards to the immune system?

Answer 1

The ability to distinguish between self and non-self

Question 2

What occurs if tolerance is broken?

Answer 2

Autoimmune disease develops

Question 3

How does clonal deletion generate tolerance?

Answer 3

Lymphocytes are selected based on their affinity to the self MHC complex
Very Strong signals co-responds to an autoreactive T Cell and will cause apoptotic death
Intermediate signals will form natural tReg cell (may be potentially autoreactive)
Weak signals will go on to produce an effector cell
A cell which receives no signal will suffer death by neglect
Some autoreactive cells will escape this process

Question 4

What are the mechanisms of peripheral tolerance?

Answer 4

Clonal anergy, immunological tolerance, suppression

Question 5

What is clonal anergy?

Answer 5

Self-reactive lymphocytes become resistant to antigens

Question 6

What is immunological ignorance?

Answer 6

Where either antigens are sequestered, lacking T celll help or co-stimulation

Question 7

What is suppression with regards to immunological tolerance?

Answer 7

Self reactive lymphocytes are present but suppressor cells keep them in check

Question 8

How does the gut generate tolerance?

Answer 8

Specialized CD103+ Dendritic Cells which secrete TGFBeta, and retinoic acid results in the development of induced tregs,
Enteric Bacteria can influence tolerogenicity

Question 9

What is sympathetic opthalmia?

Answer 9

When injury to one eye results in injury to the other eye as an immune response is generated towards the newly exposed occular antigens
The antigen is typically melanin-containing structures from the outer segment of the photoreceptor layer of the retina

Question 10

What is autoimmune orchitis?

Answer 10

After a illness of mumps the epididymis becomes infected due to release of sperm antigens

Question 11

What is molecular mimicry?

Answer 11

When the immune system thinks that a self antigen is the same as an antigen from a pathogen due to infection with a pathogen which has a similar shaped antigen

Question 12

What is rheumatic fever?

Answer 12

Disease which develops after S.Pyogenes infection, this shares an antigen with human myocardium (via protein M), self reactive B cells produce antibodies which damage heart valves
As secondary immune responses are more violent the patient will need to be on low level antibiotics for the rest of their life

Question 13

What is Coeliac disease?

Answer 13

Abnormal reaction to gliadin (gluten from wheat), cross immune reaction ensues against the transglutaminase enzyme flattening the villi of small intestine reducing the efficiency of absorption
Treatment is by removal of gluten from diet

Question 14

What is Multiple sclerosis?

Answer 14

Molecular mimicry between pathogen and components of myelin sheath resulting in an immune response causing loss of nerve cell insulation and axon damage
This results in sensory and visual problems, as well as muscle weakness and paralysis

Question 15

What is type I diabetes?

Answer 15

Immune system attacks beta islets of langerhans of the pancreas resulting in the loss of insulin production
The immune system attack is likely mediated by molecular mimicry fro things such as the coxsackie virus family

Question 16

What is chrons disease?

Answer 16

Genetically susceptible individuals become intolerant to their own intestinal flora via a TH1 mediated inflammation
This is believed to be triggered by pathogens such as mycobacterium avium subspecies paratuberculosis

Question 17

What indices the loss of tolerance of the immune system?

Answer 17

The autoreactive lymphocytes can become activated due to a loss of tregs or through actions adjuvants

Question 18

What are adjuvants?

Answer 18

Agents that non-specifically enhance the immune response, these include superantigens and the lipopolysaccharide from gram negative bacteria

Question 19

What are the genes where mutations can indicate susceptibility to autoimmune disease?

Answer 19

Immunoglobulin genes, T Cell Receptors, Complement, MHC, NOD2, CTLA-4

Question 20

How does a mutation of an immunoglobulin genes cause auto immune disease?

Answer 20

Hypermutation may result in the production of auto antibodies

Question 21

How do TCR gene mutations result in autoimmune disease?

Answer 21

VBeta genes are used preferentially by autoreactive T cells

Question 22

How do complement mutations result in autoimmune disease?

Answer 22

Systemic Lupus erythematosus causes deficiencies in the complement system, resulting in impaired clearance of immune complexes

Question 23

How do mutations in the MHC complex cause immune disease?

Answer 23

HLA-DR2 Associated with systemic lupus erythematosus, multiple sclerosis and negatively correlated to type I diabetes
HLA-DR3 associated with type I diabetes, Systemic lupus erythmatosus, myasthenia gravis
HLA-DR4 correlated to rheumatoid arthritis, type I diabetes

Question 24

How does a mutation in CTLA-4 affect the immune system?

Answer 24

CTLA-4 switches off T cell activation, mutations can prevent this function

Question 25

How is NOD2 linked to immune disease?

Answer 25

Mutations result in susceptibility for chrons disease as the function of NOD2 is to help the innate immune system recognise muramyl dipeptide of peptidoglycan resulting in the acitvation of nuclear factor and induce inflammation
In Chron’s patientes nuclear factor is not activated

Question 26

How do Treg suppress the immune respones and what can occur to this control which results in autoimmune disease?

Answer 26

Supression occurs via cytokines such as IL-10, IL-35, TGFBeta as well as direct killing of auto-reactive T cells through granzyme A/B, perforin, disruption of metabolic function via starvation of IL-2 causing apoptosis of target cell and release of immunosuppressive cAMP
The Tregs can be overcome if a large population of autoreactive cells becomes active which can occur through the actions of adjuvants

Question 27

How does gender play a role in autoimmune disease?

Answer 27

Autoimmune diseases typically occur more commonly in females suggesting sex steroids have a role, however this is still debated

Question 28

What are the environmental factors?

Answer 28

Over exposure to pesticides and toxins may induce autoimmunity
Autoimmunity is more commonly seen in regions where there are low rates of infectious diseases despite a high correlation of some infectious pathogens (such as coxsackie virus causing type I diabetes) to autoimmune disease

Question 29

How can autoimmune disease be treated?

Answer 29

Most treatments are palliative rather than cures, and may involve the replacement or inhibition of endocrine products, use of antibiotics when there is a condition which is precipitated by infection, changes of diet for food induced autoimmunity, or use of immunosuppressive agents in severe cases

Question 30

What is an example of replacement of an endocrine secretion as a treatment for immune disease?

Answer 30

Insulin injections in diabetes

Question 31

What is an example of a diet change as a treatment for a food induced auto immune disease?

Answer 31

Coeliac disease requires gluten to be removed from the diet

Question 32

What immunosuppressive agents are used to treat autoimmune disease?

Answer 32

Corticosteroids such as methylprednisolone and budesonide
Non-Steroidal anti inflammatory drugs (asprin, ibuprofen, indomethacin, naproxen, COX-2 inhibitors)
Disease Modifying anti-rheumatic drugs (azathioprine,sulfasalazins, cyclosporin, methotrexate, azathioprine, mycophenolate, gold salts
Biologics

Question 33

What are biologics?

Answer 33

Small molecules which target specific cytokines or cytokine inhibitors to block their actions
examples include TNF-Alpha antagonists in rheumatoid arthritis
Beta interferon which is used to treat multiple sclerosis patients
Humanised antibody (Tysabri) against alpha4 integrins is also used to treat multiple sclerosis