Immunology 4

Question 1

What is autoimmunity?

Answer 1

Autoimmunity- adaptive immune responses (i.e. with lymphocytes) with specificity for self-antigens.

Question 2

What is autoimmunity caused by?

Answer 2

It is caused by a mixture of genetic predisposition and environmental factors causes the breakdown of self-tolerance which lead to autoimmune disease

Question 3

Describe the influence of genes on autoimmune disease and refer to some studies

Answer 3

• Genes- discovered that genes hold significance through twins’ studies and GWAS- e.g. 40 loci key in SLE

There is a strong genetic component for that condition

Question 4

Describe the other factors that can lead to autoimmune disease

Answer 4

• Sex- females are more susceptible to autoimmune disease- however, there is a gradient of AI disease sex tropism- diabetes mellitus affects more men whilst SLE and thyroid disease affects much more women
• Infections you are exposed to- provide an inflammatory environment- e.g. EBV
• Diet- obesity, effects on the microbiome
• Stress- can release stress-related hormones- e.g. cortisol
• Microbiome- the microbiome helps shape immunity

Question 5

What are the mechanisms behind the immune reaction in autoimmunity

Answer 5

Same as the ones in immune reaction:
• Because self-tissue is always present, autoimmune diseases are chronic conditions
• Effector mechanisms resemble those of hypersensitivity reactions, types II, III and IV.

Question 6

How many (%) of individuals are affected by AI disease

Answer 6

8%

Question 7

Why do you think AI incidence is increasing?

Answer 7

The hygiene hypothesis. Immune system not being used in the same way as it was supposed to be.

Question 8

Describe type 2 hypersensitivity

Answer 8

Antibody response to cellular or extracellular (insoluble) antigen

Question 9

Give 2 examples where type 2 hypersensitivity is being used

Answer 9

• Goodpasture’s syndrome:
Autoantigen is non-collagenous domain on basement membrane collagen T4
Consequence- glomerulonephritis, pulmonary haemorrhage
• Grave’s disease:
Autoantigen- autoantibody binds to TSH receptor
Consequence- stimulation of TSHR by autoantibody so there is excessive T4 production

Question 10

What is type 3 hypersensitivity and give an example (including its auto antigens)

Answer 10

Immune complex formed by antibody against soluble antigen. Example:
• SLE
Autoantigen- DNA, histones, ribosomes, snRNP, scRNP
Consequence- glomerulonephritis, vasculitis, arthritis

Question 11

What is type 4 hypersensitivity?

Answer 11

T cell mediated (delayed type hypersensitivity reaction). Cytotoxic (CD8+) and helper (CD4+) T cell responses involved as well as B-cell responses.

Question 12

Give 3 examples of type 4 hypersensitivity autoimmunity diseases. Give the auto antigen of the condition and what happens as a result of an autoimmune reaction against it.

Answer 12

• Diabetes mellitus
Autoantigen- pancreatic beta cell antigen
Consequence- beta-cell destruction
• Rheumatoid arthritis:
Autoantigen- synovial joint antigen
Consequence- joint inflammation and destruction
• Multiple sclerosis
Autoantigen- myelin basic protein, proteolipid protein
Consequence- brain degeneration as a result of demyelination, weakness and paralysis

Question 13

what t-cells recognise which MHCs?

Answer 13

MHC class II (DR, DQ and DP) present to CD4+ TCRs
MHC class I (A ,B, C) present to CD8+ TCRs

Question 14

What was the evidence seen for tolerance against self

Answer 14

Freemartin cattle have fused placentas and exchange cells/antigens in utero.
Non-identical twins have different sets of blood group antigens. Because these are non-identical twins, you would expect that they would have an immune reaction to each other’s cells and tissues.

Adult cattle can tolerate blood transfusions and skin grafts from a non-identical twin therefore tolerance must be present.

Question 15

What experiment shows that timing of exposure is critical?

Answer 15

Mouse models:
These models show that the timing of tolerance is important.
• If the donor supplies a spleen and bone marrow cells to the neonate, that same donor can donate a skin graft to the adult later on.
• If the donor straight away supplies the skin graft to the adult mouse, that same adult cannot accept the skin graft- the cells have not been received in the neonate phase.

Question 16

What experiment shows that tolerance has specifity?

Answer 16

in the same example of the mouse model, if the donor supplies cells to neonate then the same adult could not accept a graft from a random other mouse. All donations need to come from the same donor.

Question 17

What is immunological tolerance

Answer 17

acquired inability to respond to an antigenic stimulus

Question 18

What are the 3As that are associated with immunological tolerance?

Answer 18

Acquired- involved cells of the acquired immune system and is learned
Antigen specific
Active process in neonates, the effects of which are maintained throughout life

Question 19

What are the 2 types of tolerance?

Answer 19

1. Central tolerance- occurs during development ( in thymus and bone marrow)
2. Peripheral tolerance- anergy, active suppression (t reg cells), immune privilege, ignorance of antigen. Failure in one or more of these systems may result in AI disease

Question 20

How is central tolerance of t-cells done?

Answer 20

• T-cells mature in the thymus and during, the recognise antigens that are presented on MHC inside the thymus itself (i.e. the thymic epithelial cells TEC or dendritic cells)

Question 21

what are the 3 outcomes of thymus selection?

Answer 21

1. Useless- t-cell cannot see the MHC and it undergoes apoptosis
2. Useful- t-cell can see MHC weakly (this is good and it is positive selection).
3. Dangerous- see and bind to MHC strongly (with high affinity). This is bad and they receive signal to die by apoptosis

Question 22

How much (%) survive thymocyte selection?

Answer 22

5%

Surviving cells are MHC-restricted, with low/ intermediate affinity for self-peptide

Question 23

Describe how central tolerance of b-cells occur and what are the 4 outcomes for the immature B cells in the bone marrow?

Answer 23

B cells mature in the bone marrow and their selection is as follows:
• No self-reaction means that they migrate to periphery and become a mature b-cell
• Multi-valent self-molecule will undergo clonal deletion or receptor editing  this either ends in apoptosis or mature b-cells.
• Soluble self-molecule migrates to periphery and leads to anergic b-cell (fail to respond to antigen)
• Low-affinity, non-crosslinking self-molecule migrates to periphery  mature b-cell that is clonally ignorant. THIS LAST ONE HAS A POSSIBILITY TO BECOME AUTOREACTIVITY.

Question 24

What happens when central tolerance fails?

Answer 24

Autoimmune
PolyEndocrinopathy
Candidiasis
Ectodermal
Dystrophy
(APECED)

Question 25

What causes the failure of central tolerance?

Answer 25

Failure caused but mutation in the AIRE transcription factor (autoimmune regulator). AIRE is important for the expression of tissue specific genes in the thymus and is involved in the negative selection of self-reactive t-cells in the thymus. This results in persistence of autoreactive cells

Question 26

Which organ pathologies does failure bring about?

Answer 26

* Thyroid * Kidneys * Chronic mucocutaneous candidiasis * Gonadal failure * Diabetes mellitus * Pernicious anaemia

Question 27

Which particular genes are involved in SLE and what does their dysfunction lead to?

Answer 27

* Apoptosis- failure of cell-death (Fas and Fas-L mutations) * Clearance of antigen- abundance of autoantigen (C1q, C1r, C1s complement proteins) * Induction of tolerance- failure of tolerance (CD22 and SHP-1)

Question 28

What are the protective mechanisms in place to prevent AI disease if auto reactive antibodies come out

Answer 28

1. Anergy 2. Suppression by regulatory t-cells 3. Ignorance of antigen

Question 29

What is anergy?

Answer 29

The absence of costimulation Naïve t-cells require • Co-stimulation for activation- needs co-stimulatory molecules (CD80, 86 and 40) • These are absent on most cells of the body. Without co-stimulation, cell proliferation would not proceed Subsequent stimulation then leads to a refractory state termed anergy.

Question 30

What is ignorance?

Answer 30

``` Occurs when antigen concentration is too low and when relevant APC is absent for lymphocytes to be able to see it. Most cells in the periphery are class MCHII -ve (they don't have it). Ignorance occurs at immunologically privileged sites where immune cells cannot normally penetrate as an immune reaction could do more harm than good- i.e. the brain. ``` Example of failure of ignorance- sympathetic ophthalmia- trauma to an eye leads to release of intraocular proteins which trigger immune system

Question 31

What is suppression/ regulation?

Answer 31

Autoreactive T-cells may be present but do not respond to autoantigen. This is controlled by t-reg cells: CD4+ CD25+ CTLA-4+ FOXP3+ o CD25 is the Interleukin-2 Receptor o CTLA-4 binds to B7 and sends a negative signal o FOX P3 is a transcription factor required for regulatory T-cell development IPEX (immune dysregulation, poly-endocrinopathy, enteropathy and x-linked inheritance) is when there is a mutation in FOX P3. This is a fatal recessive disorder which presents in childhood and leads to accumulation of autoreactive t-cells. Leads to early onset of DM, enteropathy, eczema, infections and autoimmune symptoms. IPEX results in an accumulation of autoreactive t-cells.

Question 32

How can infection lead to breaking peripheral tolerance?

Answer 32

* Infections can induce changes in the expression and recognition of self-proteins * Molecular mimicry of self-molecules * Induction of co-stimulatory molecules or inappropriate MHC class II expression- pro-inflammatory environment * Failure in regulation- effects on regulatory t-cells * Immune deviation- shift in type of immune response e.g. Th1 to Th2 * Tissue damage at immunologically privileged sites Infection may help break tolerance by a variety of mechanisms.