Tolerance and Autoimmunity

Question 1

4 criteria for an autoimmune disease?

Answer 1

Evidence of disease specific adaptive immune response in the affected target tissue/organ/blood

Passive transfer of auto reactive cells or antibodies replaces the disease

elimination of the autoimmune response eliminates the disease

history of autoimmune disease/MHC associations

Question 2

factors for autoimmune disease? (6)

Answer 2

Microbiome
Stress
Diet
Sex
Infections
Genes

Question 3

effector mechanism of autoimmunity resembles which HS reactions?

Answer 3

mechanisms resemble those of hypersensitivity reactions, types II, III, and IV

Question 4

What is the hygiene hypothesis? What evidence supports this?

Answer 4

that if the immune system isn’t fighting infection it may begin to fight self

• Incidence of autoimmune disease (and hypersensitivity) is increasing

Question 5

During pregnancy what happens to autoimmune diseases and why?

Answer 5

• During pregnancy there is a shift away from inflammatory responses to help protect the fetus, so often diseases go away during pregnancy then come back (e.g. arthritis)

Question 6

Some important autoimmune diseases? (5)

Answer 6

RA
T1DM
MS
SLE
Autoimmune thyroid disease

Question 7

Example of a specific target autoimmune disease? (3)

Answer 7

Graves’
T1DM
Pernicious anaemia

Question 8

Example of a nonspecific target autoimmune disease? (3)

Answer 8

SLE/RA/Vasculitis

Question 9

What is a t2 HS reaction

Answer 9

• Antibody response to cell surface or insoluble extracellular matrix antigen (against insuluble antigen

Question 10

What is a t3 HS reaction

Answer 10

• Immune complex formed by antibody against soluble antigen that go into circulation

Question 11

What is a t4 HS reaction

Answer 11

• T-cell mediated disease (Delayed type hypersensitivity reaction,

Question 12

What is Goodpastures syndrome

Answer 12

antibody binds to basement membranes in kidney- leads to complement activation and inflammation

Question 13

Summarise Graves disease

Answer 13

antibodies against TSH receptor cause release of thyroid hormone w/o negative feedback

Question 14

Example of a T3 HS disease

Answer 14

SLE

Question 15

3 examples of T4 HS diseases?

Answer 15

Insulin dependent diabetes mellitus
RA
MS

Question 16

Autoantigen and pathology and HS reaction type of:

RA

Answer 16

T4
unknown synovial joint antigen
Joint inflammation and destruction

Question 17

Autoantigen and pathology and HS reaction type of:

MS

Answer 17

Myelin basic protein, proteolipid protein

T4

Brain degeneration (demyelination) weakness and paralysis

Question 18

What do CD8+ cells recognise

Answer 18

MHC Class I

Question 19

What do CD4+ cells recognise

Answer 19

MHC Class II

Question 20

What is the dominant genetic factor affecting susceptibility to autoimmune disease?

Answer 20

MHC class II

Question 21

What is tolerance defined as

Answer 21

ACQUIRED INABILITY TO RESPOND TO AN ANTIGENIC STIMULUS

Question 22

2 types of tolerance?

Answer 22

Central and peripheral

Question 23

What is central tolerance?

Answer 23

The elimination of self-reactive lymphocytes during lymphocyte development

Question 24

What is peripheral tolerance

Answer 24

Anergy, active suppression (by regulatory T cells), ignorance of antigen (non-exposure/ignorance to antigen)

Question 25

Where does central tolerance occur (2)

Answer 25

THYMIC EPITHELIAL CELLS (TECs) and DENDRITIC CELLS (DCs)

Question 26

What 3 categories does the thymus separate lymphocytes into

Answer 26

1. Useless (can’t see MHC) die by apoptosis 2. Useful (see MHC weakly) receive signal to survive- “Positive selection” 3. Dangerous (see self strongly) receive signal to die by apoptosis- “Negative selection”

Question 27

What % of thymocytes survive thymus selection

Answer 27

5

Question 28

Which type of immune cell goes to the thymus

Answer 28

pre T-cells

Question 29

Which type of immune cell matures in the bone marrow

Answer 29

B cells

Question 30

What happens to a B cell that has no self reaction in the bone marrow

Answer 30

Migrates to periphery and matures

Question 31

What happens to a B cell that has a reaction to a multivalent self molecule in the bone marrow

Answer 31

Clonal deletion or receptor editing leading to apoptosis

Question 32

What happens to a B cell that has a reaction to a soluble self molecule in the bone marrow

Answer 32

Migrates to periphery and becomes anergic

Question 33

What happens to a B cell that has a reaction to a low-affinity-non-crosslinking self molecule in the bone marrow

Answer 33

Migrates to periphery and becomes a mature clonal ignorant B cell

Question 34

What is apeced and what does it effect? (6)

Answer 34

``` - APECED is a rare autoimmune disease which affects the endocrine glands:  Thyroid  Kidneys  Chronic mucocutaneous candidiasis  Gonadal failure  DM  Pernicious anaemia ```

Question 35

What does failure of central tolerance result in

Answer 35

- APECED

Question 36

What causes Apeced

Answer 36

mutations in the transcription factor AIRE (autoimmune regulator) gene

Question 37

What is AIRE important in

Answer 37

- AIRE is important for the expression of ‘tissue-specific’ genes in the thymus

Question 38

Many of the genes that are implicated in genetic susceptibility to autoimmune diseases are involved in... (3)

Answer 38

1. induction of tolerance 2. apoptosis 3. clearance of antigen

Question 39

3 mechanisms for inducing and maintaining tolerance in the periphery?

Answer 39

1. Anergy 2. Suppression by regulatory T cells 3. (Ignorance of antigen)

Question 40

What do naive T cells need for full activation? Examples of what they need? (3)

Answer 40

co-stimulation for full activation: CD80, CD86 and CD40 are examples of costimulatory molecules expressed on APC

Question 41

What does stimulation without a co-stimulatory molecule lead to

Answer 41

Anergy

Question 42

How does anergy occur

Answer 42

stimulation without a co-stimulatory molecule lead to

Question 43

When does immunological ignorance occur (2)

Answer 43

when antigen concentration is too low in the periphery | and when relevant antigen presenting molecule is absent:

Question 44

Which MHC class are most cells in the periphery

Answer 44

class I

Question 45

Where does immunological ignorance occur (3)

Answer 45

immunologically privileged sites such as eye, testes and PNS

Question 46

Why might cells at immunologically privileged sites react against autoantigens

Answer 46

They have never been tolerised

Question 47

What transcription factor is required for Treg development

Answer 47

FOX P3

Question 48

FOXP3 is required for what

Answer 48

Treg development

Question 49

IPEX stands for what

Answer 49

Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome

Question 50

Symptoms of IPEX? (5)

Answer 50

- Early onset insulin dependent diabetes mellitus - Severe enteropathy - Eczema - Variable autoimmune phenomena - Severe infections

Question 51

Symptoms of IPEX? (5)

Answer 51

- Early onset insulin dependent diabetes mellitus - Severe enteropathy - Eczema - Variable autoimmune phenomena - Severe infections

Question 52

Ways in which infections can cause autoimmunity? (5)

Answer 52

- Infections may carry out molecular mimicry of self-molecules - Induce changes in the expression and recognition of self-proteins - Induction of co-stimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment - Failure in regulation by effecting/infecting regulatory T-cells - Immune deviation shift in type of immune response e.g. Th1-Th2 - Tissue damage at immunologically privileged sites