Tolerance and Autoimmunity

Question 1

What type of immune response is involved in autoimmunity?

Answer 1

Adaptive immune response with specificity for self antigens

Question 2

Which cell type is always involved in autoimmunity?

Answer 2

Lymphocytes

Question 3

What proportion of people have lymphocytes with the capability of recognising self-antigens?

Answer 3

ALL of us: this is normal autoimmunity

Question 4

What are the 6 main factors that contribute to autoimmune disease?

Answer 4

Genetic susceptibility  
Sex
Infections  
Diet
Stress
Microbiome

Question 5

Why are autoimmune conditions chronic?

Answer 5

Self-tissue is always present

Question 6

The effector mechanisms in autoimmunity resemble those of which type of immune reaction?

Answer 6

Hypersensitivity reactions (types 2, 3 + 4)

Question 7

What % of people affected by autoimmune disease are female?

Answer 7

~ 80% overall

Question 8

What is a possible reason for the increase in incidence of autoimmune disease?

Answer 8

Hygiene hypothesis

Question 9

Describe the pathophysiology of autoimmune haemolytic anaemia.

Answer 9

Autoantibodies against RBCs, which bind to RBCs + activate complement
Results in clearance + complement-mediated lysis of autologous RBCs

Question 10

What is a type II hypersensitivity reaction?

Answer 10

Antibody response against cellular or ECM antigens (insoluble antigens)

Question 11

What is a type III hypersensitivity reaction?

Answer 11

Immune complex formation by antibody against soluble antigen

Question 12

What is a type IV hypersensitivity reaction?

Answer 12

T cell mediated disease: delayed type hypersensitivity

Question 13

What is Goodpasture’s syndrome?

Answer 13

Type 2 hypersensitivity reaction in which there are IgG antibodies against a type IV collagen found on the BM in the glomerulus
Results in deposition of autoantibodies in the renal corpuscle + activation of complement leading to infiltration of inflammatory cells + kidney damage

Question 14

How do type II and type III immune reactions recruit inflammatory cells?

Answer 14

Inflammatory cells are recruited via the binding of inflammatory cells to the Fc portion of antibodies via their Fc receptors

Question 15

What is the main difference between type II and type III hypersensitivity reactions?

Answer 15

Type II: insoluble antigens

Type III: soluble antigens (damage more systemic)

Question 16

What is the autoantigen in multiple sclerosis? What pathology results?

Answer 16

Myelin basic protein
Brain degeneration (demyelination)
Paralysis

Question 17

Other than antigen-TCR binding, what else is required for the activation of naïve T cells?

Answer 17

Co-stimulation

Question 18

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

Answer 18

HLA (class II in particular)

Question 19

What did the freemartin cattle experiment show about tolerance?

Answer 19

Early exposure to foreign antigens allows development of tolerance to those antigens

Question 20

Define immunological tolerance.

Answer 20

The acquired inability to respond to an antigenic stimulus

Question 21

3 A’s of immunological tolerance

Answer 21

Acquired : involves cells of acquired immune system + is “learned”
Antigen specific
Active process in neonates

Question 22

What are the 2 types of immunological tolerance?

Answer 22

Central Tolerance: occurs during lymphocyte development

Peripheral Tolerance: once we’ve developed mature lymphocytes, there are mechanisms to develop tolerance

Question 23

What are the 3 main mechanisms of peripheral tolerance?

Answer 23

Anergy
Active suppression (T regs)
Ignorance / immune privilege

Question 24

What are the 3 outcomes for T cells based on how strongly they bind to MHC in the thymus?

Answer 24

Useless: don’t recognise self MHC: die by apoptosis
Useful: associate weakly with self MHC
Dangerous: associate too strongly with self MHC: die by apoptosis

Question 25

What % of thymocytes survives selection?

Answer 25

5%

Question 26

What class of immunoglobulin are the B cell surface receptors?

Answer 26

IgD + IgM

Question 27

What happens to B cells that recognise soluble autoantigens?

Answer 27

They migrate to the periphery but don't express normal levels of IgM + they are anergic (Not very responsive) Eliminated with time

Question 28

What is the role of the AIRE transcription factor?

Answer 28

Important for low-level expression of a large variety of tissue specific self-peptides e.g. insulin in the thymus, against which T cells are selected

Question 29

What is APECED caused by?

Answer 29

Mutation in the AIRE transcription factor means T cells can’t be selected against for a wide range of self-peptides Lots of self-reactive T cells get released into the circulation + can cause AI disease

Question 30

What is anergy caused by?

Answer 30

Presentation of an antigen in the absence of co-stimulation: this makes the lymphocytes enter a refractory state

Question 31

What is immunological ignorance caused by?

Answer 31

Occurs when antigen concentration is too low in periphery Can be due to the absence of APCs- most cells in periphery are MHC class II negative Occurs at immunologically privileged sites where the immune cells don’t normally penetrate e.g. eye, CNS Ignorance: T cells never see their antigen

Question 32

Give an example of a failure of ignorance.

Answer 32

Sympathetic ophthalmia Damage to the eye can release eye antigens into the lymphatics + lymph nodes Antigens are recognised by T cells, which become activated against the eye antigens The T cells return to both eyes + cause damage

Question 33

What are the 4 main receptors expressed by Tregs?

Answer 33

CD4 CD25: IL-2 receptor, an important growth factor for T cells CTLA-4: binds to B7 + sends a negative signal FOXP3: essential transcription factor for T reg development

Question 34

What is IPEX caused by? List 3 symptoms

Answer 34

``` Mutation in FOXP3 Mutation in FOXP3 leads to accumulation of autoreactive T cells Early onset insulin dependent DM Severe infections Eczema ```

Question 35

What are the 2 types of Treg?

Answer 35

``` Natural Tregs (nTregs): generated in thymus Inducible Tregs (iTregs): produced as part of the normal T cell response as a mechanism of dampening down an immune response after it has happened ```

Question 36

How can infections affect tolerant states? (6 ways)

Answer 36

Molecular mimicry of self-molecules Induction of costimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment Failure of regulation: effects on Tregs Immune deviation: shift in type of immune response e.g. Th1 to Th2 Activation of APCs by pathogens leads to upregulation of costimulatory molecules Tissue damage at immunologically privileged sites

Question 37

What mechanisms does the adaptive immune system use in autoimmune disease?

Answer 37

Same mechanisms as immune reactions against pathogens

Question 38

What does autoimmune disease involve breaking?

Answer 38

T-cell tolerance

Question 39

How does pregnancy influence inflammatory responses in autoimmunity?

Answer 39

There are more Th2 responses (rather than cell mediated) Antibody mediated AI condition symptoms worsen Cell mediated AI condition symptoms improve

Question 40

List 5 common autoimmune diseases

Answer 40

``` Rheumatoid Arthritis Type 1 Diabetes Multiple Sclerosis SLE Autoimmune thyroid disease ```

Question 41

Give 3 examples of Type 2 autoimmune disease

Answer 41

Pemphigus vulgaris Graves disease Goodpastures syndrome

Question 42

Give an examples of Type 3 autoimmune disease

Answer 42

SLE

Question 43

Where do B and T cells mature?

Answer 43

T cells: Thymus | B cells: Bone marrow

Question 44

Defects in which processes are associated with autoimmune disease?

Answer 44

Induction of tolerance: autoantibody production Apoptosis: failure in cell death Clearance of antigen: persistence of autoantigen