Immune 2 - Tolerance and autoimmunity

Question 1

What is autoimmunity

Answer 1

Adaptive immune responses with specificity for self antigens (auto antigens)

Question 2

IgG crosses the foetus (through the placenta).

Answer 2

Y

Question 3

What genetic and environmental factors increase the chance of autoimmune disease

Answer 3

1. Genes
2. Sex (women more susceptible)
3. Infections (inflammatory environment)
4. Diet
5. Stress
6. Microbiome

Question 4

Effector mechanisms in autoimmunity resemble which types of hypersensitivity?

Answer 4

Types 2, 3 and 4

Autoimmune diseases involve breaking T cell tolerance

Question 5

List examples of important autoimmune diseases

Answer 5

1. Rheumatoid arthritis
2. T1DM
3. MS
4. SLE
5. Autoimmune thyroid disease

Question 6

Autoantibodies against RBC are responsible for autoimmune haemolytic anaemia. How

Answer 6

Antibodies bind to RBC antigen - resulting in clearance or complement-mediated lysis of autologous erythrocytes

Question 7

Differentiate type 2 and type 3 hypersensitivity

Answer 7

Type 2 = Ab response to INSOLUBLE antigen (e.g. cellular or extracellular antigen) - usually causes tissue injury

Type 3 = immune complex formed by Ab against SOLUBLE antigen - usually causes vasculitis

(Type 4 = t-cell mediated)

Question 8

Graves disease is autoimmunity leading to hyperthyroidism - how

Answer 8

Causes more and more T3/T4 to be produced, no negative feedback

Question 9

SLE is a classic example of a type 3 disease.

Answer 9

Immune complexes deposited in glomerulus (and other places)

Question 10

In type 4 (T-cell mediated delayed type), name the auto antigen and pathology of:

T1DM
RA
MS

Answer 10

T1DM - pancreatic B-cell antigen - causes B cell destruction

RA- unknown synovial joint antigen - causes joint inflammation and destruction

MS - Myelin basic protein, proteolipid protein - causes brain degeneration, weakness, paralysis

Question 11

CD4 binds to MHC Class?

CD8 binds to MHC Class …?

Answer 11

CD4 = MHC class 2

CD8 = MHC 1

Question 12

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

Answer 12

Human MHC class 2 (HLA)

HLA-DR

Question 13

What is immunological tolerance?

Answer 13

Acquired inability to respond to an antigenic stimulus

3 As -

1. Acquired (involves cells of acquired immune system)
2. Antigen specific
3. Active process in neonates (Effects of which are maintained throughout life)

Question 14

What are the 2 branches of self tolerance

Answer 14

1. Central tolerance (clearance of auto-Ab in lymphoid organs)
2. Peripheral tolerance - anergy, active suppression, immune privilege/ignorance

Question 15

Describe central tolerance - T cells

Answer 15

1. T cell precursors go to thymus during lymphocyte development
2. T cells recognise peptides presented on MHC in the thymus (on thymic epithelial cell or dendritic cell)

T cell that can’t see MHC die by apoptosis (95%) - useless.

T cells that see MHC weakly - receive signal to survive “positive selection” - useful

T cells that see self strongly receive signal to die by apoptosis - “Negative selection” - Dangerous

Question 16

Describe central tolerance - B cells

Answer 16

B cells go to Bone marrow

1. If no self reaction - migrates to periphery and becomes mature B cell
2. If multivalent self molecule reaction - clonal deletion (apoptosis) or generation of non-autoreactive B cell (via receptor editing)
3. If reacts with soluble self molecule - migrates to periphery and becomes anergic B cell (may get deleted later if useless)
4. If low affinity non-crosslinking self molecule - migrates to periphery and becomes mature T cell as clonally ignorant - THESE HAVE POTENTIAL TO CAUSE AUTOIMMUNE DISEASE

Question 17

APECED is an autoimmune disease resulting from a failure to delete T-cells in thymus. How

Answer 17

Caused by mutation in AIRE transcription factor - AIRE needed for expression of tissue-specific genes in the thymus (e.g. insulin) - so that self reactive T cells are negatively selected for.

If no AIRE - no negative selection

Question 18

What are the multiple defects and genetic traits that most autoimmune diseases are associated with (e.g. SLE)

Answer 18

1. Induction of tolerance (B lymphocyte activation)
2. Apoptosis (Fas-ligand)
3. Clearance of antigen (complement)

There are problems with these mechanism often

Question 19

Describe the mechanisms for peripheral tolerance

Answer 19

1. Anergy - naive T cells need costimulation for full activation - absent on most cells of body. No costimulation = no cell proliferation/factor production. Subsequent stimulation leads to refractory state - “anergy”
2. Suppression by regulatory T cells - autoreactive T cells present but don’t respond to auto antigen - controlled by Regulatory T cells
3. Ignorance of antigen - Occurs at immunologically privileged sites (immune cells cannot usually penetrate). Occurs when antigen conc too low in periphery - or when relevant APC is absent (most cells in periphery are not MHC class 2)

Question 20

MHC Class 2 is only on APC. MHC 1 is on most cells. So what T cells cannot be activated by most tissues

Answer 20

CD4

Question 21

Give an example of failure of ignorance

Answer 21

Sympathetic ophthalmia

Question 22

Give an example when a regulatory T cell doesn’t work - so peripheral tolerance (suppression) doesn’t work

Answer 22

IPEX - mutation in FOXP3 gene (encodes TF critical for Treg development)

Causes accumulation of auto reactive T cells

Question 23

Give an example of infections causing disease by “breaking peripheral tolerance”

Answer 23

Streptococci causing rheumatic fever

Question 24

How can infections affect the tolerant state?

Answer 24

1. Molecular mimicry of self molecules
2. Induce changes in expression and recognition of self molecules
3. Induce co-stimulatory molecules or inappropriate Class 2 expression - causing pro-inflammatory environment
4. Failure in regulation - effects on Tregs
5. Immune deviation - shift in type of immune response (e.g. th1 - th2)
6. Tissue damage at immunologically privileged sites