Diseases of the immune system 1

Question 1

What is autoimmunity?

Answer 1

Dysregulation/balance between tolerance and immunity
Tolerance - only respond to foreign materials not to self antigen
immunity - recognition of foreign antigens

Question 2

What is central tolerance?

What is peripheral tolerance?

Answer 2

Mechanisms that stop the production of self reactive lymphocytes in the lymph node capable of recognising self antigens
Some cells can escape central tolerance and migrate to the periphery, peripheral tolerance stops these cells becoming activated

Question 3

How are BCR + TCR so diverse?

Answer 3

Gene recombination

Made of clusters of alpha and beta chains with V/J/D/C regions

Question 4

How does a mature BCR form?

Pros at the TOP of their game

Answer 4

Common lymphoid progenitor

Early pro B cell : Heavy chain arrangement from D -> J

Late pro B cell : Heavy chain rearrangement from V-> DJ

Large pre B cell: VDJ is rearranged and a pre BCR is expressed

Small pre B cell: VJ Light chain rearrangement occurs successively until a functional light chain with high affinity is produced

Immature B cell: IgM expressed and cells exported to periphery

Mature B cell : IgG rearrangement so the cell expressed IgD

Question 5

How are B cells rested for auto reactivity before leaving the bone marrow?

Answer 5

B cells that don’t recognise foreign antigen are transported to the periphery expressing IgD

B cells that recognise multi valent self molecules undergo gene deletion or receptor editing

B cells that can recognise soluble self molecule become anergic in the periphery

Question 6

How do TCR develop ?

Answer 6

CLP
Thymocytes divide in the thymus

Double negative thymocyte: Lack CD3, CD4 + CD8. Some of these are transported to the gut, epithelium + lymphoid organs and express a gamma receptor.

Double negative thymocyte -> double positive thymocyte
- Express CD3, CD4 + CD8
- Become either CD4 ( MHCII)
or CD8 ( MHCI)

Question 7

How does double negative to double positive occur?

What happens after double positive?

Answer 7

Double negative 1 :
Double negative 2: Rearrangement of b chain
Double negative 3: pre TCR express a surrogate alpha chain if cell cannot make a b chain then the cell dies
Double negative 4: rearrangement stops + proliferation/selection starts

1: Positive selection -> CD4/CD8

2: Negative selection : Does cell recognise self antigen with high affinity?
CD8:
Yes - apoptosis
No - periphery

CD4:
Yes - apoptosis
No - periphery to become th1/th2/th17
Yes but low affinity -> nTreg

Question 8

`What is the function of the AIRE gene?

Answer 8

Present in thymic medullary cells surrounding T cells
Transcriptional regulator that opens up entire genome for transcription + translation

Self peptides presented on MHC
Strong interaction with T cell -> T cell death

Question 9

What are some examples of peripheral tolerance?

Answer 9

Antigen segregation
Activation induced cell death
Peripheral anergy: Lack of co stimulation
Tregs = anti inflammatory + reduce cell activation

Question 10

What are some examples of peripheral tolerance?

These help to prevent the cells recognising self antigen becoming activated

Answer 10

Antigen segregation
Activation induced cell death
Peripheral anergy: Lack of co stimulation
Tregs = anti inflammatory + reduce cell activation

Question 11

What is the role of nTREG cells?

Answer 11

Prevent activation of cells that recognise self antigen
Express FOXP3 encoding for IL-10
Has CD25 binds to IL-2 to prevent proliferation of SR T cells

Question 12

What is autoimmunity?

Answer 12

Misdirected adaptive immune response to self antigens

Innate responses to self antigens are normal -> e.g clearing defective cells, cancerous cells

Question 13

How does autoimmunity develop?

Answer 13

Genetic factors ( AIRE/MHC) + environmental factors ( chemical/infection) -> immune regulation -> autoimmunity

Question 14

How does chronic autoimmunity develop?

Answer 14

• Infection + tissue damage -> inflammation
• further damage as self antigen is unable to be cleared
• Broadening of the immune response

Question 15

How does the immune system produce antibodies to self antigens?
Exam question - talk about tolerance as well

Answer 15

APC take up self antigen
Presented on MHC molecules, co stimulation + cytokines
Activates T cells
T cells activate B cells to produce antibodies

Question 16

How does the immune system cause damage?

Answer 16

Cytotoxicity and cell killing

Question 17

How does the immune system cause damage?

Answer 17

Cytotoxicity and cell killing
antibodies
complement -> fc receptors for phagocytosis
auto antibodies
T h cells activate myeloid cells to cause inflammation + damage

Question 18

How do we overcome peripheral tolerance?

Answer 18

• Some T/B cells with a low affinity for self antigen escape negative selection + enter periphery. Inflammation associated with infection can overcome anergy
• Cryptic antigens : Antigens normally hidden from immune system
• Molecular mimicry : Some self antigens resemble similar structure to pathogen antigens. So are not destroyed by immune system. E.g Klebsiella + HLA-B27 autoantibodies
• Epitope spreading : epitope presented on MHC + self reactive WBC respond -> tissue damage and further epitope presentation
• Auto antigens that bind to TLR 9 -> auto antibodies

Question 19

Which conditions are associated with each of these genes ?
FOXP3
AIRE 
C1q
CTLA4
Fas

Answer 19

FOXP3 -> IPEX : defective Treg function
C1q-> lupus : defective clearance of immune complexes
AIRE -> APECED: Decreased recognition + death of cells that recognise self antigen
CTLA4-> Graves + T1D : SR t cell more easily activated
Fas -> Autoimmune lymphoproliferative syndrome -> failure to destroy SR T/B cells

Question 20

How is MHC polygenic + polymorphic and what does this mean ?

Answer 20

polygenic - multiple copies of different MHCI/MHCII genes
polymorphic - multiple alleles of each of these genes

It affects binding strength between TCR + antigen, affinity and antigen recognition by T cell so dif molecules bind.