Diseases of the immune system 1 Flashcards
What is autoimmunity?
Dysregulation/balance between tolerance and immunity
Tolerance - only respond to foreign materials not to self antigen
immunity - recognition of foreign antigens
What is central tolerance?
What is peripheral tolerance?
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
How are BCR + TCR so diverse?
Gene recombination
Made of clusters of alpha and beta chains with V/J/D/C regions
How does a mature BCR form?
Pros at the TOP of their game
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
How are B cells rested for auto reactivity before leaving the bone marrow?
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
How do TCR develop ?
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)
How does double negative to double positive occur?
What happens after double positive?
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
`What is the function of the AIRE gene?
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
What are some examples of peripheral tolerance?
Antigen segregation
Activation induced cell death
Peripheral anergy: Lack of co stimulation
Tregs = anti inflammatory + reduce cell activation
What are some examples of peripheral tolerance?
These help to prevent the cells recognising self antigen becoming activated
Antigen segregation
Activation induced cell death
Peripheral anergy: Lack of co stimulation
Tregs = anti inflammatory + reduce cell activation
What is the role of nTREG cells?
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
What is autoimmunity?
Misdirected adaptive immune response to self antigens
Innate responses to self antigens are normal -> e.g clearing defective cells, cancerous cells
How does autoimmunity develop?
Genetic factors ( AIRE/MHC) + environmental factors ( chemical/infection) -> immune regulation -> autoimmunity
How does chronic autoimmunity develop?
- Infection + tissue damage -> inflammation
- further damage as self antigen is unable to be cleared
- Broadening of the immune response
How does the immune system produce antibodies to self antigens?
Exam question - talk about tolerance as well
APC take up self antigen
Presented on MHC molecules, co stimulation + cytokines
Activates T cells
T cells activate B cells to produce antibodies
How does the immune system cause damage?
Cytotoxicity and cell killing
How does the immune system cause damage?
Cytotoxicity and cell killing
antibodies
complement -> fc receptors for phagocytosis
auto antibodies
T h cells activate myeloid cells to cause inflammation + damage
How do we overcome peripheral tolerance?
- 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
Which conditions are associated with each of these genes ? FOXP3 AIRE C1q CTLA4 Fas
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
How is MHC polygenic + polymorphic and what does this mean ?
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.
