Week 1: Diseases of the Immune System 1 Flashcards
What is the difference between ignorance and tolerance, in regards to the immune system?
Ignorance - T cell exists but fails to mount an ammune response against self antigen, either it never comes into contact with antigen, or cell signalling fails to trigger response
Tolerance - self targeting lymphocytes are destroyed at site of development (negative selection)by central tolerance or in peripheral tolerance, prevents an immune response even when a self reacting T cell comes into contact with an antigen.
What is the key idea of immunodeficiency?
Poor or no response to pathogens
What is the key idea of hypersensitivity and allergy?
Inappropraite response to harmless foreign antigens
What is the key idea of autoimmunity?
Innapropriate response to self - normally due to a breach in tolerance
What is an immune privledged site?
Anatomical regions that are less subject to an immune response, contain less immune system cells/tissues, for example the meninges.
Describe the structure of a TCR
TCR are heterodimeric membrane receptors
95% consist of an alpha and a beta chain
5% consist of a gamma and a delta chain γδ
The two chains both contain a variable (specific for binding to epitope) and a constant segment.
Describe the structure of a BCR
BCR consists of two heavy chains and two light chains
The two heavy chains are linked by disulfide bonds, 1 heavy chain is also linked to one light chain by a disulfide bond.
Each light and heavy chain consists of a variable region (infinite possibility) and a constant region (five isotypes)
Total of two binding sites for antigens.
Describe the structure of a BCR gene.
Somatic recombination occurs in the variable regions encoding DNA for the heavy and light chain
Heavy VDJC
Light VJC
What is the process of somatic recombination in order to make a functional BCR/TCR gene?
Recombination starts by an enzyme complex including proteins coded for by RAG-1 and RAG-2 genes binding to RSS (recombination signal sequence) neighbouring the functional gene segment (V D J C) (chosen gene segment selected at random).
RAG enzymes act as a paired complex to cleave the DNA and bring the gene segments together.
More enzymes aid the formation of a signal joint from the cleaved signal complex, signal joint is lost and no longer has a role. Alternatively, the region may be retained but inverted.
Additional nucleotides may be added by terminal deoxynuclotidyl transferase enzymes or removed by endonuclease enzymes.
The two DNA segments to be joined are joined together by another enzyme complex.
This creates different combination of gene segments, in the variable region encoding DNA. The final outcome is a gene that can be expressed.
What order does somatic recombination occur in BCR genes?
Heavy chain - D-J recombination first, then V-DJ recombination, then VDJ-D recombination last.
Light chain - V-J recombination first, followed by VJ-C recombination
Only one of each segment is present in the final functional gene
What is the basic process of somatic recombination?
Enzymes (coded for by RAG-1 and RAG-2 genes) act on particular gene segments of DNA involved in coding for the variable region of a BCR and TCR.
To cut up DNA and join back together to create different combinations of gene segments.
The final functional gene can be expressed, creates wide diversity in resulting variable regions.
What is Severe Combined Immunodeficiency?
SCID - range of different genetic disorders, that affect the development/functioning of T-cells, and sometimes B cells/NK cells.
https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702078446000180#hl0000418
What is the link between somatic recombination and SCID?
Mutation in RAG-1 or RAG-2 gene, unable to undergo somatic recombination, so can not produce and TCR or BCR, hence have no mature T or B cells.
What are the two types of tolerance and what is their purpose?
Central tolerance
Peripheral tolerance
- to detect and prevent unwanted self antigen detecting T cell/B cells from triggering an immune response
What is central tolerance?
Occurs in the bone marrow (B cells) and thymus (T cells)
Tests antigen receptors to identify self recognising TCR, determines cell fate appropriatly
What is peripheral tolerance?
Occurs in the periphery
Acts as aback up method to central tolerance, to prevent any unwanted immune reactions by self recognising T cells.
Methods include T reg cells among others
Explain how T cells develop in the thymus from stem cells to double positive thymocytes?
Common Lymphoid Progenitors produced in the bone marrow migrate to the thymus, hence called thymocytes (check this).
THymocytes then become double negative thymocytes (CD3-4-8-)
Some thymocytes will develop a gamma delta+ CD3+ TCR ( CD4- CD8-) and are exported to periphery mainly epithelial sites (function unknown)
Remaining thymocytes become double positive thymocytes
alpha beta + CD3+ CD8+ CD4+, then enter a process to determine their identity.
What processes does a double positive thymocyte undergoes to determine its fate as a nTreg, cytotoxic or T helper cell?
Positive selection
negative selection
What (where) is the process of positive selection in T cell development?
Positive selection occurs in corticalal epithelial cells in thymus, thymocytes able to recognise self MHC and peptide survive, those unable to undergo apoptosis.
Those with a preference for MHC2 become CD4+, become CD8-.
THose with a preference for MHC1 become CD8+, become CD4-
What and where is the process of negative selection in T cell development?
Occurs in thymus medullar
Same process for CD4+ and CD8+
Determins if the TCR binds with strong affinity to self peptide?
If yes undergoes apoptosis
If no is released into periphery
Some CD4+ that bind with low affinity to self peptide can become Natural T reg, becomes CD25+
What is the function of CD25 for Treg cells?
Sequester IL-2 reduce availability for other effector cells, deprives other pehontypes of T helper from stimulatory signals.
What is the funcrion of AIRE gene in T cell development?
AutoImmune REgulator gene codes for autoimmune regulator protein
Role in negative selection in T cell development
Allows expression of self-proteins in the thymic medullary stomal cells.
Hence allows testing of developing T cells to identify self peptide recongising T cells