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.
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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
Describe how a double negative thymocyte develops into a double positive thymocytes?
- Double negative CD3-4-8-
- Begins to rearrange beta chain D-J segments
- Continues rearranging beta chain V-DJ segments. Should create a successful Beta chain, express a surrogate alpha chain. If beta chain not functional undergoes apoptosis
- Temporarily stops rearrangement and proliferates
- Functional B chain allows expression of CD4 and CD8, so now double positive, Alpha chain rearrangement starts and continues until a functioning receptor produced or undergoes apoptosis.
What are the gene segments in a TCR gene?
Alpha chain - V segment, J segment and C segment
Beta chain - V segment, J segment, D segment and C segment
What order to gene segments in a TCR/BCR chain recombine?
D-J recombination (if D segment present)
V-(D)J recombination
V(D)J-C recombination
What is APECED?
Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy
Can be caused by many mutations in AIRE gene, self antigen recognising T cells are able to mature, results in immune system attacking multiple endocrine tissues.
What is the benefit of the thymus being capsulated in regards to T cell development?
Capsulated - prevents pathogen/pathogen antigens from entering the thymus, ensures pathogen detecting T cells are not lost during maturation by negative selection.
What can be beneficial of an nTreg TCR recognises the same epitope as a dangerous T helper that escaped central tolerance?
Recongise same epitope
Should be activated in some location in periphery
nTreg CD25 sequester IL-2, reducing stimulatory signals to dangerous T helper cell, help prevent damage
This is a form of peripheral tolerance
What are the mechanisms of peripheral tolerance?
Anergy
Ignorance
Deletion
Inhibition
Supression
What is anergy as a mechanism of peripheral tolerance?
Anergy -. no co-stimulation from APC so no response from naive cell, Is hyporesponsive
What is ignorance as a mechanism of peripheral tolerance?
Anatomical barrier between self reacting T cell and antigen
What is deletion as a mechanism of peripheral tolerance?
Self recognising T cell recieves all three activation signals.
However FasR on T cell is activated by FasL on APC triggers apoptosis of T cell before fully activated.
What is suppression as a mechanism of peripheral tolerance?
Self recognising T cell recieves all three activation signals,
However action of iTreg/nTreg suppresses activity, by sequestering IL-2 (due to CD25 receptor) and secreting anti-inflammatory IL-10 and TGF-beta which recruits more T reg.
What is ALPS?
Autoimmune LymphoProlifertive Syndrome
Range of genetic mutations that result in inability of lymphocytes to undergone apoptosis, mutation is typically in FasR gene, but may be other molecules involved in apoptosis pathway.
Results in increases autoimmune lymphocytes, increase in double negative lymphocytes, lymphocytes with faulty receptors and increased lymphocyte proliferation (cancer, splenomegaly, lymph node megaly).
What transcription factor is common in Treg cells?
FoxP3
What mechanisms may Treg cells use to provide peripheral tolerance?
Competition - compete for co-stimulatory molecule B7 (binds to T reg co receptor CTLA4) and MHC molecule
Cytokine secretion - secretes IL-10 and TGFbeta to alter phenotype of activated T helper
Cell killing - can release perofin and granzyme
IL-2 depletion - Cd25 has high affinity for IL-2, deprives SR T cell from proliferation signals
What is IPEX?
Immunodysregulation Polyendocrinopathy Enteropathy X-lined
Mutation is FOX-P3 gene, unable to develop regulatory T cells, results in large amounts of proliferating Autoimmune lymphocytes, struggle to turn off adaptive immune response and inflammation
What are some of the role fo inducible T reg in regard to tolerance?
Several subsets of iTreg
Suppress effector responses to not harmful foreign antigens and suppress autoimmunity
May migrate through circulation and spleen - to be recruited to site of inflammation
May reside naturally in tissue, promote tolerant environment by receiving signals that indicate no pathogen
Secrete IL-10 and TGF-b
Describe the process of B cell development.
Common Lymphoid Progenitor remains in bone marrow
Early Pro-B cell undergoes heavy chain D-J rearrangement
Late Pro-B cell undergoes heavy chain V-DJ rearrangement
Large pre-B cell expresses functional heavy chain with a surrogate light chain (pre B cell receptor)
Functional heavy chain triggers rearrangement of V-J in light chain (now small pre-B cell)
Light chain continues rearrangements until functional
Rearrangment finished, immature B cell expresses functional variable regions on an IgM constant region on surface
Becomes a mature B cell as immunoglobulin genes changed to allow expression of IgD.
What are the different cell names in the stages of B cell development?
Early Pro-B cell
Late Pro-B cell
Large pre-B cell
Small pre-B cell
Immature B cell
Mature naive B cell
What is X-linked agammaglobulinaemia?
Mutation in Bruton Tyrosine Kinase - prevents pre-B cell from giving signal to rearrange light chain so mature B cells do not develop
Form of primary autoimmunodeficiency
Describe how B cells are tested for autoreceptivity before leaving the bone marrow?
Encounter self antigens whilst maturing
If no self reaction - migrates to periphery
Binds to multivalent self molecule - (one molecule two epitopes) - apoptosis or receptor editing so no longer reacive before release
Binds to soluble self molecule - typically anergic, migrate to and die quickly in periphery
Binds to self antigen but with low affinity and no cross linking - migrates to periphery but doesn’t react with antigen in normal conditions.
What is the origin and treatment of a primary immunodeficiency?
Genetic cause
Severe cases can only be cured by a bone marrow transplant
What is the origin and treatment of a secondary immunodeficiency?
Are acquired, e.g infection, malnutrition or medication
Variable management including anti-microbials and new therapies
How does HIV/AIDs cause a secondary immunodeficiency?
HIV attachment proteins bind to CD4 found on T helper, NK cells and dendtritic cells.
Also requires binding to CXCR4 or CCR5 co-receptors
Initially infects cells at mucosa then travels to lymph nodes
CD4 cells rapidly deplete causing immunodeficiency as persistent infection
How might the number of CD4+ cells change over the course of a HIV/Aids infection?
After infection intitial rapid depletion as infected CD4+ cells killed by CD8+ or by viral burst out of cell
Numbers recover slightly as infection becomes latent.
Gradually decrease as virus start to replicate again, die faster than can be replenished
Eventually develop prodromal symptoms then AIDs and CD4+ cells reduce enough
What are symptoms of HIV?AIDS?
Initial flu like symptoms as rapid decrease in Cd4
promodoral symptoms (Symptoms that are a precurosor to a disease) at around 2-3 years include loe grade fever, night sweats, excessive fatigue and weight loss
AIDs - serious opportunistic infections and cancers (kaposi sarcoma)
How can clearance of HIV be achieved?
Require HAART treatment immediatly - aims to inhibit viral replication before it enters latent period.
Case study man received stem cell treatment, donor CD4+ cells had mutation in CCR5 gene so could no longer be infected by HIV.
What are some minor examples of innate primary immunodeficiencies?
Mutated -
MyD88 - failed TLr signalling - vulnerable to pyogenic bacterial infections
C5-C9 - failed complement - recurrent Neisseria meningitidis
CYBB - unable to produce ROS in phagosome membrane so no ROS-mediated killing - recurrent bacterial and fungal infections
What are some minor examples of adaptive primary immunodeficiencies?
Mutated
STAT3 - defective cytokine signalling - resulting in recurrent skin and respiratory tract infections
What is X-linked SCID?
Caused by loss of function mutation in IL2RG on x-chromosome. So are unable to produce the common gamma chain.
This gene would be used in creating functional receptors for many cytokines, expressed on many immune cells.
Inhibits activation of immune cells, particularly interferes with IL-7 and IL-15 signalling in T and NK cell development
What are some therapies for SCID?
Prophylactic antimicrobials
Bone marrow transplants can be curative in children
Gene therapy is being trialed
Drug therapy - to replace missing enzymes or missing functions
Cell therapy - transplant of missing cells often HSC
Describe the process of gene therapy for SCID?
Patients bone marrow harvested
patient stem cells are extracted from marrow
Missing gene is transferred into a viral vector
Virus introduced to cells to transform stem cells to express gene
Stem cells are cryopreserved until needed
Patient bone marrow depleted to make room for new cells which then repopulate the patient bone marrow.
What is chronic granulomatous disease (CGD)?
X-linked Mutated NADPH oxidase complex in phagosomal membrane, unable to produce cytosolic reactive oxygen species.
Macrophages are ineffective at killing pathogen
Resulting in chronic inflammation due to persistent infection
Results in granuloma formation
What is the link between TYK2 and COVID-19?
TYK2 is a gene involved in the production of type 1 interferons in macrophages
Mutations in this allele - gain or loss of function - can affect suspecitbility to myobacterial and viral infections such as SARS-COV2
What is the structure of a TCR gene?
Alpha chain - V segment, J segment and a C segment
Beta chain - V segment, D segment, J segment and a C segment
Describe the link between primary immunodeficiencies and an autoimmune condition?
Primary immunodeficiency - mutation in gene, loss of function of a regulatory part of the immune system, e.g loss of FOXP3 unable to produce Treg cells is an deficiency
However, this deficiency can result in autoimmunity.
