Disease of the immune system - 1 Tolerance + Immunodeficiency Flashcards
What are the 3 aims to inflammation?
- Localise and eliminate the causative agent
- Limit tissue injury
- Repair tissue
What is central tolerance?
- During development of lymphocytes we have mechanisms to prevent the generation of cells which may recognise self antigens.
Here’s how central tolerance works for each type of immune cell:
- TCells: In thymus > Education + selection T cells that recognize and bind too strongly to the body’s own antigens (self-antigens) are typically eliminated through a process called negative selection.
- BCells: In bone marrow > Production of selection of B cells B cells that produce antibodies that react strongly against self-antigens are usually eliminated or rendered non-functional.
What is VDJ rearrangement?
- Variability - Diversity - Joining > to generate massive diverse set of receptors that are unique
- We inherit multiple VDJ segments
- VDJ segments randomly combine
- Random reassortment of 2 different chains further increases diversity
What is peripheral tolerance?
- Peripheral tolerance mechanisms come into play in the peripheral tissues once mature immune cells have entered circulation.
- Peripheral tolerance mechanisms serve as a backup system to catch any autoreactive immune cells that may have escaped central tolerance and prevent them from causing autoimmune reactions.
Central tolerance:
Describe the stages for the development of functional B cells RECEPTOR
- B cells develop from hematopoietic stem cells in the bone marrow. (Common lymphoid progenitor)
- Heavy chain rearrangement Pre-B cell receptor expressed due to VDJ rearrangement
- Rearrangement of functional heavy chain initiates V-J light chain gene rearrangement
- Light chain gene rearranges until functioning receptor formed
- Light chain arrangement finished = IgM receptor expressed on surface = Immature b cell
- Mature B cell immunoglobulin genes rearrange and B cell produce IgD antibodies
B cells are tested for auto reactivity before leaving the bone marrow.
What happens when there is:
1- No self reaction
2- What happens when the receptor recognises a MULTIVALENT self molecule?
3- What happens when the receptor recognises SOLUBLE self molecules?
4- What happens when there is low affinity no cross linking?
Central tolerance:
Briefly describe T cell receptor development.
- Tcells Start development in bone marrow
- Migrate to thymus where we get T cell precursors thymocytes they undergo proliferation
- Thymocytes initially express neither CD4 nor CD8 co-receptors on their cell surface. They are considered “double-negative
> Some thymocytes are exported to periphery some undergo the following processes: - Beta (β) Selection and TCR β Chain Rearrangement
= double positive thymocytes - Alpha (α) Selection and TCRα Chain Rearrangement
= single positive thymocytes - Positive selection
= CD4+ / CD8+ thymocytes respectively single positive TCell - Negative selection
- Migration to Peripheral Lymphoid Organs
Describe how double-negative CD4-CD8- thymocytes become double positive.
- Double negative thymocytes undergo TCR β Chain Rearrangement
- Sart to rearrange β chain D-J
- Continue to rearrange chain V-DJ
- Express pre-TCR with surrogate α chain
- If a functional TCRβ chain is produced
- pre-TCR signals to the thymocyte, a process known as beta (β) selection
- Stops rearrangement and leads to the survival and proliferation of thymocytes
How do double positive thymocytes become single positive thymocytes?
- Double positive thymocytes undergo TCRα Chain Rearrangement
- Continued rearrangements until a functional TCRα chain is produced and successfully paired with the beta (β) chain
- The resulting TCR complexes signal alpha (α) selection.
- Successful alpha selection results in the survival of thymocytes and their differentiation into single-positive CD4+ or CD8+ T cells.
> Life span of 3-4 days either selected or apoptosed
Describe the process of positive selection.
- If the TCR can recognise self MHC presented by thymic epithelial cells
- Thymocytes with TCRs that interact with MHC molecules undergo positive selection and differentiate into CD4+ or CD8+ single-positive T cells depending on their affinity for MHC class II or MHC class I, respectively.
- If they don’t recognise Self MHC they undergo apoptosis
Describe the process of negative selection.
- Thymocytes also undergo negative selection, where those with TCRs with strong affinity for self-antigens presented by MHC molecules are eliminated to prevent the development of self-reactive T cells.
Why are not ALL self reactive T cells removed?
- Severly limit out recognition repertoire. Only strong reactive are removed… peripheral mechanism are in place to help prevent activation.
How do we teach T cells about all antigens in the body?
- Autoimmune regulator (AIRE)
> transcriptional regulator which induces the expression of self proteins in the thymus
1- Where is the AIRE gene expressed?
2- What happens when there are defects in the AIRE gene?
1- Expressed in the nucleus of the medullary stromal cells a subset of the thymic cortical epithelium.
2- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, where the immune system attacks multiple endocrine tissues including pancreatic insulin producing cells
What mechanisms are implemented to ensure tolerance, even if AIRE is lost? (Peripheral tolerance) (4).
Peripheral anergy note Co stimulatory molecules are activated by TLRs, which can only be activated if pathogens are present
How are natural T regulatory cells made? What is their function?
-
TCRs of CD4+ have low affinity to self peptides
> Act to prevent an immune response to self antigens interfere with activation of self reactive T cel via dendritic cell.
What mechanisms are in place to prevent an APC, presenting a self antigen and co-stimulatory molecules, activating a self reactive T cell? (4)
How Treg cells induced in the absence of pathogens and IL6?
- TGFß is produced by tissues. Antigens which are presented by dendritic cells favour the differentiation of T cells into Tregs, which then go onto produce more TGFß and IL10 (regulate aberrant self reactivity)
How are iTregs induced in the gut?
- CD103+ dendritic cells in the gut produce TGFß and retinoic acid to promote FoxP3 expression, which means that iTregs are present in large numbers to control the number of effector T cells in the gut
Graphs shows phases during a normal immune response:
- What happens when this graph is for autoimmune conditions?
- Relate this to treatments too.
- Because in autoimmune conditions, there are no pathogens, so self molecules still remain high so the graph gets halted with high levels of Th17 levels present.
- Chronic inflammation and tissue damage continuously promotes expansion of Th17, which releases IL17
- IL17 promotes release of more pro-inflammatory mediators and MMPs
> Treatments: Anti IL-6 receptor antibody to disrupt Th17 cells
What is immunosuppression?
How can our immune system be supressed by pathogens:
- Herpes simplex
- TB, Epstein-Barr
- Influenza, S.pneumonia, Trypanosomes
- Herpes simples, Varicella Zooster
- Epstein- Barr, Virus
- The reduced activity/efficacy of the immune response
1- What is immunodeficiency?
2- What are the two types of immunodeficiency?
3- Why can you still be healthy even if there are hereditary deficiencies?
1- The failure of the immune response, due to an absence or insufficiency of some component process or substance
3- Multiple protective immune mechanisms that compensate for deficiencies in one component
What is Severe Combined ImmunoDeficiency (SCID)?
- Defects in T cell development due to gene loss, and cannot make T cell dependant antibody responses.
- Absence or severe impairment of both T cells and B cells
*dont need to know these processes. Just understand where gene loss can occur, and the effect it will have on the B/T cells
What 3 approaches are their for treating SCID?
- Prophylactic treatment – Sterile environment, antibiotics, immunoglobulins.
- Bone Marrow Transplant – Relies on close HLA match and successful reconstitution
> HLA complex: (helps the immune system distinguish the body’s own proteins from proteins made by foreign invaders such as viruses and bacteria) - Gene therapy – First trial in 1990s with adenosine deaminase (ADA) SCID replaced the gene in peripheral T cells which survived for a decade
How does gene therapy for SCID work?
- Avoids issue with needing a HLA gene match as you’re using patient’s own bone marrow
1- What causes AIDS?
2- What is the problem with HIV? Describe the mechanism.
1- HIV
2- Usually viruses produce an acute infection, which induces lasting protection or are latent but chronically controlled…. but HIV rarely leads to an immune response
> HIV targets cells which express CD4 and uses CCR5 or CXCR4 as a co-receptor. Infects mucosal CD4+ cells and spreads in lymph nodes as T cells enriched with CCR5
What 3 phases occur when infected with HIV?
What happened to Berlin Timothy Ray Brown in 2007?
- His leukaemia treatment had resulted in HIV being removed from his body due to a mutation (CCR5- delta 32) from his donor in the CCR5 receptor
1- What are chimeric antigen receptor T cells?
2- How do they work in HIV treatment?
3- What are the benefits?
1- Genetically engineered T cells express a receptor which recognise a disease specific epitope and induces an MHC independent cytotoxic T cell response.
3-
- Remain active for 6 months
- Independent of MHC I which HIV suppresses
- Can access the CNS
1- What is CRISPR/Cas9?
2- How does CRISPR/Cas9 work to treat HIV?
1-
- Uses RNA molecules which bind to and target an endonuclease To cause Double stranded DNA breaks in the genome
2- These can be designed to recognise HIV sequences in the genome and excise them.
