diseases of the immune system 1

• what is the function of the AIRE transcriptional regulator

  The autoimmune regulator (AIRE) protein is expressed by medullary thymic stromal cells and is critical for the generation of self-tolerance. This transcription factor regulates expression of tissue-specific antigens (TSAs). Presentation of these TSA to developing T cells constitutes the antigenic mirror of self.
• what is an example of a disease that an AIRE mutation can cause?

  Autoimmune PolyEndocrinopathy Candidiasis   Ectodermal Dystrophy

  The immune system attacks  multiple endocrine tissues: parathyroid glands, adrenal glands, pancreatic insulin-producing cells …
• Central tolerance doesn’t cover every self antigen, so we have peripheral tolerance, outline 5 mechanism of peripheral tolerance

  Ignorance- anatomical barrier or no contact/interaction

  Deletion- cytotoxic mechanism where it kills cells if there are too activated  by Fas:FasL interaction

  Inhibition- by CTLA-4 which is a costimulatory molecule present on T regs that can distract the APC so that it is occupied and cannot interact with dangerous cells

  Suppression- if there is enough TGF-beta and IL-10 the activation of dangerous T cells can be supressed

  
• what causes ALPS disease (hint it is a disrupted mechanism of peripheral tolerance)

  Most cases of ALPS are caused by mutations in the FAS gene. FAS produces a receptor that, when activated, leads to apoptosis. This is an important part of the normal cell lifecycle. When cells do not receive the message that it is time for them to die,

  leads to an excessive number of lymphocytes (lymphoproliferation), leading to enlargement of the lymph nodes (lymphadenopathy) and the spleen (splenomegaly).
• how do natural T regulatory cells prevent autoimmunity?

  1. competition -TCR and CTLA-4 binds to the expressed antigen and inhibits activation by SR Th cell
  2. cytokine secretion - nTreg secrete IL-10 change the phenotype of the self reactive T helper
  3. cell killing - nTregs release perforin and granzyme
  4. IL-2 depletion - has a CD-25 receptor which has a high affinity for IL-2, mops it up and prevents the SR T proliferation
• IPEX is a condition where there there is loss of functional FOX3 -> cannot suppress the immune system properly
• what happens in the disease XLA?

  XLA- tyrosine kinase in gene rearrangement doesn’t do job properly, left with lots of immature B cells without a functional BCR
• what is primary immunodeficincy? an example? how is it tx?

  •Origin: genetic

  •Examples: Severe Combined Immunodeficiency, Agammaglobulinaemia

  •Treatment: severe cases -> bone marrow transplantation
• what is secondary immunodeficiency?

  •Origin: acquired

  •Examples: AIDS, impaired immunity from starvation, immunosuppression by drugs, nutritional deprivation

  •Treatment -> variable, management with anti-microbials / new therapies
• AIDS - a secondary immunodeficiency

  • caused by HIV
  • Receptor is CD4 and CXCR4 and CCR5 are obligatory coreceptors
  • these receptors are on dendritic cells and immune cells
  • spread to lymph node the systemically
  • depletion of CD4 T cells - they are a key controller of the effector arm of the immune system
• symptoms of HIV infection? and when does it become AIDS?

  Low-grade fever, night sweats, excessive fatigue, weight loss, muco. candidiasis

  when the T cell count is under 200 T cells per microlitre
• what happens in chronic granulomatous disease

  normally - immune cells can do intracellular killing and neutrophils can phagocytose microbes

  what's affected - mutation affects the NADPH complex

  so defective killing, poor infection control and chronic inflammation -> formation of granulomas
• what happens in SCID?

  • loss of function mutation in IL2RG
  • IL-2R common gamma chain needed for multiple cytokine receptor signalling
  • on many immune cells
  • also don't respond to IL-7 and IL-15 which are needed in T and NK cell dvelopment
• How is SCID treated?

  •Prophylactic use of anti-microbials

  •If appropriately matched donor can be found, BM transplantation has a very high success rate in children and is in many cases curative

  •Gene therapy now being trialled (stem cells from harvested marrow is transformed by viral vector transfected with missing gene) - transformed stem cells are cyropreseved and the patients BM is depleted -> patient receives cells to repopulated BM and make missing protein (IL-2R)
• how does chronic autoimmune disease perpetuate itself?(IMID)

  here

  
• the pathogenesis of autoimmunity is not fully understood but is thought to be due to a perfect storm, explain what this means(IMID)


  here

  
• list 5 ways that peripheral tolerance mechanisms are overcome(IMID)

  1. cryptic antigens
  2. molecular mimicry
  3. bystander activation
  4. epitope spreading
  5. antigen is also a DAMP
• describe how cryptic antigens allow for the overcoming of peripheral tolerance?(IMID)


  •Some antigens are hidden within cells or are altered in changing environmental conditions (e.g., hypoxia).

  •These appear differently in the bone marrow and thymus and therefore look like non-self in the periphery.

  •These are cryptic antigens.

  •They can activate T and B cells to cause damage and further antigen release.
• how does molecular mimicry overcome peripheral tolerance mechanisms?(IMID)

  •Some pathogen antigens structurally resemble self antigens and may bind BCR/TCR with higher affinity.

  •Infections can activate cross reactive responses to self antigens and initiate autoimmunity.

  •Ankylosing spondylitis. Antibodies against K. pneumoniae antigens can cross-react with HLA-B27.

  •Guillain-Barré syndrome. Antibodies against C. jejuni antigens can cross-react with gangliosides.
• how does bystander activation overcome peripheral tolerance? (IMID)

  •T and B cells with low affinity for self-antigen escape selection and go to the periphery.

  •Antigen alone cannot activate these cells.

  •Inflammation/ infection causes co-stimulatory molecules to be expressed by antigen presenting cells (APC).

  •These APC overcome T cell anergy. The T cells become activated and attack self.
• how does the antigen acting as a DAMP overcome peripheral tolerance mechanisms?(IMID)

  •Some autoantigens are also DAMPs (Toll-Like Receptor ligands) – such as unmethylated CpG nucleic acid.

  •Host unmethylated CpG usually only becomes available during cell death (apoptotic chromatin).

  •If the unmethylated CpG is not cleared quickly, a self-reactive B cell could receive signals through the TLR and BCR - and become activated.

  •Overcoming of the need for T cell help produces lots on antibody like IgM WHICHH DESPITE THE FACT IT IS NOT CLASS SWTCHED IT IS VERY DESTRUCTIVE
• how does epitope spreading allow for peripheral tolerance mechanisms to be overcome?(IMID)

  Epitope spreading refers to the phenomenon where an immune response initially directed against a specific epitope on an antigen gradually targets additional epitopes on the same antigen (intramolecular spreading) or on different antigens (intermolecular spreading). This process is often seen in chronic autoimmune diseases and can contribute to the progression and diversification of the immune response.

  leads to activation of more T and B cells of different specificities – the immune response spreads
• what is the immune system doing in response to cells overcoming immune tolerance?(IMID)

  here

  
• how does the immune system cause damage? (IMD)

  here

  
• Tocilizumab is a target for autoimmunity therapy, what does it do?(IMID)

  •IL-17 promotes the release of more pro-inflammatory mediators and MMPs. Disruption of this is a target for treatment of inflammatory diseases

  •Tocilizumab is a humanized anti-IL-6 receptor antibody which disrupts the pro-inflammatory actions of IL-6 (which include promoting differentiation of Th17 cells)
• what is the difference between autoimmunity/immune mediated inflammatory disease and immunodeficiency?(imid)

  immunodeficiency - mutation causing immune related loss of function, cannot fight disease

  IMID - if the mutation is in a regulatory gene, immunodeficiency can cause IMID/autoimmunity
• genes affecting ... increase susceptibility to autoimmunity(IMID)

  • disrupt tolerance
  • disrupt apoptosis
  • promote inflammation
  • promote cell activation
• what is meant by an autoimmunity being monogenic? (IMID)

  A predominant genetic risk with minor additional genetic and environmental factors (e.g., APECED and IPEX)
• what is meant by an autoimmunity being complex? (IMID)

  Complex - Multiple genetic and environmental factors (e.g., MS and RA)
• which disease is AIRE associated with and what is the mechanism of immunity? (IMID)

  AIRE is associated with APECED -> causes decreased expression of self antigens in  the thymus, resulting in defective negative  selection of self reactive T cells
• which disease is CTLA4 associated with and what is the mechanism of immunity? (IMID)

  CTLA4 is associated with Grave's, T1DM -> causes failure of T-cell anergy, reduced  activation threshold of self-reactive T cells, reduced Treg function
• which disease is FOXP3 associated with and what is the mechanism of immunity? (IMID)

  FOXP3 -> immune dysregulation, IPEX syndrome -> causes decreased Treg function
• which disease is FAS associated with and what is the mechanism of immunity? (IMID)

  FAS -> autoimmune lymphoproliferative syndrome -> Failure of apoptotic death of self-reactive B and T cells
• which disease is C1q associated with and what is the mechanism of immunity? (IMID)

  C1q -> SLE -> defective clearance of immune complexes by apoptotic cells
• the MHC/HLA genes are polygenic and polymorphic, what does this mean?(IMID)

  polygenic - the gene locus contains several different MHC class I and II genes, so an individual expresses several kinds of MHC class I and II molecules on their cells, with different peptide binding specificities.

  polymorphic – there are multiple alleles of each  gene within the population. Some genes have hundreds of variants.
• examples of where risk alleles can act (IMID)


  here

  
• apart from environment factors being linked to autoimmunity, viruses are also linked to autoimmunity, which autoimmunities is EBV linked to?(IMID)

  • Myasthenia Gravis
  • Multiple Sclerosis
• what property of HLA molecules affect antigen recognition by T cells? (IMID)

  polymorphism

  • change peptide:HLA binding
  • change interaction between the TCR and HLA+peptide
• which gender is more likely to experience autoimmunity and why? (IMID)

  females -> hormonal input, estrogen can enhance B cell responses and at a high concentration can inhibit inflammation by downregulating cytokines