Autoimmunity Flashcards
Define what autoimmunity is
- This is the presence of immune responses (autoreactive T & B-cells) of an organism against self-tissue/cells
- Resulting in significant tissue/organ damage &/or chronic inflammation
Describe the pathogenesis of autoimmune diseases
Autoimmunity diseases develop when self-reactive lymphocytes escape from these tolerance mechanisms and become activated
Autoreactive T cells and B cells are generated normally in primary lymphoid tissues during lymphopoiesis but are normally killed or inactivated by protective (tolerance) mechanisms, what are these mechanisms ?
- Deletion of self-reactive lymphocytes in primary lymphoid tissues (central tolerance) where they are made
- Inactivation of self-reactive lymphocytes in peripheral tissues that escape central tolerance (peripheral tolerance) e.g. Regulatory T cells (TREG cells)
Define what is meant by self-tolerance
Self-Tolerance = non-responsiveness of lymphocytes to specific self-antigens
What is the funtion of regulatory T-cells ?
- Regulatory T Cells make up 5-10% of the normal CD4+ T cell population
- They function to suppress hyper-reactive or auto-reactive T cells (inactivation of lymphocytes –Via production of anti-inflammatory cytokines
Describe the genetic influences in autoimmune disease development
Autoimmune disorders may result from:
- Single gene defects causing autoimmune diseases are rare such as IPEX syndrome
- Most autoimmune diseases result from complex genetic interplay involving HLA genes, Genes determining sex & Other immune response genes
Describe what IPEX syndrome is and its inheritance
- It is a rare X-linked autoimmune disorder which results from mutation in the FOXP3 gene, which is essential for the normal development of regulatory T-cells.
- Hence, IPEX is a failure of peripheral tolerance mechanisms due to defective/absent regulatory T cells (Tregs)
Who is only affected by IPEX syndrome and why?
Males - due to being X-linked
What are the clinical features of IPEX syndrome ?
Presents early in childhood with:
- Severe infections
- Intractable diarrhoea
- Eczema
- Very early onset insulin dependent diabetes mellitus
- Autoimmune manifestations
What is the treatment of IPEX syndrome ?
- Cure: hematopoietic stem cell transplantation (HSCT)
- Supportive care: immunosuppressive drugs + total parental nutrition
What are Major Histocompatibility (MHC) molecules/ HLA (Human Leucocyte Antigen) molecules and what are they needed for ?
- MHC molecules in humans are also referred to as HLA (Human Leucocyte Antigen) molecules
- T-cells require protein antigens to be processed and presented to their T-cell antigen receptor (TCR) in complex with Major Histocompatibility Complex (MHC) molecules
What are the different types of HLA/MHC molecules and which cells express them?
There are class I & class II molecules:
- All nucleated cells express several types of Class I molecules on their cell surface - HLA-A, HLA-B and HLA-C
- Specialised antigen-presenting cells also express additional Class II molecules - HLA-DR, HLA-DQ and HLA-DP
HLA/MHC class I and II molecules are encoded by what?
HLA (MHC) class I and II genes, each of which is highly polymorphic
Why are HLA/MHC genes & in turn molecules highly pleomorphic ?
To maximise the net ability to bind all antigenic peptides through having:
- Multiple different subtypes of HLA molecules
- Individual HLA molecules exhibit significant allelic diversity
List some of the risk factors for the development of autoimmune disorders
- Women of childbearing age
- People with a family history
- People who are around certain things in the environment - infection, smoking, hormone levels
- People of certain races or ethnic backgroundse.g. T1DM is more common in white people. Lupus is most severe for African-American and Hispanic people.
- Antigen sequestration - tissues which do not communicate with blood or lymph (testis, eye, brain). Self-antigens normally sequestered from the immune system can become exposed and cause an autoimmune reaction during infections/trauma
How are autoimmune diseases classified ?
- Organ-specific diseases
- Non-organ specific or multisystem autoimmune diseases
