How does central tolerance work for T cells? What is AIRE?
When immature developing lymphocytes (T cell and B cells) encounter self-antigens in generative organs (thymus or bone marrow)
1) die,
2) change receptors, or
3) become Regulatory T cells (Tregs).
If weak signal is received through the receptor, the cells are allowed to mature.
Not all tissue specific self antigens are found in the thymus or BM, but AIRE (AutoImmune Regulator) is a transcription factor that causes tissue specific antigens to be expressed in the thymus.
What is peripheral tolerance for T cells? What 3 things can happen when mature lymphocytes are allowed into the periphery?
Mature lymphocytes in the periphery that are specific for self:
- Can be functionally inactived (anergized).
- Can be deleted by activation-induced cell death (AICD).
- Can be actively suppressed (Regulatory T cells prevent from responding).
This type of tolerance important for antigens not found in the thymus.
Backup mechanism to central tolerance (when it fails).
What is T-Cell anergy? What signals it?
Functional inactivation of T cells after antigenrecognition without adequate second signals.
Simply put, an induced a state of non-
responsiveness in T/B cells.
– Stimulated without adequate levels of second signals
– Engagement of CTLA-4 with B7 (low conc. on resting APC)
– Cell is signaled incompletely and is unresponsive to re-stimulation
– Occurs for presentation of self-antigens in tissue in the absence of infection/inflammation.
What is AICD (Activation Induced Cell Death? What causes it to occur?
Deletion (apoptosis)
Lymphocytes that recognize self-antigens in periphery can trigger apoptosis, this process is called Activation Induced Cell Death (AICD):
- Occurs when cells are stimulated in absence of costimulation and/or inflammation.
- Occurs when cells express more apoptotic proteins than anti-apoptotic or growth factors -> death.
- Occurs in certain tissues (eyes, testes) that are coated in ‘death receptors’(Fas/FasL), and signal AICD.
- Mutations in death pathways/receptors can cause autoimmunity.
What are Tregs (regulatory t cells)? Where do they develop? How are they identified? What do they do?
- Tregs are a subpopulation of CD4+ T Cells.
- Most develop in the thymus, but can also be generated in the periphery.
- They are identified by high levels of CD25 (IL-2 receptor) and FOXP3 (transcription factor).
- When they are activated they suppress immune responses.
- Without regulatory T cells humans (and mice) develop autoimmunity.
What 3 things can happen with self-antigen recognizing b cells in the BM?
Change the receptor
Deletion of Cell (apoptosis)
Anergic B cell (inactive)
What are 3 ways in which b cells have peripheral tolerance?
Anergy
Deletion
Regulation by inhibitory receptors
What are 2 ways in which autoimmunity develops? What percentage of people are affected in developed countries?
- Can develop when lymphocytes escape tolerance respond to self-antigens in periphery.
- Can develop when regulatory T cells (Tregs) do not develop and/or function.
- Affects at least 1-2% of persons in developed countries.
What factors contibute to autoimmunity?
• Genetics – Can inherit susceptibility genes. Most autoimmune diseases are polygenic and are associated with multiple gene loci, the most important of which are the MHC genes (class I-A, B,C, class 2-DR,DQ), but other genes too.
• Environmental Triggers – Can induce inflammation, mimic self-Ag, and release
sequestered Ags that can promote autoimmunity.
• Sex - many autoimmune diseases occur more frequently in females.
What happens if there is a mutation on the FoxP3 gene? where is gene found? symptoms? treatment?
Severe autoimmunity b/c you don’t get Tregs. Gene is located on X chromosome.
Young males gets
vomiting and severe blood diarrhea, autoimmune enteropathy, diabetes, eczema, endocrine disfunction, die early.
Can be treated with BM transplant if found in time.
How can environmental triggers lead to autoimmunity?
An infection will cause upregulation of co-stimulators, cytokines, etc. They will also recruit lymphocytes and caused them to be released. If self-antigen recognizing lymphocytes are released during this time, due to all the costimulators and cytokines present, they may not be recognized and won’t be tolerized.
Also, molecular mimicry is when a bacterial or viral peptide mimics a self-antigen so when a T or B cell is developed to combat the bacterial antigen, it also ends up recognizing self-antigen leading to autoimmunithy.
What are some treatment types for autoimmune disorders? What do they do? Examples?
Immunosuppressive Drugs:
- Drugs: Cortisone, methotrexate, azathioprine, cyclosporin.
- Can have harmful side effects, and increase risk of infection/cancer.
Anti-inflammatory:
- Steroids reduce pain and swelling by binding to cortisol receptors.
- Non-steroidal anti-inflammatory drugs (NSAIDs) (COX inhibitors). aspirin, ibuprofen, naproxen.
- Analgesics (Tylenol, acetaminophen) to reduce pain.
Plasmaphoresis:
- removes the cells and harmful molecules from the blood circulation.
Palliative:
- Reduce the severity of disease symptoms.
- The goal is to improve the quality of life, manage pain, replace deficient hormones, nutrients, etc.
