Tolerance And Autoimmunity - Bowden (Completed) Flashcards
What is central tolerance? 6
Happens in primary lymphoid organs
Ensuring lymphocytes are tolerant to self
Where does central tolerance for T lymphocytes occur? 8
In the thymus
What will a defect in AIRE lead to? 8
AIRE - autoimmune regulator protein
Defects in AIRE results in autoimmune polyendocrinopathy
What is responsible for negative selection in developing T cells? 8
AIRE - autoimmune regulator protein
What can happen when a thymocyte has intermediate affinity for self Ag? 9
If FOXp3 is upregulated in the thymocyte it will mature into a Treg cell
What mediates peripheral tolerance? 10
Treg cells
What do Treg cells secrete? 10
IL-10 (anti-inflammatory)
TGF-β
What would a loss of FOXp3 TF in the body result in? 10
Widespread NK cell autoimmunity
What can Treg cells inhibit? 10
Effector T cells
B cells
NK cells
Naive T cell activation
Why is B7-1/2 (CD80) down-regulated when the body is not fighting disease? 11
Pro-inflammatory cytokines are responsible for up regulation of B7-1/2 (CD80)
Where would you expect ot find a high concentration of Tolerogenic self Ags and immunogenic foreign Ags? 15
Tolerogenic self Ags highly concentrated in primary lymphoid organs
Immunogenic foreign Ags are highly concentrated in secondary lymphoid organs
What can contribute to autoimmune disease? 18
Susceptibility genes
Infections
Environmental factors/triggers
All of the above lead to breakdown of tolerance
What are the effector mechanisms of auto-immunity? 19
Circulating auto-Abs
Auto-reactive T lymphocytes
What acuity would you expect for an autoimmune disease that was organ-specific vs systemic? 20
Organ-specific –> acute
Systemic –> chronic and progressive
Why can autoimmune diseases be chronic? 21
Because the self-Ag specific lymphocyte undergoes clonal expansion making many copies that persist and cause disease
Why can autoimmune diseases be persistent? 21
With the destruction of target cells via self-reactive lymphocytes new Ags are released into inappropriate compartments and are responded against via normal healthy immune cells
What are the main environmental inducers of autoimmune disease? 22
Infection - Rheumatic fever
Physical trauma - sympathetic ophthalmia
Drug induced - SLE
What can mediate autoimmunity? 23
Can be mediated by both the humoral immunity and cel-mediated immunity
What protein is most prevalent in genetic autoimmune diseases? 25
HLA alleles (primarily HLA Class II)
What HLA allele has been shown to have a 90% relative risk for developing ankylosis gentlemen spondylitis when mutated? 25
HLA-B27
Defects in Foxp3 results in? 26
Breakdown of peripheral tolerance
Defects of FAS results in? 26
Defective apoptosis in B and T peripheral cells (adrenals)
What is molecular mimicry? What’s an example? 27
In the process of destruction of a microbe people with certain mutations in HLA genes accidentally identifies normal tissue
Ex. Strep, immune system accidentally identifies cardiac tissue as strep because of the resemblance of the Ags
What is the Ag, Ab, and consequence in Graves’ disease? 29
Ag - thyroid stimulating hormone receptor
Ab - agonist
Consequence - hyperthyroidism
What is needed to induce SLE (systemic lupus erythromysis)? 30
Susceptibility genes + external triggers
Immune complexes are not cleared and therefore auto-abs are eventually made
What’s happening in RA? 31
Inflammation of the synovium
- inflammation sustained by Th17/Th1 response
- auto-ab production (rheumatoid factor)
What is rheumatoid factor? 31
An Ab that binds the Fc portion of IgG (prevalent in RA)
What is a biological therapy targeted against IL-6? 33
Tocilizumab
What is a biological therapy targeted against IL-1? 33
Anakinra Rilonacept
What is a biological therapy targeted against IL-23? 33
Uztekinumab ABT874
What is the biological therapy role of Anti-CD25? 34
Decreases T cell autocrine response to IL-2
What is the biological therapy role of Anti-CD20? 34
Targets mature naive B cells for deletion
What is IPEX? 40
Mutated FOXP3 resulting in loss of function of Treg cells (uninhibited T cell activation)
What are the most common symptoms of IPEX? 40
Inflammation of gut –> colitis–> Intractable diarrhea –> failure to thrive
Dermatitis
Autoimmune diabetes (type I)
What is the inheritance of IPEX? 40
X-linked –> male susceptibility
What would you expect to see from a serum Ab panel taken from an IPEX patient? 40
Normal serum levels of all Abs except elevated IgE (hyper-IgE)
