Autoimmunity Flashcards
Autoimmunity
Normal
kept in check by tolerance mechanisms
Autoimmune disease
Clinical damage to self tissues
due to dysregulation of autoimmunity
Contributing factors: internal vs external
- Internal factors: genetic, hormonal
- external triggers: infections, stress, physical trauma, chemicals
What are some genetic elements that contribute to AI disease?
- single gene mutation
- polymorphisms
- polygenic predisposition
Examples of single gene mutation/polymorphism
AIRE Foxp3 Fas/FasL CTLA-4 C4
What is the result of C4, C2 (complement) deficiency
Deposit of Ag-Ab complex in BV – activation of alternative pathway
–> Type III hypersensitivity
–> inflammatory tissue damage
What is necessary for clearance of Ag-Ab complexes?
Classical pathway
Strongest genetic predisposition to AI disease?
HLA
esp HLA class II gene
B27 (class I allele) - strongest association
What are some other reasons for disease-associated polymorphism?
- AA residues in the peptide binding cleft
- Co-inhertited with certain HLA alleles
What are the two main genes outside HLA associated with AI disease?
- PTP22 : gain of function - Protein tyrosine phosphatase
- NOD2 : cytoplasmic sensor of bacteria
Which gender does autoimmune disease preferentiall affect? (hormonal influence)
Females
What are the mechanisms by which infection triggers AI disease?
- Molecular mimicry
- Bystander activation
- Epitope spreading
What type of Ag activates autoreactive T cells in molecular mimicry?
microbial Ag (that resembles self-Ag)
What are some infections that trigger AI disease via molecular mimicry?
Acute rheumatoid fever (ARF): epitope of GAS
Multiple sclerosis: epitope on Epstein-Barr virus protein
What does the M protein on GAS mimic?
Human myosin
What does the Epstein-Varr virus protein mimic?
Human myelin basic protein
What type of Ag activates autoreactive T cells in by-stander activation
self-Ag
What is epitope spreading?
Autoimmune responses expand beyond the original epitope
Epitope spreading contributes to what features of AI disease?
“self-perpetuation”
“flare-up”
What is cryptic epitope?
Antigenic epitopes that are insufficiently presented to T cells, but becomes abundant after tissue destruction
Examples of epitope spreading
Pemphigus (active learning)
T1D
How can Trauma cause AI disease?
exposure to sequestered self-antigens
post-traumatic uveitis, orchitis
What does immunotherapy do?
- Block actions of pro-inflammatory cytokines
- Administer anti-inflammatory cytokines
- target autoreactive T and B cells
What is the use of conventional therapies
anti-inflammatory
immunosuppressive drugs to Inhibit lymphocyte
procedures that remove autoantibodies
