Autoimmunity Flashcards
What is central tolerance?
Self-tolerance induced in central lymphoid organs due to the killing of self-reactive lymphocytes. Prevents emergence of lymphocytes with high affinity receptors
What is the impact of a partial defect in central tolerance?
Onset of autoimmunity
What is peripheral tolerance?
Unresponsiveness to self antigens in the periphery induced via recognitions of antigens without adequate levels of costimulators or repeated stimulation.
What is the result of complete loss of peripheral tolerance?
Increased risk for autoimmunity
What are the 3 outcomes of central tolerance?
- No selection and cell dies
- Negative selection and cell dies
- Positive selection and cell released to periphery
What type of selection is a driver for T reg development?
Strong positive selection (almost near negative selection levels)
What surface receptors and txn factor are associated with Treg cells?
CD4+ and CD25+. Fox P3 txn factor
What is the function of the autoimmune regulator (AIRE) protein?
Txn factor that brings tissue specific antigens to the thymus so reactive t cells are deleted
What is autoimmune polyendocrine syndrome?
Mutation in APECD so there’s defective AIRE causing the destruction of multiple endocrine tissues including the beta islet cells
What is anergy?
A state of unresponsiveness to antigenic stimulation. Mechanism to maintain immunologic tolerance to self.
What are three T cell outcomes if the are presented a self antigen or Ag without costimulation?
- Anergy
- suppression via T reg
- Deletion via apoptosis
What are two ways that non-costimulation can lead to anergy?
- signaling block
2. reception of an inhibitory signal
What is CTLA4?
Inhibitory receptor on CD4/CD8 and Treg cells
How does CTLA4 function?
Binds B7 with more affinity than CD28 in unactivated APCs and causes B7 down regulation for unresponsive T cells
What is the impact of deleted CTLA4?
Increased risk for autoimmunity
How do Treg cells inhibit or dampen the immune response?
CTLA4 expression, TGF-beta release, IL-10 release, express high affinity IL-2R to mop up extra IL-2
What are two ways T cells can be killed?
- Deficiency in survival signals= activated pro-apoptotic proteins (intrinsic apoptosis)
- Fas/ Fas Ligand interaction (extrinsic apoptosis) (Fas=CD95)
What happens if there is a mutation interrupting Fas/FasL binding?
profound autoimmunity
What happens in central B cell tolerance if there is a strong BCR binding to self antigen?
Either receptor editing (via RAG proteins and new light chain combos) or apoptosis
What happens if there is recognition of soluble self antigens in central tolerance in b cells?
Anergic b cells
T helper cells are essential for B cell maturation in the periphery, what are three outcomes if B cells bind antigens without T helpers?
Anergy, apoptosis, or expression of inhibitory receptors. Anergic B cells are banned from lymphoid follicles and usually die
What is autoimmunity and what is its clinical presentation?
Breakdown of tolerance where the antigen targeted is the clinical presentation
What is one factor that will increase the chance of autoimmunity occurring?
If binding of the self-antigen occurs with infection, it is more likely to induce autoimmunity due to increased B7 expression
Genes associated with an increased risk of autoimmunity are involved in what mechanisms?
Peripheral mechanisms
Genes causing autoimmunity are involved in what mechanisms?
Central tolerance mechanisms
ex. AIRE, FOXP3, FAS
What genotype is one of the clearest associations with autoimmunity?
HLA genotype
What HLA genotype is ankylosing spondylitis associated with?
HLA-B27 = 90% relative risk
What genotypes are associated with an increased risk and protection from diabetes type I?
DR3/4 variant = increased risk
DR2/x variatint= protection
What is an adjuvant?
substance to enhance B&T cell activation (NOT an antigen) by promoting APC accumulation and activation at the antigen site.
How do adjuvants work?
Stimulate expression of T cell-activating costimulators and cytokines or promoting peptide-MHC complexes. **how vaccines work
What are some implications of a chronic immune response?
Break down of sequestration barriers
New antigens being revealed= chriptic epitopes
Evolving tissue destruction
New self-antigens involved= epitope spreading
Excess soluble antigen complexes and joints in pain and kidneys
What are three treatments for autoimmune response?
- non-steroidal anti-inflammatory drugs (anti-TNF for RA)
- corticosteroids and immunosuppressants
- Biological therapy (anti-cytokine/ cell depletion)
