Tolerance and Autoimmunity Flashcards
Define Immunogenic?
Elicits an immune response
Define Tolerogenic?
Does not elicit a functional lymphocyte response
-As a result lymphocytes are either killer, inactivated, or there is no reaction at all (Immune ignorance)
What two locations are best examples of immune ignorance?
The eyes and the testis
Compare Central tolerance to Peripheral tolerance
Central: occurs during lymphocyte development in primary lmyphoid organs (thymus and BM)
Peripheral: Occurs in periphery (Secondary lymphoid organs or non-lymphoid tissue
What happens to the thymus as we age?
It involvues with age, becomes for adipose tissue
What is positive selection in the thymus?
When T cells recognize MHC for self with low affinity
What is negative selection in the thymus?
When T cells recognize MHC with strong affinity and undergo apoptosis (this is not 100% efficient and hence you need peripheral tolerance)
What are the three populations of T cells that come from the thymus
Regulatory T cells (Tregs), CD4s, or CD8s
What is death by neglect?
In the thymus when T cells do not recognize MHC at all and undergo apoptosis
How are Tregs selected for? What must they express?
They recognize MHC with strong affinity, and survive, they contribute to peripheral tolerance
-must express FoxP3 genes
What is the fate, and how is it done, of a T cell specific for antigen that is not expressed in the thymus?
They are negatively selected by the AIRE gene (autoimmune regulator)
-AIRE induces the expression of peripheral tissue antigens by cells in the thymus. That way if a maturing T cell has afffinity for these antigens, it can be negatively selected against.
What happens if there is a mutation in AIRE?
APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrohpy syndrome)
-this is a multi-organ autoimmunity
In peripheral tolerance, what are the 4 options for dealing with autoreactive T cells?
- Anergy (functional inactivation)
- Treg- mediated suppression
- Death (apoptosis)
- Ignorance (this is most dangerous)
What induces anergy, and how long does it last? (for T cells)
Anery is long-lived functional inactivation
- Induced in two ways.
1. Lack of costimulation by CD28 to B7 (also known as CD80/84)
2. Stimulation of an inhibitory signal like CTLA-4 with B7 or PD-1 with PDL
note: CTLA-4 is expressed in high levels on activated T cells making it a good off switch.
What are the targets of Ipilimumab and Nivolumab?
Ipilimumab is a anti-CTLA-4 antibody
Nivolumab is a anti-PD-1 antibody
- both work to prevent T cell anergy or inactivation
- this is dangerous and can lead to autoimmunity
What transcription factor is required for Tregs, and what would a mutation in this cause?
FoxP3, a mutation in FoxP3 leads to IPEX (multiorgan autoimmunity)
- FoxP3 is a transcription factor
- Tregs suppress the function of other T cells specific for self-antigens that did not get negatively selected
What interaction is responsible for lymphocyte activation induced cell death (AICD)?
Fas-FasL interaction
- make effector T cells short lived
- helps to return to homeostasis after infection
What is induced upon on effector T cell upon activation?
Fas is induced
FasL is always expressed
What causes Autoimmune Lymphoproliferative Syndrome?
Mutation in genes involved in FAS signaling
-leads to autoimmunity, and lymphocyte accumulation
What is receptor editing?
Immature B cells (that mature in the BM) that recognize self antigens, they will reexpress RAG genes, resume Ig light chain recombination and rexpress a new Ig light chain to avoid self recognition
-25-50% of B cells undergo receptor editing
How is Ig concentration related to Ig Half-life?
Inverse. The higher the Ig conc, the shorter the half life
What receptor interaction is required for B cell stimulation by T cells and what happends without it?
CD40L (on T cell) with CD40 (on B cell) is required for B cell stimulation.
-without you get anergy, this is an example of B cell peripheral tolerance
What is the main inhibitory receptor of both B cells and machrophages?
Fc receptors
-although there are both stimulatory and inhibitory Fc receptors
What is the main inhibitory signal for B cells?
Co-cross linking of BCR and Fc-gamma-Receptor II turns off the B cell.
-this co-cross linking is more likely to happen at high Ig concentrations.
What is Rhogam and what is it used for?
Rhogam is immune gammaglobulin to Rh antigens (IgG ab)
- given to Rh neg mothers with an Rh+ fetus during pregnancy.
- elimantes fetal Rh pos RBCs from maternal circulation
- turns off maternal B cells by cross-linking BCR and FcgammaRII
- Rh- mom would have Rh antibodies that would attack the Rh antigens of the Rh+ fetus.
Which three cytokines are secreted by macrophages to aid in the return to homeostasis after infection? What does each inhibit?
IL-10 inhibits Th1 cells
TNF-beta inhibits macrophage and T cell activation
PRGe2 inhibits lymphocyte proliferation
What Ab is present in Graves disease, what does it cause? and what type of hypersensitivity is it?
Graves disease has agonistic TSH antibodies that over stimulate the Thryoid stimulating hormone receptor.
- leads to hyperthyroidism, also Goiter (thyroid hyperplasia)
- leads to B and T cell infiltration
type II hypersen. b/c ab mediated
What causes Goodpasture’s disease?
Ab against non-collagenous domains of type IV collagen of glomerular basement membrane (GBM)
- leads to linera IgG in kidney GBM and anti-GBM antibodies
- neutrophil mediated cytotoxicity
- Bleeding in the lungs and progressive kidney failure
- type II hypersen.
What causes Systemic Lupus Eryhtematosus?
- Ab against nuclear contents; dsDNA, snRNPs
- leads to skin, kidney, joint symptoms reflect immune complex deposition
- type III hypersen, ab-ag-immune complex
- prevalent immune-complex mediated diease in developed countries among women
- fever, arthritis, myalgia, skin involvement, photosensitivity, anemia
What is a ANA test?
Cells fixed on slide, add patient serum, anti-nuclear ab bind, secondary antiody against human ab taged with a fluorescent dye
- 95% of SLE patients test postivie
- up to 15% of healthy patients have anti-ANA ab and would also test positive, this would be false positive
What causes MS?
Immune attack of myelin sheath that cover nerve fibers
-type IV hypersens (cell mediated)
What causes DM type I?
Descrution of insulin-producing Beta cell in pancreatic islets
- type IV hypersen (cell mediated)
- CD4 and CD8 T cells specific for Beta cell antigens responsible for islet cell desrtuction
What does infection have to do with risk of autoimmunity?
Hypothesis that infection increases risk of autoimmune disease because it increases co-stimulation. So you have a higher risk of co-stimulating cells that recognize self that would normally be anergetic.
- also molecular mimicry: peptide antigens from a microbe is very similar to a self antigen : like rheumatic fever, where antibodies against streptococci cross-react with myocardial antigen
- remember though in some cases infection can be protective from autoimmunity
What set of genes has a strong association with AI dz?
HLA genes
HLA-B27 is 90 relative risk in developing AI
-important is HLA does not cause disease, and vast majority of peopple with HLA allele do not develop disease
-
What are 5 polymorphisms that affect a person’s genetic susceptibility to an AI dz? What dz’s are they associated with?
PTPN22: involved in B and T cell signaling – RA, SLE, TIDM
NOD-2: involved in NLR (innate) – 25% of Crohn’s dz
high affinity chain of IL-2 receptor (CD25): effector Treg balance – multiple AI dz
IL-23R: involved in Th17 differentiation – multiple AI dz
CTLA-4: multiple AI dz
What is Abatcept?
CTLA-4-Ig biologic
- fusion or protein composed of Fc region of IgG fused to CTLA-4
- trigger off switch, treat autoimmune
Name an anti-CD20 antibody?
Rituximab
What are the 3 anti-TNF abs?
Infliximab
Adalimumab
Certolizumab Pergol
What is the Anti-IL-6 Ab?
Toclizumab
