2.2.1 Tolerance and Autoimmunity Flashcards
Define immunogenic.
Elicits proliferation, differentiation, and effector function from lymphocytes
Define tolerogenic.
does not elicit a functional lymphocyte response (lymphocyte killed, inactivated, or no reaction at all)
Distinguish b/t central and peripheral tolerance. Where do they occur?
Central: occurs during lymphocyte development in primary lymphoid organs (Thymus and BM) Peripheral: occurs in the periphery (SLOs or non-lymphoid tissues)
What is the term for the promoting survival of T cells that recognize MHC molecules with low affinity for self-peptides?
Positive Selection
What happens to T cells that have a strong affinity for self-peptides in the thymus? Is this a perfect process?
Negative selection, not 100% effective
If cells don’t recognize MHC at all, what happens?
Death by neglect
If cells recognize MHC with strong affinity for self-peptides but survive thymic development, what is their mature cellular form? What do they contibute to?
Treg; peripheral tolerance
How do T cells specific for Ag not expressed in the thymus get negatively selected?
AIRE gene (autoimmune regulator) - induces the expression of peripheral tissue Ag by cells in the thymus
What happens if there is a mutation in AIRE?
APECED (autoimmune polyendocrineopathy-candidiasis-ectodermal dystrophy syndrome): a multi-organ autoimmunity
What are the four peripheral responses to an autoreactive T cell?
- Functional inactivation (anergy)
- Treg-mediated suppression
- Death (apoptosis)
- Ignorance
What type of signal leads to anergy?
Naive T cells recognize MHC/peptide complex (signal 1) in the absence of costimulation (signal 2) or in the presence of inhibitory signals
What is the main co-receptor on T cells involved in the signal 2 of the 2-signal theory?
CD28 (on T cell) binds B7-1/2 of APC
What are two inhibitory recepors-lignand interactions responsible for angery?
PD-1 (T cell)/PDL (APC)
CTLA-4 (T cell)/B7 (APC) blocks binding of CD28 to B7 and can deliver inhibitory signals
What are the targets of ipilimumab and nivolumab?
ipilimumab: anti-CTLA-4 Ab
nivolumab: anti-PD-1 Ab
What transcription factor is important in Treg development and function?
FoxP3
A mutation in FoxP3 leads to a lack of functional Treg, which yields mulitorgan autoimmunity. What is the acronym for this disorder?
IPEX
What interaction is responsible for lymphocyte activation induced cell death that clears effector lymphocytes?
Fas-FasL
What is the genetic cause of autoimmune lymphoproliferative syndrome (ALPS)? What are the two results of this mutation?
Mutated Fas signaling; autoimmunity and lymphocyte accumulation
What is receptor editing?
Immature B cells that recognize self Ag reexpress RAG genes, resume Ig light recombination and express a new Ig light chain
What are the three mechanisms of peripheral tolerance?
Anergy, Death (apoptosis), Ignorance
How is Ig concentration related to Ig half-life?
Higher concentration, decreased half-life
Which receptors on B cells and macrophages have an immunoregulatory function?
Fc receptors
Co-cross linking of what turns off the effector B cell?
BCR and FcgammaRII
What is Rhogam? When is it administered?
Immune gammaglobulin (IgG Ab) to Rh Ag; given to Rh neg mothers during pregnancy and at parturition
What is the mechanism of rhogam?
Eliminates fetal Rh pos RBCs from maternal circulation
Turns off maternal B cells by cross-linking BCR and FcgammaRII
Which three cytokines are secreted by macrophages to aid in the return to homeostasis after infection? What do they inhibit?
IL-10: inhibits Th1
TGF-beta: inhibits macrophage activation and T cells
PGE2: inhibits lymphocyte proliferation
What are the three types of autoimmunity tissue damage?
Ab-mediated (Type II)
Immune complex-mediated (Type III)
T cell-mediated (Type IV)
[No Type I]
What is the autoimmune receptor Ab present in Graves dz (Type II)? What can lead to the diagnosis of Graves dz?
Anti-TSH receptor Ab;
Agonistic thyroid-stimulating Ab
In Graves Dz, what is the resulting effect on the thyroid?
Thyroid hyperplasia (goiter) and hyperthyroidism - due to constitutive activation of TSH receptor by auto-antibody.
What type of autoimmunity dz is Goodpasture’s Dz?
Type II
What is the Ab directed against in Goodpasture’s Dz?
Non-collagenous domains of type IV collagen of glomerular basement membrane (GBM)
What is enough to diagnose Goodpasture’s Dz?
Linear IgG in kidney GBM and anti-GBM Ab
What type of toxicity is present in goodpasture’s dz? What are the clinical symptoms of goodpasture’s?
Neutrophil-mediated cytotoxicity; bleeding in lungs and progressive kidney failure
What type of autoimmune dz is systemic lupus erythematosus? What are some associated symptoms?
Type III
fever, arthritis, myalgia, skin involvement, photosensitivity, anemia, IC desposition in kidneyand joints
What is an ANA test?
Cells fixed on slide, patient serum added, antinuclear antibodies bind, secondary antibody against human antibodies tagged with a fluorescent dye
What type of AI dz is multiple sclerosis? Pathogenesis?
Type IV
Immune attack of the myelin sheath that covers nerve fibers
What are some of the autoantigens present in MS? What immune cells are involved in this AI distruction?
myelin basic protein, myelin oligodendrocyte glycoprotein, proteolipoprotein
CD4+ Th1 (IFN-gamma) and Th17 (IL-17)
What occurs in Type I DM, a type IV AI dz? Which cells are involved?
Destruction of beta cells in pancreatic islets
CD4+ and CD8+ T cells
What are 5 genes 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 abatacept?
CTLA-4-Ig
Name an anit-CD20 Ab.
Rituximab
Name 3 Anti-TNF Ab
Infliximab, Adalimumab, Certolizumab pegol
Name an Anti-IL-6 Ab.
Tocilizumab
