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MICB 402 > Levings Content > Flashcards

Levings Content Flashcards

1
Q

immune tolerance

A
  • state of unresponsiveness to an antigen
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2
Q

antigens that should not become targets of effector cells (2)

A
  1. self-antigens
  2. non-harmful foreign antigens
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3
Q

self-antigens (3)

A
  • systemic (eg. RBC)
  • tissue specific
  • developmental stage specific
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4
Q

non-harmful foreign antigens examples (4)

A
  • allogeneic fetus
  • commensal bacteria
  • food
  • inhaled antigens
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5
Q

how are TCRs and BCRs made

A
  • somatic recombination to make random receptors
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6
Q

what occurs when tolerance goes wrong (3)

A
  • autoimmunity
  • allergy (to non-harmful antigens)
  • auto-inflammation
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7
Q

what occurs when tolerance works too well (2)

A
  • cancer
  • persistent infections
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8
Q

what are some clinical uses for tolerance

A
  • induce tolerance to transplanted cells and organs/foreign tissues
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9
Q

two layers of tolerance (2)

A
  • central
  • peripheral
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10
Q

central tolerance (3)

A
  • bone marrow (B cells)
  • thymus (T cells)
  • regulates tolerance to self by removing potentially self-reactive immature lymphocytes
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11
Q

peripheral tolerance (2)

A
  • tolerance in places other than BM and thymus
  • regulates tolerance to self and non-harmful foreign antigens
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12
Q

central T cell tolerance (2)

A
  • T cells that bind antigens too loosely do not pass
  • T cells that bind antigens too strongly do not pass
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13
Q

AIRE (2)

A
  • thymic epithelial cells express this TF
  • allows expression of as many genes as possible in thymus
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14
Q

AIRE genetic mutation

A
  • results in severe autoimmune disease as process if negative selection is defective
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15
Q

how does AIRE work

A
  • as a TF, it worked by controlling transcription
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16
Q

thymic “mimetic” cells (3)

A
  • express peripheral tissue antigens
  • mirror extra-thymic cell types but maintain thymic epithelial cell identity
  • allows for negative selection of all cell types in the thymus
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17
Q

AIRE and Treg development

A
  • AIRE-deficiency results in T cell escape from negative selection AND defective Treg cell development
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18
Q

thymic development of FOXP3+ Tregs (2)

A
  • immature CD4+ T cells that have medium-high affinity for self-antigens take on FOXP3-CD25+ Treg cell precursor phenotype in a TCR dependent manner
  • FOXP3+ Treg cell develops in a TCR independent manner, but relies on IL-2 and IL-15
19
Q

how accurate is central T cell tolerance (2)

A
  • not perfect; some self-reactive T cells escape negative selection
  • to handle this, peripheral tolerance is employed as a second level of control
20
Q

T cell activation signals (3)

A

signal 1: antigen (presence, absence, affinity)
signal 2: co-stimulation vs co-inhibition
signal 3: cytokines

21
Q

what is peripheral T cell tolerance controlled by

A
  • quality of T cell activation
22
Q

major mechanisms of peripheral tolerance (3)

A
  • deletion
  • anergy
  • suppression
23
Q

peripheral tolerance: deletion (2)

A
  • activation induced cell death
  • Fas/FasL pathway critical for deletion of T cells that have been stimulated repeatedly in periphery by antigen
24
Q

result of mutations of Fas/FasL

A
  • lymphadenopathy (swelling lymph nodes) and autoimmunity
25
Q

what is an analogous mutation in humans of the Fas/FasL mutation in mice (2)

A
  • autoimmune lymphoproliferative syndrome
  • defective lymphocyte apoptosis, lymphocyte accumulation, anemia, and thrombocytopenia (low platelet count)
26
Q

peripheral tolerance: anergy/exhaustion (3)

A
  • lack of responsiveness and inability to perform any activity
  • results from lack of signal 1 or lack of signal 2 as cell will be half activated and unable to have effector function
  • lacks positive or negative signal
27
Q

anergy vs exhaustion

A
  • phenotypically similar hyporesponsive states, but different characteristics behind state
28
Q

anergy vs exhaustion: anergy characteristics (3)

A
  • low transcription of cytokines and cell cycle genes
  • gene expression enforces the anergic phenotype
  • hyporesponsiveness even if they receive a full activation signal in the future
29
Q

anergy vs exhaustion: exhaustion characteristics (3)

A
  • caused by strong and sustained signals
  • fail to secrete cytokines, lyse target cells, or proliferate effectively
  • sustained expressed of co-inhibitor molecules
30
Q

positive vs negative signal 2 (3)

A
  • can be used in therapies to alter T cell responses
  • therapeutic manipulations to induce tolerance
  • describe co-stimulation that can either be stimulatory or inhibitory
31
Q

peripheral tolerance: suppression

A
  • by regulatory cells
32
Q

positive vs negative signal 2: CTLA-4 (2)

A
  • important Treg mechanism of suppression
  • activation-induced CTLA-4 expression will terminate the immune response
33
Q

positive vs negative signal 2: PD1

A
  • reduces TCR signaling, cytokine production, and target cell lysis
34
Q

peripheral tolerance: regulatory cells

A
  • immune cells which actively stop immune response
35
Q

regulatory cell examples and most known examples (2)

A
  • many different types: macrophages, B cells, NK cells, T cells, etc
  • most is known about CD4+ Treg cells which express FOXP3 TF
36
Q

FOXP3+CD4+ Treg cells (3)

A
  • defined by FOXP3 and CD25 expression
  • do not produce T-cell derived cytokines
  • suppress many diff types of cells and immune responses
37
Q

how does the proportion of Treg cells change throughout your life (2)

A
  • throughout life, proportion of effector cells increases due to expansions after infection, leading the Treg proportion to become smaller (~1-3%)
  • as babies, Tregs are very important for tolerance and are present at high proportions
38
Q

how were Tregs discovered (3)

A
  • classification of IPEX disease
  • discovery that CD25+CD4+ T cells control autoimmunity in mice
  • link between FOXP3, IPEX, and CD4+CD25+ T cells was made
39
Q

IPEX disease (3)

A
  • multi-organ autoimmunity
  • due to X-linked mutations in FOXP3 gene
  • caused by lack of Treg cells, which are essential to tolerance development
40
Q

cell therapy with FOXP3+ Tregs (2)

A
  • Tregs can work for drug therapy as they can rescue phenotypes that lack Tregs with a single injection
  • Tregs can proliferate and turn other cells in Tregs
41
Q

mechanism of FOXP3+ Treg action (3)

A
  • bystander suppression by reducing APC effectiveness: effects all cells in local environmental even if antigen isn’t specific to Treg
  • infectious tolerance: can turn other CD4+ T cells into Treg cells
  • secretes anti-inflammatory cytokines
42
Q

FOXP3 locus

A
  • Treg cells can be distinguished from T cells as their CNS2 locus is not methylated
43
Q

peripheral development of FOXP3+ Tregs (2)

A
  • evolution with placental mammals (carry fetus within body); likely evolved to protect baby from own immune system
  • oral tolerance and the microbiome

MICB 402 (11 decks)

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