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IHL Exam 2 > tolerance and autoimmunity (michels) > Flashcards

tolerance and autoimmunity (michels) Flashcards

2
Q

tolerance

A

unresponsiveness to self antigens

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3
Q

anergy

A

functional unresponsiveness/inactivation that occurs when T cells recognize antigens without adequate levels of costimulators that are needed for full T cell activation

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4
Q

central tolerance

A

takes place in central lymph organs-B cells in bone marrow-T cells in thymus

when developing lymphocytes encounter these antigens

ex/ negative selection

principal mechanism is cell death (negative selection) and generation of CD4 regulatory T cells

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5
Q

peripheral tolerance

A

what mature lymphocytes undergo out in body-lymph nodes and spleen

ex/ T reg function, anergy, cell death

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6
Q

T cell development?

A

positive and negative selection

ons that recognize MHC - selected for central tolerance

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7
Q

Foxp3

A

transcription factor

signals to become a T reg cell

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8
Q

where are T reg cells formed?

A

thymus

formed when some immature CD4 t cells recognize self antigen with high affinity, and they do not undergo apopotosis but rather develop into T regs

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9
Q

when does selection for T reg cells occur?

A

intermediate affinity in thymus (central)

also can happen in periphery when t cells recognize self antigen

leads to upregulation of Foxp3

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10
Q

function of T reg cell

A

check on immune system to keep it from going out of control

prevent autoimmune diseases

Downmodulate immune response to allergens, pathogens, and cancer cells

also involved transplantation tolerance

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11
Q

T cell development

A

First step:
DP cells interact with MHC’s on TECs
those that interact are selected positively

Second step:
interact with macrophages, dendritic cells and TEC
sample with self antigen
negative selection–> die b/c bound with high affinity to self antigens
positive selection–> released into periphery as SP that either had weak affinity for Class I (CD8) or Class II (CD4)
intermediate/high affinity–> T regs

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12
Q

what do T reg cells express?

A

Foxp3 and CD25

CTLA-4–> blocks/depletes B7 from APC’s

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13
Q

CD25

A

on T reg cells

is the IL-2 receptor

purpose of having this is to bind IL-2 which is the essential T cell growth factor, reducing its availability for responding t cells

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14
Q

what do T reg cells secrete?

A

IL-10 and TGF-beta

these inhibit the activation of lymphocytes, dendritic cells and macrophages

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15
Q

autoimmunity

A

results when immune system recognizes self antigens

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16
Q

T reg cells depend on what for survival?

A

IL-2

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17
Q

T reg cells?

A

CD4+

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18
Q

anergy?

A

peripheral T cell tolerance-occurs when T cells activated without co-stimulation**

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19
Q

what can lead to anergic T cell?

A

1 signal without co-stimulation

2 engagement of inhibitory receptors (CTLA-4)

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20
Q

what happens without co-stimulation in T cell activation?

A

leads to signaling block-leads to anergy of T cell

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21
Q

co-stimulation in T cells?

A

B7:CD28 interaction

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22
Q

cell death in mature T cells?

A

peripheral tolerance-

1- self antigen recognition induces production of pro-apoptotic proteins that induce cell death by the mitochondrial pathway (leak out, activate caspases, etc) normally with costimulation anti-apoptotic signals couteract pro-apoptotic but without costimulation this doesn’t happen

2- recongition of self antigens may lead to coexpression of death receptors and their ligands Fas and FasL

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23
Q

Fas and FasL?

A

upregulated when T cell recognizes self antigen results in apoptosis

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24
Q

what could break anergy?

A

a very strong danger signal

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25
Q

tolerogenic antigens? (self)

A

usually in generative organs

high concentrations

long-lived exposure (bc its self) which means prolonged TCR engagement inducing anergy and apoptosis

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26
Q

immunogenic antigens? (microbes)

A

in blood and periphery

expression of costimulators typically seen with microbes, which promotes lymphocyte survival and activation

short lived

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27
Q

central B cell tolerance?

A

in bone marrow

if recognizes self antigen (T-independent antigen)-can die (apoptosis)-can undergo receptor editing

self polysaccharides, lipids, and nucleic acids are t-independent antigens that are not recognized by T cells –> these must induce B cell tolerance to prevent autoantibody production

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28
Q

peripheral B cell tolerance

A

anergic-if self antigen recognition without T cell help

apoptosis

exclusion from the lymphoid follicle so b cell does not receive survival stimuli

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29
Q

what can mutations in Fas result in?

A

children with autoimmune diseases

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30
Q

immature B lymphocyte?

A

IgM+ and IgD-

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31
Q

effector mechanisms of autoimmunity?

A

circulating autoantibodies

immune complexes

autoreactive T lymphocytes

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32
Q

principle factors in development of autoimmunity?

A

susceptibility genes and environmental triggers (such as infections)

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33
Q

Type I diabetes

A

autoimmune destruction of beta cells in pancreas-genetic predisposition - Dq8-thought to be an environmental trigger

can predict the onset based on presence of certain autoantibodies

goes through phases:-genetic predisposition-insulitis-pre-diabetes (loss of first phase insulin response)-diabetes

34
Q

tolerance-sensitive cell for T cells?

A

CD4+ CD8+ (double positive) T cells

35
Q

insulitis

A

beta cell death (type I diabetes)

36
Q

types of autoimmune disease?

A

organ-specific and systemic

37
Q

what sex has more autoimmune diseases?

A

female-much more likely in women-don’t know why

38
Q

factors contributing to autoimmunity

A

genes, infections, and environmental factors

39
Q

HLA-B27

A

ankylosing spondylitisautoimmune disorder

40
Q

HLA-DR4

A

rheumatoid arthritisautoimmune disorder

41
Q

HLA-DR3/DR4

A

Type I diabetes mellitus

42
Q

AIRE

A

gene that if we lose will result in autoimmune polyendocrine syndrome (APS-1)

in this disorder several tissue antigens are not expressed in the thymus so immature T cells specific for these antigens are not eliminated. therefore T cells specific for these antigens are released into the periphery and attack the

43
Q

Foxp3

A

defects in this gene lead to deficiency of regulatory T cellscan lead to X-linked polyendocrinopathy and enteropathy (IPEX)

Foxp3 plays a role in the gut

44
Q

HLA-DR4

A

pemphigus vulgarisautoimmune disorder

45
Q

Fas

A

defect leads to autoimmune hypoproliferative syndrome (ALPS)defective apoptosis of self-reactive T and B cells in periphery

46
Q

IPEX

A

from loss of Foxp3 gene

47
Q

what would cue you to think a single gene defect?

A

multiple autoimmune disease at early age

48
Q

action of TGF-beta

A

inhibit IgE prduction

sooo…. someone with Foxp3 knockout would have decreased Tregs which means they wouldn’t be secreting alot of IL-10 (which normally suppresses IgE production) so their IgE would be very increased (too much TH2 response)

49
Q

what does finding autoantibodies to GD65 or to pancreatic islets tell you?

A

it means the person probably has type I DM

50
Q

action of IL-10

A

suppress IgE production

51
Q

how does TGF-beta inhibit IgE formation?

A

inhibit Id2-repressor of IgE isotype switching

52
Q

treatment of IPEX

A

bone marrow transplant-to restore Foxp3 expressing cells

poor prognosis for IPEX

53
Q

triggers of autoimmunity?

A

presence of microbe induces co-stimulators on the APC presenting self antigen

molecular mimicry - microbe antigen resembles the self tissue–> leads to self-reactive T cell that recognizes microbial peptide (that is mimicing a self antigen) leading to activation of T cells–> autoimmunity

54
Q

streptococcus pyogenes?

A

causes strep throat and rheumatic fever

molecular mimicry for protein on heart muscleactivated T cells will attack cardiac muscle

55
Q

what is pathogenic in lupus?

A

auto-antibody

56
Q

what is pathogenic in diabetes?

A

T cells

57
Q

what is pathogenic in myasthenia gravis?

A

antibody

autoantibodies against acetylcholine receptor

58
Q

what is pathogenic in multiple sclerosis?

A

T cells (Th1 cells)

59
Q

how does IL-4 and IL-13 induce IgE formation?

A

activate STAT6 to induce isotype switching

60
Q

stimulatory autoantibodies?

A

ex/ autoantibodies against TSH receptor bind the TSH receptor and result in upregulation of thyroid hormones (antibody looks like TSH)

Graves disease

61
Q

inhibitory autoantibodies?

A

ex/ autoantibody bind the acetylcholine receptor (without activation)–> prevent the muscle activity
by blocking it

myasthenia gravis

62
Q

autoantibodies

A

can be stimulatory or blocking

63
Q

effect of corticosteroids?

A

immunosuppression

64
Q

multiple sclerosis

A

Th1 cell response against myelin –> lymphocytes are releasing cytokines (TH1 cytokines–TNF-alpha and IFN-gamma) leading to vascular permeability (makes it easier for lymphocytes to get into the CNS)

linked to class II alleles

more likely in women with HLA-DR2

characterized by lymphocytes in the CNS (not supposed to be there)

relapsing–> remitting–> this is typical of autoimmune condition

65
Q

oligoclonal immunoglobulins in central nervous system for MS?

A

never been exposed to all these new self antigens!

B cells got into the CNS–> now producing a bunch of oligoclonal Ig’s b/c they have never been exposed to those antigens

66
Q

treatment of multiple sclerosis?

A

corticosteroid, cyclophosphamide, IFN-beta

trying to dampen immune response

these people are then more susceptible to infections

67
Q

treatment of MS with IFN-gamma not favorable?

A

because promoting Th1 cytokines (don’t want that)

since MS is already caused by TH1 response

68
Q

why feed MBP (myelin basic protein) to mice to prevent EAE?

A

fed prior to immunizing them with MBP they are protected from EAE

give this protein that has no co-stimulatory molecules/danger signal present causing anergy–>
because this would place self-antigen in their bodies (induce peripheral tolerance)

69
Q

can you induce EAE in CD28 knockout mice?

A

no because no co-stimulation
CD28 is the costimulatory signal and is the second signal for activation of T cells

CTLA-4 mice would be really terrible EAE
wouldn’t be a mechanism to shut off t cell activation/responses, so propagation of immune response

70
Q

cyclophosphamide

A

immunosuppression

71
Q

negative selection

A

negative selection happens if an immature lymphocyte (in thymus) interacts strongly with a self antigen, dsiplayed as a peptide bound to a self MHC. which then leads to that lymphocyte going through apoptosis

72
Q

CTL4

A

on recognition of self antigens T cells may also engage this CTL4, which functions to terminate T cell activation

CTL4 recognizes B7 and removes it from the surface of APC’s, reducing costimulation

CTL4 has higher affinity for B7 molecules than CD28, so when B7 levels are low (as normally expected when APC’s are displaying self antigens) then CTL4 is preferentially engaged

73
Q

TGFbeta

A

plays a role in the generation of T regs perhaps by stimulating expression of the FoxP3 transcription factor

74
Q

why is peripheral tolerance necessary?

A

b/c central tolerance is not absolute

some T cells escape from thymus and are self reactive

75
Q

what induces co-stimulatory signals

A

LPS through toll like receptors

chronic inflammation also puts B7 onto APC’s

76
Q

HLA alleles in autoimmunity

A

HLA-B27 -Ankylosing spondylitis

HLA-DR4

  • RA
  • pemphigus vulgaris

HLADQ8- DM type I

usually expressed later on in life

77
Q

Non-HLA alleles in autoimmunity

A

Usually these genes are developed early on in life
so children show symptoms ***

single gene defects:

AIRE–> leads to APS-1

FOXP3–> leads to IPEX

FAS–> leads to ALPS

genes that contribute
CD25

78
Q

CD25 mutation

A

similar presentation as Foxp3 mutation

CD25 induces transcription of Foxp3 so without this it would look like a Foxp3 deficiency

79
Q

IL-2

A

secreted by T cells after they are activated

causes proliferation and differentation of T cells

IHL Exam 2 (14 decks)

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