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Tolerance And Mechanisms Of Autoimmunity Flashcards

1
Q

What is tolerance

A

Controlled unresponsiveness

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2
Q

Where is central tolerance achieved

A

Thymus

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3
Q

How is central tolerance acheived

A

Deletion of t cellls with the potential to react against self at too high an affinity

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4
Q

What percent of T cells entering thymus fail to come out the other side

A

95-99

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5
Q

What happens when T cell is deleted

A

Killed, or rendered anergi(unresponsive)

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6
Q

Problem with anergic cells

A

Remain available. If activated could participate in autoimmune responses at a later stage

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7
Q

Indifference or ignorance

A

T cell fails to encounter a peptide presented bc not there or insufficient levels

In periphery available to activation possibly to self

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8
Q

Peripheral tolerance

A

When peripheral T cells encounter. Exceptionally high peripheral antigen levels, this may lead to activation induced cell death (ACID) and deletion

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9
Q

Example of peripheral tolerance

A

Common self antigen is taken up by a resting nonactivated dc. In absence of danger signal costimulatory molecules are not up regulated by DC.

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10
Q

Final mechanism of peripheral tolerance

A

Self antigens ma simply not be presented int h periphery as a mechanism of attaining and maintains tolerance through ignorance
-limit mhc
-restrict expression to intracellular compartment or to a tissue that is unavailable for presentation
-

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11
Q

Immunologic police

A

Treg

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12
Q

The activation of Tregs s antigen __

A

Specific

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13
Q

Treg have tcr and require activation through the tcr to regulate

A

Once activated treg can regulate the cells around them .

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14
Q

What are the three Treg

A

CD4, CD25 cells
Tr1
TH3

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15
Q

CD4 CD25 T reg

A

CD4+, TCR +
Inhibits T cell responses
Arises naturally, mainly thymus derived;high expression of Foxp3

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16
Q

Foxp3

A

Transcription factor important in Treg function and low expression of CD127 (IL7 receptor)

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17
Q

TR1

A

CD4, TCR+
Inhibits T cell responses
Produced IL10
Arises naturally or may be induced by repeated antigen injection

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18
Q

TH3

A

CD4, TCR+
Produces TGFb
Induced by oral administration of antigen

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19
Q

Treg is able to suppress the activation of an effector cell recognizing the same ___ WHEN BOUNT TO SAME APC

A

Peptide

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20
Q

Autoimmunity

A

Loss of immunological tolerance to self

Common

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21
Q

What are the two main reasons for autoimmunity

A
  1. Not all T cells are deleted in the thymus and so some T cells remain available
  2. As discussed in, T cell receptors show enormous plasticity for the peptide -MHC complexes with which they can interact
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22
Q

One TCR can interact with many more that one ___

A

Peptide

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23
Q

So, under normal circumstances, there are T cells that can recognize _ antigens

A

Self

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24
Q

What happens when self t cels are activated

A

Tissue damage , then autoimmune disease

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25
Q

How may people have autoimmune disease at some point int heir life

A

5%

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26
Q

Autoimmune potential

A

Ubiquitous
Reflects t and B cell receptor diversity
Healthy response

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27
Q

Physiological autoimmunity

A

Non pathogenis may include t regs

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28
Q

Pathological autoimmunity

A

Results in autoimmune disease, common 5% result of complex interactions of genetic and environmental factors

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29
Q

Autoantigens to acetylcholine receptor

A

Myasthenia Travis

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30
Q

Autoantigens of thyroid stimulating hormone receptor

A

Graves

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31
Q

Autoantigens is thyroid peroxidases; thyroglobulin

A

Hashimoto thyroiditis

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32
Q

Autoantigens islet cell cytoplasmic targets, insulin, glutamic acid decarboxylase, IA-2, zinc transporter 8

A

Type 1 diabetes

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33
Q

H+, K+, ATPase (gastric pump); intrinsic factor

A

Pernicious anemia

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34
Q

21a hydroxylase

A

Addison’s disease

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35
Q

Desmoglein 3

A

Pemphigus vulgaris

36
Q

Tyrosinase

37
Q

Cytochrome p4502D6

A

Autoimmune hepatitis

38
Q

Various rbc surface targets

A

Autoimmune haemolytic anemia

39
Q

Pyruvate dehydrogenase complex in mitochondria

A

Primary biliary cirrhosis

40
Q

Collagen type IV

A

Good pasture syndrome

41
Q

IgG

42
Q

Double stranded DNA; Sm; SS-A;SS-B;histones

A

Systemic lupus erythematosus

43
Q

SS-A, SS-B

A

Sjorgrens syndrome

44
Q

DNA topoisomerase

A

Systemic sclerosis

45
Q

Ribonucleotides

A

Mixed CT disease

46
Q

Important principles of autoimmune disease

A

Multifactorial
Often progresses much more slowly than immune reactions to pathogenic control, suggesting that control mechanisms may continue
Has tendency to remit and relapse, indicating that control mechanisms may recover and temporarily restore tolerance

47
Q

What is the key event of developing an autoimmune disease

A

Activation cd4 that recognize rely peptide

48
Q

What are the four checkpoints that must be overcome for autoimmunity

A

Failure of central tolerance
Failure of peripheral regulation
Presentation of autoantigens(or mimic)
Costimulatory

49
Q

Autoimmune polyglandular syndrome type I APS the I

A

Multiple autoimmune disorders
AD
Mutation in nuclear protein that regulates the transcription of other genes in the thymus
CHECK POINT 1

50
Q

Defective AIRE

A

Incomplete tolerance toa. Range of autoantigens and multiple organ specific autoimmune diseases
Rare

51
Q

CD4, 25 TRegs needs what transcription factor

52
Q

Foxp3 defective

A

IPEX

2nd checkpoint

53
Q

IPEX

A

Immune dysregulation, polyendocrinopathy, enteropathy, x linked syndrome
Rare
Defective tregs and develop a range of organ specific autoimmune disease

54
Q

CTLA4

A

Switches off activated T cells

55
Q

Ctla4 knockout

A

Severe uncontrolled T cell activation and proliferation with manifestations of autoimmunity

56
Q

In humans with CTLA4 polymorphism

A

Increased risk of developing autoimmune thyroid disease and type 1 diabetes although precisely how this leads to reduced T cell regulation and autoimmunity is not known

57
Q

Checkpoint three

58
Q

Some form of tissue damage or injury leads to release of hidden self antigens

A

Or mimicry
Antigen or epitope in the pathogen looks like a self antigen or epitope
T or B cells made that can recognize self

59
Q

Strep M protein antigen’s autoantigens (mimicry_

A

Cardiac myosin

60
Q

Result of cardiac myosin/strep M protein issue

A

Autoimmune cardiomyopathy in post strep rheumatic fever

61
Q

Trypanosomiasis cruzi b13 antigen’s mimic

A

Cardiac myosin

62
Q

Result of cardiac myosin attack frommimicry on trypanosoma cruzi b13

A

Chagas’ disease with associated cardiomyopathy

63
Q

Hepatitis C virus E1 protein mimic

A

Cytochrome p4502d6

64
Q

Effect of hepatitis c virus e1 protein and attack on cytochrome p4502d6 mimicry

A

Autoimmune hepatitis type 2

65
Q

H pylori acetate kinase mimic

A

H+K+ atpase (gastric proton pump)

66
Q

Result of mimic attack of gastric proton pump with h pylori

A

Autoimmune gastritis

67
Q

Pyruvate dehydrogenase complex E2 of bacteria mimic

A

Pyruvate dehydrogenase e2 complex in human

68
Q

Attack of pyruvate dehydrogenase e2 complex

A

Primary biliary cirrhosis

69
Q

Type 1 diabetes hla susceptibility

A

DQA10301/DQB10302 (DQ8) high risk

DQA10501/DQB10201 (DQ2)high risk

70
Q

Type 1 diabetes protection hla

A

DQA10102/DQB10602 (DQ6)

71
Q

MS HLA susceptibility

A

DRB1*1501 (DR2)

72
Q

RA hla susceptibility

73
Q

Coeliac disease hla susceptible

A

DQA10501/DQB10201 (DQ2)

74
Q

HLADQB57

A

Strong influence over shape of protein

75
Q

HLADQB57Asp

A

Closed groove

76
Q

HLADQb57ala or ser

A

More relaxed
Favor presentation of an important epitope(islet or mimicry) (ASP fail to present)
Poor at presentation of critical islet autoantigens epitope in thymus , thus failing to delete potential islet autoreactive T cells(Asp good at this)
Poor at presentation of critical islet autoantigen epitope in thymus, thus failing to generate regulatory T cell populations that can prevent autoimmunity developingin the periphery (asp good at thymus expression

77
Q

Major criteria for being an autoimmune disease

A

Evidence of loss of tolerance:presence of T or B cell autoimmunity
Clinical response to appropriate immune suppression
Passive transfer of the putative immune effector causes the disease

78
Q

Minor criteria of autoimmune disease

A

Animal model that resembles
Evidence that in animal model, passive transfer of the putative immune effectors reproduces the disease in a naive animal
HLA association

79
Q

Diabetes arises spontaneously

A

NOD-animal

Type 1 diabetes human

80
Q

Immunization with myelin basic protein or key peptides

A

Animal-experimental allergic encephalomyelitis

MS

81
Q

Immunization with adjuvant(M Tb)

A

Adjuvant arthritis -animal

RA-human

82
Q

Immunization with collagen

A

Collagen induced arthritis -animal

RA-human

83
Q

Treatment for autoimmune diseases

A

Blanket immune suppression-replacement therapy or suppression with corticosteroids
Immune suppression targeted at t or B cell

84
Q

Corticosteroids

A

Have effects on almost every compartment of the immune system interfering with cell activation and migration

85
Q

Downside of corticosteroid thepay

A

Side effects

86
Q

Effectors (bad guys)

A

Immune system

87
Q

Cops

Immunology (14 decks)

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