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MIMM 314 > Lecture 21 - T1D > Flashcards

Lecture 21 - T1D Flashcards

1
Q

which type of diabetes is triggered by immune system?

A

T1D

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2
Q

2 things that can lead to T1D development

A
  1. genetic predisposition
  2. environmental factors
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3
Q

what happens in T1D?

A

destruction of insulin-producing beta cells in islets of Langerhans

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4
Q

describe the 6 stages in development of T1D

A
  1. underlying genetic susceptibility
  2. environmental triggers
  3. beta cell antigens taken up by APC and stimulate CD4/CD8 T cells
  4. T cells destroy islets and B cells produce autoAb
  5. epitope spreading
  6. cross threshold –> clinical disease
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5
Q

does genetic predisposition cause T1D?

A

genetic predisposition is not sufficient to cause T1D but in combination with environmental factors can lead to T1D

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6
Q

3 examples of environmental triggers that can lead to T1D

A
  1. infection
  2. chemicals
  3. pollutants
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7
Q

combo of genetic predisposition and environmental factors leads to:

A

combo of genetic predisposition and environmental factors leads to release of antigens of insulin-producing beta cells that can be taken up by APCs

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8
Q

what happens to Treg function in T1D?

A

Treg function is reduced

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9
Q

When does Treg function decrease in T1D development?

A

once CD4/CD8 T cells are stimulated by APCs presenting beta cell antigens

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10
Q

2 types of epitope spreading

A
  1. Intramolecular
  2. Intermolecular
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11
Q

what is intramolecular epitope spreading?

A

T cells recognize diff parts of the SAME protein

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12
Q

what is intermolecular epitope spreading?

A

T cells evolve their response to respond to different antigens

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13
Q

what causes you to transition into clinical diabetes?

A

cross threshold of amount of remaining beta cells = diabetes

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14
Q

what happens in the honeymoon phase of T1D development?

A

temporary, transient phase where there’s normal control of glucose

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15
Q

what % of remaining beta cells is required to become clinical diabetes?

A

need 90% decline in islet cell mass

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16
Q

what is an odds ratio determined from GWAS?

A

tells you how much a gene is contributing to T1D

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17
Q

what gene has highest odds ratio in T1D?

A

HLA –> 50% of genetic risk

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18
Q

describe insulin in non-diabetic people

A

non-diabetic ppl can also make insulin in thymus which may help them negatively select auto-reactive lymphocyte

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19
Q

purpose of looking at GWAS of T1D

A

to see which genes contribute to onset of T1D

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20
Q

2 ways that genes can become T1D trigger

A
  1. germ-line changes
  2. allelic variations/genetic polymorphisms
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21
Q

how do genes induce T1D?

A

push innate and adaptive respnoses towards self-Ag

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22
Q

if you combine all genes described for T1D, what is the genetic risk of these components?

A

genes represent ~5% of disease susceptibility

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23
Q

what is the significance of only 5% of disease susceptibility coming from genes?

A

environment plays a major role

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24
Q

in general what types of genes are involved in T1D?

A

both HLA and non-HLA genes

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25
Q

what mutation in HLA alleles can cause T1D susceptibility?

A

mutation in Asp57 –> 1 single aa change can determine whether you have HLA-associated risk

26
Q

why does Asp57 induce T1D?

A

peptides in MHC have anchor points, but with mutation the peptide has low affinity to MHC –> causes defective central tolerance

27
Q

what is the most important biomarker for T1D?

A

islet autoAb –> predictors of disease

28
Q

when do islet autoAb appear?

A

when insulin-producing beta cells are damaged

29
Q

how does amount of autoAb correlate to T1D risk?

A

more autoAb = increase in T1D risk

30
Q

what do initial autoAb responses tell us about T1D?

A

initial autoAb responses can help predict disease progression

31
Q

4 autoAg

A
  1. islet-APP
  2. glutamic acid decarboxlase
  3. phogrin
  4. INSULIN
32
Q

what allows for there to be multiple auto antigens?

A

epitope spreading

33
Q

are auto antigens related to central or peripheral tolerance?

A

unknown whether auto antigens related to ineffective central or peripheral tolerance

34
Q

3 ways that immune regulation prevents T1D in healthy person

A
  1. suppressive mediators
  2. inhibitor receptors
  3. Tregs
35
Q

what determines whether the immune regulation fails to cause T1D?

A

environment and genetics, and lack of function of suppressive mechanisms

36
Q

what happens to Tregs in T1D with age?

A

with age, suppression and activation fall out of balance so Tregs become fatigued

37
Q

what causes T1D in babies

A

monogenic form of T1D –> mutations in Foxp3 to induce IPEX

38
Q

what happens in monogenic form of T1D?

A

defective Treg development

39
Q

what % of kids with IPEX develop T1D?

A

80% of kids with IPEX develop T1D

40
Q

what can reverse IPEX-based T1D?

A

BM transplant

41
Q

what is a NOD mouse?

A

Non-Obese Diabetes –> non-obese relative T2D

42
Q

2 distinct phases of NOD mouse

A
  1. Non-destructive peri-insulitis
  2. Destructive insulitis
43
Q

what happens in non-destructive peri-insulitis in NOD mice?

A

activation/development of autoreactive T cell responses –> autoreactive cells enter but don’t cause destruction

44
Q

what happens in destructive insulitis in NOD mice?

A

T1D pathology –> autoreactive cells infiltrate and cause damage

45
Q

what happens to Tregs in islets?

A

reduced proliferation –> loss of cycling and IL2

46
Q

do Tregs outside of pancreas also have reduced proliferation?

A

no! only in iselts

47
Q

what is a result of reduced Treg cycling in islets?

A

fitness of Tregs reduced

48
Q

what are 2 results of reduced IL2 in islets?

A

reduced IL2
= reduced Bcl2 = apoptosis

= reduced Foxp3 epigenetics/survival, etc

49
Q

why does reduced IL2 in islets cause reduced Tregs?

A

Tregs are so dependent on paracrine IL2 for expansions, survival, function, epigenetics

50
Q

what is a good target for T1D?

A

IL2 –> increase IL2 so Tregs can be better suppressors in the pancreas

51
Q

what happens if IL2 is neutralized in NOD mice?

A

accelerated T1D onset

52
Q

describe T cell responsiveness in NOD mice

A

T cell has less responsiveness to TCR stimulation in NOD mice

53
Q

how do defective IL2/IL2R signals affect Foxp3 Tregs

A

defective IL2/IL2R signals REDUCE survival of Foxp3 Tregs in islets

54
Q

what happens if IL2 is restored in defective IL2/IL2R signals?

A

IL2 restores intra-islet Foxp3 Treg survival and function

55
Q

what are previous treatments for T1D?

A

Insulin injection, pancreas transplant, islet transplant, etc.

56
Q

issue with transplants for T1D?

A

underlying autoimmunity is still there

57
Q

what is the new method of T1D treatment?

A

immunomodulation

58
Q

what is the goal of immunomodulation?

A

inhibit inflammation and potentiate regulatory function

59
Q

2 examples of immunomodulators

A
  1. IL2 therapy
  2. cell therapy
60
Q

explain IL2 therapy for T1D

A

use mutant cytokines (muteins) –> very good at binding IL2Ra, there it is a Treg-directed IL2

61
Q

explain cell therapy for T1D

A

boost Tregs, fix Tregs, condition Tregs, give more Tregs

62
Q

2 issues with Treg cell therapy (donor cells)

A
  1. Treg is hyperstimulated and may become anergic, fatigued and not actually be protective
  2. Tregs could become inflammatory

MIMM 314 (23 decks)

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