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
what mutation in HLA alleles can cause T1D susceptibility?
mutation in Asp57 --> 1 single aa change can determine whether you have HLA-associated risk
26
why does Asp57 induce T1D?
peptides in MHC have anchor points, but with mutation the peptide has low affinity to MHC --> causes defective central tolerance
27
what is the most important biomarker for T1D?
islet autoAb --> predictors of disease
28
when do islet autoAb appear?
when insulin-producing beta cells are damaged
29
how does amount of autoAb correlate to T1D risk?
more autoAb = increase in T1D risk
30
what do initial autoAb responses tell us about T1D?
initial autoAb responses can help predict disease progression
31
4 autoAg
1. islet-APP 2. glutamic acid decarboxlase 3. phogrin 4. INSULIN
32
what allows for there to be multiple auto antigens?
epitope spreading
33
are auto antigens related to central or peripheral tolerance?
unknown whether auto antigens related to ineffective central or peripheral tolerance
34
3 ways that immune regulation prevents T1D in healthy person
1. suppressive mediators 2. inhibitor receptors 3. Tregs
35
what determines whether the immune regulation fails to cause T1D?
environment and genetics, and lack of function of suppressive mechanisms
36
what happens to Tregs in T1D with age?
with age, suppression and activation fall out of balance so Tregs become fatigued
37
what causes T1D in babies
monogenic form of T1D --> mutations in Foxp3 to induce IPEX
38
what happens in monogenic form of T1D?
defective Treg development
39
what % of kids with IPEX develop T1D?
80% of kids with IPEX develop T1D
40
what can reverse IPEX-based T1D?
BM transplant
41
what is a NOD mouse?
Non-Obese Diabetes --> non-obese relative T2D
42
2 distinct phases of NOD mouse
1. Non-destructive peri-insulitis 2. Destructive insulitis
43
what happens in non-destructive peri-insulitis in NOD mice?
activation/development of autoreactive T cell responses --> autoreactive cells enter but don't cause destruction
44
what happens in destructive insulitis in NOD mice?
T1D pathology --> autoreactive cells infiltrate and cause damage
45
what happens to Tregs in islets?
reduced proliferation --> loss of cycling and IL2
46
do Tregs outside of pancreas also have reduced proliferation?
no! only in iselts
47
what is a result of reduced Treg cycling in islets?
fitness of Tregs reduced
48
what are 2 results of reduced IL2 in islets?
reduced IL2 = reduced Bcl2 = apoptosis = reduced Foxp3 epigenetics/survival, etc
49
why does reduced IL2 in islets cause reduced Tregs?
Tregs are so dependent on paracrine IL2 for expansions, survival, function, epigenetics
50
what is a good target for T1D?
IL2 --> increase IL2 so Tregs can be better suppressors in the pancreas
51
what happens if IL2 is neutralized in NOD mice?
accelerated T1D onset
52
describe T cell responsiveness in NOD mice
T cell has less responsiveness to TCR stimulation in NOD mice
53
how do defective IL2/IL2R signals affect Foxp3 Tregs
defective IL2/IL2R signals REDUCE survival of Foxp3 Tregs in islets
54
what happens if IL2 is restored in defective IL2/IL2R signals?
IL2 restores intra-islet Foxp3 Treg survival and function
55
what are previous treatments for T1D?
Insulin injection, pancreas transplant, islet transplant, etc.
56
issue with transplants for T1D?
underlying autoimmunity is still there
57
what is the new method of T1D treatment?
immunomodulation
58
what is the goal of immunomodulation?
inhibit inflammation and potentiate regulatory function
59
2 examples of immunomodulators
1. IL2 therapy 2. cell therapy
60
explain IL2 therapy for T1D
use mutant cytokines (muteins) --> very good at binding IL2Ra, there it is a Treg-directed IL2
61
explain cell therapy for T1D
boost Tregs, fix Tregs, condition Tregs, give more Tregs
62
2 issues with Treg cell therapy (donor cells)
1. Treg is hyperstimulated and may become anergic, fatigued and not actually be protective 2. Tregs could become inflammatory