Lecture 21 - T1D Flashcards
which type of diabetes is triggered by immune system?
T1D
2 things that can lead to T1D development
- genetic predisposition
- environmental factors
what happens in T1D?
destruction of insulin-producing beta cells in islets of Langerhans
describe the 6 stages in development of T1D
- underlying genetic susceptibility
- environmental triggers
- beta cell antigens taken up by APC and stimulate CD4/CD8 T cells
- T cells destroy islets and B cells produce autoAb
- epitope spreading
- cross threshold –> clinical disease
does genetic predisposition cause T1D?
genetic predisposition is not sufficient to cause T1D but in combination with environmental factors can lead to T1D
3 examples of environmental triggers that can lead to T1D
- infection
- chemicals
- pollutants
combo of genetic predisposition and environmental factors leads to:
combo of genetic predisposition and environmental factors leads to release of antigens of insulin-producing beta cells that can be taken up by APCs
what happens to Treg function in T1D?
Treg function is reduced
When does Treg function decrease in T1D development?
once CD4/CD8 T cells are stimulated by APCs presenting beta cell antigens
2 types of epitope spreading
- Intramolecular
- Intermolecular
what is intramolecular epitope spreading?
T cells recognize diff parts of the SAME protein
what is intermolecular epitope spreading?
T cells evolve their response to respond to different antigens
what causes you to transition into clinical diabetes?
cross threshold of amount of remaining beta cells = diabetes
what happens in the honeymoon phase of T1D development?
temporary, transient phase where there’s normal control of glucose
what % of remaining beta cells is required to become clinical diabetes?
need 90% decline in islet cell mass
what is an odds ratio determined from GWAS?
tells you how much a gene is contributing to T1D
what gene has highest odds ratio in T1D?
HLA –> 50% of genetic risk
describe insulin in non-diabetic people
non-diabetic ppl can also make insulin in thymus which may help them negatively select auto-reactive lymphocyte
purpose of looking at GWAS of T1D
to see which genes contribute to onset of T1D
2 ways that genes can become T1D trigger
- germ-line changes
- allelic variations/genetic polymorphisms
how do genes induce T1D?
push innate and adaptive respnoses towards self-Ag
if you combine all genes described for T1D, what is the genetic risk of these components?
genes represent ~5% of disease susceptibility
what is the significance of only 5% of disease susceptibility coming from genes?
environment plays a major role
in general what types of genes are involved in T1D?
both HLA and non-HLA genes
what mutation in HLA alleles can cause T1D susceptibility?
mutation in Asp57 –> 1 single aa change can determine whether you have HLA-associated risk
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
what is the most important biomarker for T1D?
islet autoAb –> predictors of disease
when do islet autoAb appear?
when insulin-producing beta cells are damaged
how does amount of autoAb correlate to T1D risk?
more autoAb = increase in T1D risk
what do initial autoAb responses tell us about T1D?
initial autoAb responses can help predict disease progression
4 autoAg
- islet-APP
- glutamic acid decarboxlase
- phogrin
- INSULIN
what allows for there to be multiple auto antigens?
epitope spreading
are auto antigens related to central or peripheral tolerance?
unknown whether auto antigens related to ineffective central or peripheral tolerance
3 ways that immune regulation prevents T1D in healthy person
- suppressive mediators
- inhibitor receptors
- Tregs
what determines whether the immune regulation fails to cause T1D?
environment and genetics, and lack of function of suppressive mechanisms
what happens to Tregs in T1D with age?
with age, suppression and activation fall out of balance so Tregs become fatigued
what causes T1D in babies
monogenic form of T1D –> mutations in Foxp3 to induce IPEX
what happens in monogenic form of T1D?
defective Treg development
what % of kids with IPEX develop T1D?
80% of kids with IPEX develop T1D
what can reverse IPEX-based T1D?
BM transplant
what is a NOD mouse?
Non-Obese Diabetes –> non-obese relative T2D
2 distinct phases of NOD mouse
- Non-destructive peri-insulitis
- Destructive insulitis
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
what happens in destructive insulitis in NOD mice?
T1D pathology –> autoreactive cells infiltrate and cause damage
what happens to Tregs in islets?
reduced proliferation –> loss of cycling and IL2
do Tregs outside of pancreas also have reduced proliferation?
no! only in iselts
what is a result of reduced Treg cycling in islets?
fitness of Tregs reduced
what are 2 results of reduced IL2 in islets?
reduced IL2
= reduced Bcl2 = apoptosis
= reduced Foxp3 epigenetics/survival, etc
why does reduced IL2 in islets cause reduced Tregs?
Tregs are so dependent on paracrine IL2 for expansions, survival, function, epigenetics
what is a good target for T1D?
IL2 –> increase IL2 so Tregs can be better suppressors in the pancreas
what happens if IL2 is neutralized in NOD mice?
accelerated T1D onset
describe T cell responsiveness in NOD mice
T cell has less responsiveness to TCR stimulation in NOD mice
how do defective IL2/IL2R signals affect Foxp3 Tregs
defective IL2/IL2R signals REDUCE survival of Foxp3 Tregs in islets
what happens if IL2 is restored in defective IL2/IL2R signals?
IL2 restores intra-islet Foxp3 Treg survival and function
what are previous treatments for T1D?
Insulin injection, pancreas transplant, islet transplant, etc.
issue with transplants for T1D?
underlying autoimmunity is still there
what is the new method of T1D treatment?
immunomodulation
what is the goal of immunomodulation?
inhibit inflammation and potentiate regulatory function
2 examples of immunomodulators
- IL2 therapy
- cell therapy
explain IL2 therapy for T1D
use mutant cytokines (muteins) –> very good at binding IL2Ra, there it is a Treg-directed IL2
explain cell therapy for T1D
boost Tregs, fix Tregs, condition Tregs, give more Tregs
2 issues with Treg cell therapy (donor cells)
- Treg is hyperstimulated and may become anergic, fatigued and not actually be protective
- Tregs could become inflammatory
