Pathology of Type 1 Diabetes Flashcards
Can you biopsy a live pancreas?
No
What do the islets look like in a pancreas of someone who had chronic T1D?
- Scar tissue
- Pseudoatrophic islets
- Devoid of beta cells
- Retaining alpha (glucagon) and gamma (somatostatin) cells
Describe immune cells in the islets in T1D
- Immune cell infiltration of the islets occurs = insulitis
- T cells, B cells, macrophages
What is CD3?
A marker associated with T cells
Why is T1D autoimmune?
1) Evidence of loss of immunological tolerance to self
2) Passive transfer of disease by immune effectors e.g. T cells, antibodies
3) Clinical responsiveness to immune suppression or to re-establishment of tolerance
4) Genetic predisposition
Describe use of islet cell autoantibodies in T1D?
- Important diagnostic tool
- Useful for predicting future disease (can be detected up to 25 years before onset but mostly in children)
- Can measure at least one islet cell autoantibody in 99.9% of T1D patients
- Not pathogenic
Describe mother to child transfer of T1D?
- Babies of T1D mothers are not born with diabetes
- Therefore islet cell autoantibodies are not pathogenic bc they are transferred but the child is not born with beta cell damage/dysfunction
- Mum T1D 4% risk, dad 6-8% risk
What is evidence that T cells cause diabetes?
- If someone with T/B cell leukaemia without islet autoantibodies/T1DT1D gets a bone marrow transplant from someone with T1D they get T1D with autoantibodies
- This rarely happens anymore bc use progenitor cells in transplant
What do residual C-peptide levels reflect?
The remaining beta cell mass
Describe cyclosporin in T1D
- It stops T cells from proliferating (from T lymphocyte therefore action of T helper and T killer cels)
- Increases the length of ‘honeymoon period’
- Associated with unacceptable malignancy and OI rate so not used
What genes are affected in T1D?
- Mainly HLA class I and II involved in presenting peptides
- Affects immune system
What is the action of helper T (CD4) cells in T1D?
Th1/Th17 cells release IFN-gamma and IL-17 (pro-inflammatory) in response to islet antigens (proinsulin and IA-2) which are toxic to islet cells
What is the action of cytotoxic T (CD8) cells in T1D?
- CD8 cells release IFN-gamma which kills islet cells
- CD8 cells are targeted to kill beta cells in patients with T1D through recognition of a glucose-regulated preproinsulin epitope
- As insulin is increased (beta cells working too hard), CD8 cells do more killing
Describe Treg cells in T1D
- Treg generally releases IL-10 (immunosuppressive)
- Only find these cells in 25% of patients and they tend to develop T1D later and have better glucose control
- If clone and expand these cells can stop harmful activities of T cells
Describe Decreased CD25+ Treg cell function in T1D
- Resistance to regulation of Th17 cells (associated with resistance to suppression)
- Linked to poor function of Treg cells (cells die) due to poor IL-2 signalling
Describe the autoantigen specific immune imbalance in T1D
- More CD8 and Th1/17 than Treg
- May have cells in circulation but not activated
- This balance could be corrected with therapies (more Treg, less killer T cells and less activated Th cells i.e. Th1/17)
Describe % of beta cells in T1D
- At diagnosis have 10-30% of beta cells, not enough to have euglycaemia
- Can control diabetes much more easily with 30% beta cells
What is the aim of treatment in recent onset diabetes?
- Trying to preserve honeymoon stage
- Stop autoimmunity, induce immunoregulation and restore/preserve beta cells
- Improve glucose control
What is the aim of treatment in established diabetes?
Prevent, arrest and reverse complications
What would be the aim of treatment in patients pre-diabetes or at risk of T1D?
Prevent/stop autoimmunity and preserve beta cells
Describe autologous haematopoeitic stem cell transplantation for T1D
- Like restarting system
- Risk of neutropenic fever and sepsis
What is the goal in T1D treatment?
Restoration of immunological tolerance to beta cells
What type of autoimmune disease in T1D?
Cell specific
What happens in T1D?
- No insulin = no dampening effect of glucagon
- Uncontrolled protein breakdown
- Gluconeogenesis occurs despite high blood glucose bc liver responds to insulin not high blood glucose
- Uncontrolled increase production of KB (bc KB produce a bit of insulin but not in T1D)
- Hyperglycaemia and DKA
