The pathogenesis of Type 1 diabetes Flashcards
What is the target HbA1c for a diabetic now?
<6.5%
Define microalbuminuria
- A term to describe a moderate increase in the level of urine albumin
- Occurs when the kidney leaks small amounts of albumin into the urine, in other words, when an abnormally high permeability for albumin in the glomerulus of the kidney occurs
Outline the pathology of the islets of Langerhans in type I diabetes
-Pseudoatrophic islets; small, devoid of Beta cells,but retaining glucagon (alpha) and somatostatin (delta)
Define insulitis
Disease of the pancreas caused by the infiltration of lymphocytes
Outline the auto immune response in diabetes
- an APC expressing an autoantigen activates autoreactive T lymphocyte
- T helper and T killer cells that kill the patients own cells making up their islets of langerhans are produced
- B lymphocytes which produce autoantibodies are also produced and help in the detsurction of the islet cells
Which cells produce insulin
The Beta cells of the islets of Langerhans
Which cells produce glucagon
The alpha cells of the islets of Langerhans
Which cells produce somatostatin
The delta cells of the islets of Langerhans
Why is T1DM defined as autoimmune?
- Theres evidence of loss of immunological tolerance to self
- Passive transfer of disease by immune effectors eg T cells, antibodies
- Clinical responsiveness to immune suppression, or to re-establishment of tolerance
- Genetic predisposition
What is the fate of babies of type 1 DM mothers
-Not born with diabetes although they are born with adult cell autoantibodies
What could a lower than normal C peptide level indicate
Your body isn’t making enough insulin, or that your pancreas isn’t working properly
What is the function of cyclosporine?
- Used to prevent organ rejection in people who have received a liver, kidney, or heart transplant.
- Usually taken along with other medications to allow your new organ to function normally.
- Belongs to a class of drugs known as immunosuppressants.
How can the autoantibodies involved be measured?
- By RIA or ELISA
- Useful in diagnosis: neonatal diabetes, older cases, gestational diabetes
How can islet cells autoantibodies be useful in diagnosis?
ICAs do not cause T1D but they are highly predictive of disease
- Predict future type 1 diabetes
- If you have multiple then you are almost certain to develop type 1 diabetes
- ‘Multiple islet cell ab positive’ = stage 1 type 1 diabetes
List the different types of auto abs involved in type I diabetes
What can they be used as in terms of ICA
- Insulin
- Glutamic acid decarboxylase (GAD65)
- Insulinoma-associated antigen-2( IA-2)
- Zinc transporter 8 (ZnT8)
-They can be used as the 4 main molecular targets of Islet cell autoantibodies
How are CTLs targeted to kill Beta cells in patients with type I diabetes
-Through recognition of a glucose-regulated preproinsulin epitope
How are regulatory T cell responses affected in T1D?
-Decreased CD25+ regulatory T cell function
Outline the idea of immune imbalance in T1D
- Imbalance between Th + Tc cells compared to T reg cells.
- Autoreactive T cells are pro-inflammatory and lead to the destruction of nearly all the Beta cells
- Insufficient T reg function to keep autoimmunity from occuring
What is AHSC?
Autologous Hematopoietic stem cell transplantation
-The idea is to develop tolerance again by removing or partially remove the current immune system
Outline targetted immunosuppression in T1D
- ) Block T cell signalling
- CTLA-4-Ig
- Anti-CD3 ab
- Binds to all T cells
- Preferentially affects activated cells - ) Remove key APCs
- Anti-CD20 ab
- Pan B cell depletion - ) Block effector cytokines
- Anti-IL-17 ab
- Blocks cytokine signalling
How can we correct immune imbalance in T1D?
- ) Adoptive cell therapy
- ) Low dose IL-2 therapy
- Isolate Tregs
- (Modify)
- Expand with IL-2
- Re-infuse
Explain antigen specific immunotherapy
- The principle= immunization of peptide in saline ( i.d or s.c)
- Peptides presented by iDCs
- Tolerance inducing
- effective in allergy
