The pathogenesis of Type 1 diabetes

Question 1

What is the target HbA1c for a diabetic now?

Answer 1

<6.5%

Question 2

Define microalbuminuria

Answer 2

• 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

Question 3

Outline the pathology of the islets of Langerhans in type I diabetes

Answer 3

-Pseudoatrophic islets; small, devoid of Beta cells,but retaining glucagon (alpha) and somatostatin (delta)

Question 4

Define insulitis

Answer 4

Disease of the pancreas caused by the infiltration of lymphocytes

Question 5

Outline the auto immune response in diabetes

Answer 5

• 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

Question 6

Which cells produce insulin

Answer 6

The Beta cells of the islets of Langerhans

Question 7

Which cells produce glucagon

Answer 7

The alpha cells of the islets of Langerhans

Question 8

Which cells produce somatostatin

Answer 8

The delta cells of the islets of Langerhans

Question 9

Why is T1DM defined as autoimmune?

Answer 9

• 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

Question 10

What is the fate of babies of type 1 DM mothers

Answer 10

-Not born with diabetes although they are born with adult cell autoantibodies

Question 11

What could a lower than normal C peptide level indicate

Answer 11

Your body isn’t making enough insulin, or that your pancreas isn’t working properly

Question 12

What is the function of cyclosporine?

Answer 12

• 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.

Question 13

How can the autoantibodies involved be measured?

Answer 13

• By RIA or ELISA

- Useful in diagnosis: neonatal diabetes, older cases, gestational diabetes

Question 14

How can islet cells autoantibodies be useful in diagnosis?

Answer 14

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

Question 15

List the different types of auto abs involved in type I diabetes

What can they be used as in terms of ICA

Answer 15

• 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

Question 16

How are CTLs targeted to kill Beta cells in patients with type I diabetes

Answer 16

-Through recognition of a glucose-regulated preproinsulin epitope

Question 17

How are regulatory T cell responses affected in T1D?

Answer 17

-Decreased CD25+ regulatory T cell function

Question 18

Outline the idea of immune imbalance in T1D

Answer 18

• 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

Question 19

What is AHSC?

Answer 19

Autologous Hematopoietic stem cell transplantation

-The idea is to develop tolerance again by removing or partially remove the current immune system

Question 20

Outline targetted immunosuppression in T1D

Answer 20

1. ) Block T cell signalling
   - CTLA-4-Ig
   - Anti-CD3 ab
   - Binds to all T cells
   - Preferentially affects activated cells
2. ) Remove key APCs
   - Anti-CD20 ab
   - Pan B cell depletion
3. ) Block effector cytokines
   - Anti-IL-17 ab
   - Blocks cytokine signalling

Question 21

How can we correct immune imbalance in T1D?

Answer 21

1. ) Adoptive cell therapy
2. ) Low dose IL-2 therapy

• Isolate Tregs
• (Modify)
• Expand with IL-2
• Re-infuse

Question 22

Explain antigen specific immunotherapy

Answer 22

• The principle= immunization of peptide in saline ( i.d or s.c)
• Peptides presented by iDCs
• Tolerance inducing
• effective in allergy