Pathogenesis of T1DM

Question 1

Descent from which continent has the highest rates of T1DM

Answer 1

Europe

Question 2

What cells in the body are destroyed in T1DM and how are they destroyed

Answer 2

Immune destruction of beta cells of the islets of the pancreas via infilitrating cytotoxic (CD8+) T cells

Question 3

Describe the pathogenesis “model” of T1DM

Answer 3

1) After birth an immune balance is established in which autoreactive T-cells are kept in check by immune regulation
2) Unknown trigger changes the immune tolerance to an unbalanced state
3) This imbalance is between autoreactive T cells and T-regulatory cells
4) This unbalanced state results in activation of B cells (to produce islet autoantibodies) and effector T cells

Question 4

Which chromosome contains all HLA genes

Answer 4

6

Question 5

What are the two main types of HLA genes that are linked to diabetes

Answer 5

HLA-DQ and HLA-DQ

Question 6

What immune cells do class II MHC antigens present to

Answer 6

CD4 lymphocytes

Question 7

What important genetic concept is present between DR and DQ genes

Answer 7

Linkage disequilibrium

Question 8

What HLA gene is protective against T1DM

Answer 8

DQ-6

Question 9

When do islet autoantibodies typically develop

Answer 9

Between 9 months and 2 years

Question 10

Describe the two main theories behind environmental causes of T1DM

Answer 10

Viral infections and the north/south hypothesis

Question 11

What virus is thought to be the most strongly linked to T1DM and why

Answer 11

Enterovirus (coxsackie B) because development of autoimmunity follows seasonal enterovirus infection (associated with DAISY cohort)

Question 12

Describe the molecular mimicry hypothesis

Answer 12

Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides.

Question 13

Describe the north south hypothesis

Answer 13

T1DM is much higher in the northern hemisphere and this is suspected to be due to vitamin d deficiency during pregnancy

Question 14

What antibodies are markers for T1DM pathogenesis

Answer 14

Islet autoantibodies

Question 15

What are the 4 beta-cell protein autoantibodies produced in diabetes

Answer 15

Insulin, GAD65, IA-2 and ZnT8 transporter (93% of T1DM patients have at least one of these)

Question 16

What percentage of the islet cells are destroyed when T1DM becomes present

Answer 16

90%

Question 17

Describe the ideal therapeutic goals in T1DM (4)

Answer 17

1) Prevention of immune destruction
2) Preservation of beta cell mass
3) Replacement or regeneration of beta cells
4) Automated insulin delivery

Question 18

Describe primary prevention of type 1 diabetes

Answer 18

Targeting high risk individuals prior to developing islet autoimmunity

Question 19

Describe secondary prevention of type 1 diabetes

Answer 19

Aimed at targeting individuals once autoantibodies have developed (non-autoantigen approach and auto-antigen approach)

Question 20

Describe intervention of type 1 diabetes

Answer 20

Targeting individuals newly diagnosed with T1DM

Question 21

Describe teplizumab

Answer 21

It is an anti-CD3 antibody that can prevent the development of type 1 diabetes