Immunological Mechanisms of Diabetes

Question 1

What characterizes obesity?

Answer 1

Chronic activation of inflammatory pathways

Question 2

In normal weight subjects, _______ is high in serum and ________ is low in serum.

Answer 2

IL-R alpha = high

IL-1 beta = low

Question 3

Which macrophages are pro-inflammatory?

Answer 3

M1

Associated w/ chronic obesity (inflammation)

Question 4

Which macrophages are anti-inflammatory?

Answer 4

M2

Question 5

Which cells are associated with lean people?

Answer 5

M2-macrophages

T regs

Th2

eosinophils

Question 6

Which cells are assocated w/ obese people?

Answer 6

M1 macrophages

Th1

CTLs

Neutrophils

Question 7

Which cytokines are anti-inflammatory?

Answer 7

IL-4

IL-13

(M2 macrophages secrete IL-10 that inhibits inflammation)

Question 8

Which cytokines are pro-inflammatory?

Answer 8

TNF alpha, IL-I beta, IL-6, resistin, NO

Question 9

Which long chain fatty acid induces beta cell dysfunction by activating inflammatory processes in the islets?

Answer 9

Palmitate

Question 10

What is your risk of getting type 2 diabetes if one or both of your parents has it?

Answer 10

one = 40%

both = 70%

Also, pollution + behavioral factors such as a sedentary lifestyle + high fat diet contribute 66% of diabetes.

Question 11

What can also contibute towards weight gain, insulin resistance, and inflammation?

Answer 11

gut microbiota

Studies think fecal transplantation of butyrate-producing intestinal bacteria = important for cure

Question 12

Who recieved the nobel prize for diabetes?

Answer 12

Banting

Question 13

Before treatment w/ insulin in 1922, what was diabetes considered as?

Answer 13

A terminal condition

Question 14

What cells infiltrate the islets of langerhans during the onset of type 1 diabetes?

Answer 14

mononuclear cells + CD8+ T cells (Insulitis)

Question 15

Enviornmental factors such as a virus, diet, toxins, phychological stress can cause _____.

Do you remember some of the virus’s linked to it?

Answer 15

Type 1 diabetes

Virus’s = enteroviruses, mumps, rubella

via cytotoxicity + molecular mimicry

Question 16

Review this chart for what can cause type 1 diabetes

Answer 16

Question 17

If a child is not breast fed and has an early exposure to cow’s milk early in life this could cause ______.

Answer 17

Immune tolerance to insulin (cause cow milk has less insulin)

Question 18

What is a possible diabetogen (causes diabetes)?

Answer 18

Wheat gluten

Question 19

Patients with T1D often have celiac disease, but what do they usually lack in their gut microbiota?

Answer 19

Butyrate - Producer genera

Question 20

What is your risk of getting T1D before age 20?

Answer 20

0.4%

But it does have familial clustering

Question 21

What genes determine T1D susceptibility?

Answer 21

Insulin gene (IDDM2) (chromosome 11)

HLA DQ2 + DQ8 (chromosome 6)

CTLA-4 (IDDM12) (chromosome 2)

Question 22

What genes regulate insulin gene expression in the thymus?

Answer 22

AIRE (chromosme 21)

Question 23

What maintains the central tolerance and controls auto-Ag expression in the thymus?

Answer 23

Thymic epithelial cells –> negative selection –> Autoimmune Regulator Transcription Factor (AIRE)

Question 24

What happens if the central tolerance is broken?

Answer 24

AIRE failed to control the transcriptional expression of insulin, and the absense of insulin results in failure of deleting insulin reactive T cells.

Question 25

What are the 2 ways CTLA-4 inhibits T cell activation?

Answer 25

1. Cell-Intrinsic CTLA-4 Function
   - signal block
2. Cell-Extrinsic CTLA-4 Function
   - reduced B7 costimulation

Question 26

The instability of microbiomes + low ratio of ____________________ may be early diagnostic markers of pending autoimmune disorders such as T1D.

Answer 26

Bacteroidetes/Firmicutes in gut microbiota

This ratio modifies the balance of Tregs

Question 27

What type of antibodies are detected in T1D?

Answer 27

Islet cell autoantibodies (ICA)

These are present in increased frequency w/ people recently diagnosed (can predict disease) and can confirm a diagnosis.

Question 28

When combined with HLA typing (remember 90% of people with T1D have them), autoantibodies can predict the possibility of getting T1D.

1 Ab =

2 Ab’s =

3 Ab’s =

w/in 5 yrs

Answer 28

1 Ab = 10%

2 Ab’s = 40%

3 Ab’s = 60%

2 + 3 Ab’s = highly predictive

Question 29

What results in a widespread automiimunity?

Answer 29

FoxP3 (CD25) –> Treg

Question 30

What does B7 bind?

Answer 30

CD28

Question 31

What does AIRE do?

Answer 31

AIRE expression and presentation of insulin in thymus to developing T cells in critical to protecting against development of T1D.

Question 32

What is found in the insulin gene (IMMD2 on chromosome 11)?

Answer 32

Variable Number Tandem Repeats (VNTR) in promoter region:

– Class I: 26-63 repeats

• Relative increase in risk ~2 fold with two class I alleles

Class I is associated with lower insulin mRNA synthesis.

Question 33

What does CTLA-4 do?

Answer 33

Chromosome 2 (IDDM12) Defect in CTLA-4 expression on Tregs and activated T cells decreases ability down-regulate immune response and maintain tolerance

Question 34

How does the environmental factor of breastfeeding impact type 1 diabetes?

Answer 34

Breast-feeding: inverse correlation between decreased breast-feeding and increased T1D • Early exposure to cow milk may contribute to the development of T1D as cow milk contains much less insulin than breast milk

Question 35

MEMORIZE (environmental causes of T1D)

Question 36

GAD65

IA-2

IAA

are what?

Answer 36

ICA’s (Islet cell autoantibody)

Question 37

MEMORIZE

Answer 37

Question 38

What deystroys beta cells?

Answer 38

CTLs + CD8+

via Th1 (which suppresses th2 –> the good guy)

Question 39

Dysregulation of Tregs leads to?

Answer 39

Type 1 Diabetes