Immunology Mechanisms of Diabetes

Question 1

Changes in the concept of T2D

past

present

Answer 1

in the past it was thought obesity led to insulin resistance and hyperinsulinemia, now it is undersootd that beta cell loss leads to reduced beta cell mass and a reduced insulin secretion. So now its insulin resistance and at later stages a low production

Question 2

Genetics of T2D

how do you know its genetic and environmental?

what population has strangely high risk

Answer 2

• know its genetic because offspring of parent has 40% chance, if both parents have it, there is a 70 percent chance.
• concordance rate of T2D was 34% among MZ twins and 16% of fraternal, suggests significant environtmental role

pima indians have 10 fold higher prevalence than general US population

environmental: sedentary/high fat lifestyles, studies have shown pollution and exposure to organic land pollutants induces insulin resistance.
- traffic related pollutants (particulate matter and nitrogen dioxide, is associated with higher risk of t2d)

Question 3

In a normal individual how does insulin sensitivity work?

• affect on glucose uptake, fatty acid release, hepatic gluconeogenesis
• what do adipose tissue macrophages and Kupffer cells express? suppress?
• overall serological state?

Answer 3

Question 4

what happens in insulin resistance? (general mechanism)

Answer 4

inflammation leads to beta cell death

Question 5

What type of macrophages dominate in lean vs obese person?

Answer 5

Question 6

Lean conditions:

what do adipocytes secrete?

promotes activation of what?

why is this important?

Answer 6

Question 7

obesity conditions:

adipocyte changes result in increased what?

what do the adipocytes release?

why is this important?

Answer 7

Question 8

Palmitate-TLR4 pathway:

what is palmitate?

Beta cells sense palmitate how?

what do the beta cells recruit?

end result?

Answer 8

Question 9

What is Type 1 Diabetes?

• characterized by?
• ketoacidosis?
• HLA associations and autoantibody
• mediated by what kind of cell?
• what is insulitis? caused by?

Answer 9

Question 10

Genetics of Type 1 Diabetes:

Familial clustering?

before 20 years old?

concordance (MZ vs DZ)

Answer 10

Question 11

what genes are associated with T1D

• HLA?
• insulin gene, mechanism, chromosome #
• regulators, expression location
• CTLA-4, roll

Answer 11

Question 12

How is central tolerance to insulin established?

Answer 12

Question 13

Role of HLA in T1D:

high risk allelles?

most common heterozygous genotypes in children

Asp57?

which class II haplotypes confer dominant protection?

Answer 13

Question 14

The Insulin Gene (IDDM2)

• where is the VNTR located?
• Classes
• which class are susceptible?
• what happens to central tolerance?

Answer 14

Question 15

Transcriptional AutoImmune Regulator (AIRE)

• what does it control?
• malfunction of AIRE leads to?
• Critical for what?

Answer 15

Question 16

CTLA-4 gene (IDDM12)

• susceptibility locus
• encodes what glycoprotein which binds to what?
• CTLA4 may counter regulate what?
• what is its overall function?

Answer 16

Question 17

what is the mechanism of action of CTLA-4

Answer 17

Question 18

CTLA-4 peripheral tolerance

• Early vs Late
• mechanism of inhibition of Tcell

Answer 18

early T cell expresses only CD28, when its been activated for several days, it starts to express CTLA-4 (Late). this is the way it inhibits. so if you have defect in CTLA-4, t cell will be persistent in circulation wont be inhibited by CTLA-4.

Question 19

Answer 19

E

Question 20

Environmental factors in T1D

-concordance for MZ suggests?

Answer 20

Question 21

Breast-Feeding vs. Cow Milk

• correlaton between breast feeding and diabetes
• early exposure to cow milk

Answer 21

Question 22

Environmental Factors of T1D

• wheat gluten?
• Vitamin D
• Chemicals?

Answer 22

vitamin D higher in North and South latitudes lower in equatorial

Question 23

Role of infection in T1D

• Streptozozocin/bafilomycin A1 from Streptomyces
• viruses implicated in T1D, and through what possible mechanisms?

Answer 23

Question 24

• level of C peptide in blood can show what?
• modern model of pathology of T1D and timeline

Answer 24

Question 25

Autoantibodies in T1D:

• what autoantibodies are detected with increased frequency in T1D?
• does production increase correlate directly with initiation of T1d?
• specific autoantibodies

Answer 25

Question 26

T1D onset and development overview:

Answer 26

Question 27

Pathogenic role of auto abs:

• controversial?
• likely role?

Answer 27

Question 28

Initiation of Immune response in T1D

• Beta cell
• DCs take up what?
• DCs then activate what cells?

Answer 28

Question 29

Immune response in T1D

• CTL role
• CD4 activate what?
• Mechanisms regulated by what?

Answer 29

Question 30

Pathogenic role of T cells:

• where are t cells activated and where do they end up?
• Local APCs secrete what?
• IFN gamma roll

Answer 30

Question 31

Cell-mediated immunity and T1D

-role of Treg

best mechanisms supported by data

Answer 31

Question 32

CD4+/CD25+ Treg cells in T1D

• islet cells release what?
• what do Cd4/cd25 treg cells do?

Answer 32

Question 33

Answer 33

C

Question 34

IPEX syndrome:

how does it relate to diabetes and to tregs?

Answer 34

Question 35

Answer 35

C

Question 36