Immune Diabetes

Question 1

What are microbiome triggers/RF of Type 2 DM?

Answer 1

Deliver mode, Abx, processed foods from diet

Question 2

What are diet triggers/RF of Type 2 DM?

Answer 2

total calorie intake

macro and micro nutrients

vitamins

Question 3

Describe normal insulin metabolism in circulation

Answer 3

Low serum insulin, glucose, FFA, IL-1

High serum IL-1 receptor antagonist (block IL-1 receptors so that it doesn’t cause inflammation)

Question 4

What are energy expenditure triggers/RF of Type 2 DM?

Answer 4

Basal metabolism
Exercise
Sedentary behavior
Ambient Temp

Question 5

How is inflammation controlled in normal insulin metabolism?

Answer 5

Large quantities of M2 (anti-inflammatory) macrophages in ADIPOSE tissue and kupffer cell in LIVER

Question 6

What happens in insulin resistance r/t adipose tissue?

Answer 6

increased lipolysis–> increased macrophage accumulation–> INFLAMMATION

Question 7

What are early life influence triggers/RF of Type 2 DM?

Answer 7

Maternal disease
Placental fxn
Maternal nutrition
Postnatal growth

Question 8

What are other triggers/RF of Type 2 DM?

Answer 8

No2
Particulate matter
Pesticide
Sleep debt
Endocrine disruption
Chronic inflammation

Question 9

What genetic RF are associated with Type 2 DM?

Answer 9

Higher risk for AA>Histpanic>Native American

both parents have it: 70% risk

monozygotic twins

Question 10

Describe characteristics/cells in normal adipose tissue

Answer 10

Spaces between adipocytes

Treg cells
Th2 cells
NKT and M2 cells
Eosinophils

*****all contribute to anti-inflammatory state

Question 11

Describe characteristics/cells in obese adipose tissue

Answer 11

No longer spaces betweeen adipocytes d/t increased lipids in them–> FFA production in spaces between cells

~~~secrete inflammatory cytokines (TNF and IL-1)

Th1 cells
M1 macrophages
CD8+ T cells
B cells
DCs
Mast cells 
Neutrophils

*****contribute to INFLAMMATORY state

Question 12

What is secreted by M1 and adipocytes, activates liver to secrete acute phase proteins and has role in insulin resistance and adipose inflammation?

Answer 12

IL-6

Question 13

How does FFA induce adipose inflammation?

Answer 13

Palmitate (long chain FFA) is ligand for TLR4 on adipocytes–> pro-inflammatory cytokine and chemokine on binding–> recruit more M1–> inflammatory states leads to sustained B cell dysfunction (insulin resistance)

Question 14

What cytokines decrease in obese adipose tissues?

Answer 14

IL-4
IL-10
IL-13
Th2 response

Question 15

What cytokines increase in obese adipose tissues?

Answer 15

TNF-alpha
IFN-gamma
IgG2c antibodies
Th1 responses

Question 16

What type of hypersinsitivity is Type 1 DM?

Answer 16

type 4

Question 17

Describe Type 1 DM

Answer 17

True autoimmunity
—–> CD8+T cell-mediated destruction of beta cells–> insulin deficiency

Strong HLA associations

Markers of beta cell destruction are autoantibody production

***prone to KETOACIDOSIS

Question 18

What type of T helper cells do autoantigens in Type 1 DM activate?

Answer 18

Th1 and Th2

Question 19

Th1 cells secrete IFNy in Type 1 DM to activate?

Answer 19

macrophages and release of IL-1 and TNFaplha

Question 20

Th1 cells secrete IL-2 in Type 1 DM to activate?

Answer 20

autoantigen-specific CD8+ cells (cytotoxic T cells)

Question 21

Th2 cells secrete IL-4 in Type 1 DM to activate?

Answer 21

B lymphocytes to produce islet cell autoantibodies and antiGAD65 antibodies

Question 22

What are the ultimate consequences of Th1 and Th2 activation in Type 1 DM?

Answer 22

descruction of beta cells with decreased insulin secretion

Question 23

What set of twins are more likely to have Type 1 DM?

Answer 23

monozygotic (30-50%)

Question 24

Which DM makes pt and relatives increased risk for autoimmune diseases?

Answer 24

Type 1

Question 25

30% lifetime risk for Type 1 DM if

Answer 25

both parents have it

Question 26

What 4 genes are implicated in Type 1 DM?

Answer 26

HLA ***major INS (insulin gene) AIRE (necessary for expression of self proteins) CTLA-4 (nml shut down T cell development)

Question 27

Are risk additive in Type 1 or Type 2 DM?

Answer 27

Type 2 DM

Question 28

What HLA haplotype is protective in DM?

Answer 28

DR2 | DQ6

Question 29

What is the high risk HLA class 2 allele?

Answer 29

Chromosome 6 -->DQ2/DQ8 and DR3/DR4

Question 30

What HLA haplotypes are gound in most Type 1 DM individuals?

Answer 30

DQ2/DQ8 DR3/DQ2 DR4/DQ8

Question 31

What genotype is most common in children dx before 5?

Answer 31

DR3/DR4

Question 32

HLA class 2 that lack ______ of beta chain are often found in Type 1 DM individuals

Answer 32

Asp57

Question 33

What autoimmunity is seen in tyrosine phosphatase (PTPN22) gene dysfunction?

Answer 33

Rheumatoid Arthritis Type 1 DM autoimmune thyroid

Question 34

What autoimmunity is seen in CTLA 4 gene dysfunction?

Answer 34

many autoimmune syndromes d/t impaired inhibitory checkpoint of regulatory T cells

Question 35

What autoimmunity is seen in AIRE gene dysfunction?

Answer 35

Diabetes Adrenal autoimmunity Parathyroid autoimmunity

Question 36

What autoimmunity is seen in FAS gene dysfunction?

Answer 36

Splenomegaly Lymphadenopathy Adrenal autoimmunity

Question 37

What autoimmunity is seen in FoxP3 gene dysfunction?

Answer 37

Immune dysregulation Polyendorinopathy Enteropathy ***essentially widespread autoimmunity d/t deficient # Treg cells

Question 38

What is necessary to present insulin in thymys to developint T cells so it doesn't attack itself?

Answer 38

AIRE -->normally protective against Type 1 DM development

Question 39

What is the relative risk when 2 class 1 alleles of the insulin gene (r/t tandem repeats) are present?

Answer 39

risk of Type 1 DM increases 2 fold -->associated with lower insulin mRNA synthesis (reduced tolerance d/t low presentation)

Question 40

What gene is found on Chromosome 2 and decreases ability to down-regulate immune response if defective?

Answer 40

CTLA-4 gene -->normally maintains tolerance

Question 41

Is Type 1 DM risk factors purely genetic?

Answer 41

NO--> monozygotic risk same in 1 and 2 DM increasing risk 3%/year too high to be d/t genes alone

Question 42

What is the relationship of breast-feeding with Type 1 DM?

Answer 42

INVERSE decreased breastfeeding--> increased risk

Question 43

What is the relationship with cow milk and Type 1 DM

Answer 43

early exposure increases risk d/t less insulin c/t breast milk

Question 44

What food increases risk for Type 1 DM in CD patients?

Answer 44

Wheat gluten

Question 45

Does Vitamin D deficiency increase or decrease risk for Type 1 DM?

Answer 45

increase risk

Question 46

What viruses are implicated in development of Type 1 DM?

Answer 46

``` Mumps Rubella Cytomegalovirus Enterovirus Retrovirus ```

Question 47

What chemicals cause direct destruction of beta cells?

Answer 47

N-nitroso compunds Alloxan smoked meat/foods

Question 48

Describe the processing, presentation and activation of autoantigen by APCs

Answer 48

DC pick up DAMPs by beta cells-->process and present to T cells (CD8+ and Th1) via IL-2, 12, IFNy--> activate B cells-->autoantibodies

Question 49

What are the islet cell autoantibodies (ICAs)?

Answer 49

GAD65 IA-2 Insulin autoantibodies (AA) -->presence confirms Type 1 DM

Question 50

Antibody production appears _________ in advance of metabolic changes from beta cell destruction

Answer 50

months to years --->used to predict disease course

Question 51

Does autoantibody (ICA) production affect pathogenesis of Type 1 DM?

Answer 51

no, only course of disease development

Question 52

What destroys beta cells?

Answer 52

CD8+ T cell via Th1 cells and IL-10, TGFbeta (IL-2 for CD8 to survive)

Question 53

How are Th1 and Th2 in Type 1 DM?

Answer 53

Th1 (inflammatory) suppresses Th2 responses (anti-inflammatory)

Question 54

What is more prevalent in Type 1 DM children c/t non-diabetic children?

Answer 54

Asthma --> both have dysregulation of Tregs

Question 55

What is being researched for treatment of Treg dysfunction in Type 1 DM?

Answer 55

CTLA 4