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GIGU > Immune Diabetes > Flashcards

Immune Diabetes Flashcards

1
Q

What are microbiome triggers/RF of Type 2 DM?

A

Deliver mode, Abx, processed foods from diet

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2
Q

What are diet triggers/RF of Type 2 DM?

A

total calorie intake

macro and micro nutrients

vitamins

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3
Q

Describe normal insulin metabolism in circulation

A

Low serum insulin, glucose, FFA, IL-1

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

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4
Q

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

A

Basal metabolism
Exercise
Sedentary behavior
Ambient Temp

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5
Q

How is inflammation controlled in normal insulin metabolism?

A

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

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6
Q

What happens in insulin resistance r/t adipose tissue?

A

increased lipolysis–> increased macrophage accumulation–> INFLAMMATION

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7
Q

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

A

Maternal disease
Placental fxn
Maternal nutrition
Postnatal growth

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8
Q

What are other triggers/RF of Type 2 DM?

A 
No2
Particulate matter
Pesticide
Sleep debt
Endocrine disruption
Chronic inflammation
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9
Q

What genetic RF are associated with Type 2 DM?

A

Higher risk for AA>Histpanic>Native American

both parents have it: 70% risk

monozygotic twins

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10
Q

Describe characteristics/cells in normal adipose tissue

A

Spaces between adipocytes

Treg cells
Th2 cells
NKT and M2 cells
Eosinophils

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

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11
Q

Describe characteristics/cells in obese adipose tissue

A

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

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12
Q

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

A

IL-6

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13
Q

How does FFA induce adipose inflammation?

A

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)

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14
Q

What cytokines decrease in obese adipose tissues?

A

IL-4
IL-10
IL-13
Th2 response

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15
Q

What cytokines increase in obese adipose tissues?

A

TNF-alpha
IFN-gamma
IgG2c antibodies
Th1 responses

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16
Q

What type of hypersinsitivity is Type 1 DM?

A

type 4

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17
Q

Describe Type 1 DM

A

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

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18
Q

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

A

Th1 and Th2

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19
Q

Th1 cells secrete IFNy in Type 1 DM to activate?

A

macrophages and release of IL-1 and TNFaplha

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20
Q

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

A

autoantigen-specific CD8+ cells (cytotoxic T cells)

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21
Q

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

A

B lymphocytes to produce islet cell autoantibodies and antiGAD65 antibodies

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22
Q

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

A

descruction of beta cells with decreased insulin secretion

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23
Q

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

A

monozygotic (30-50%)

24
Q

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

A

Type 1

25
Q

30% lifetime risk for Type 1 DM if

A

both parents have it

26
Q

What 4 genes are implicated in Type 1 DM?

A

HLA ***major

INS (insulin gene)

AIRE (necessary for expression of self proteins)

CTLA-4 (nml shut down T cell development)

27
Q

Are risk additive in Type 1 or Type 2 DM?

A

Type 2 DM

28
Q

What HLA haplotype is protective in DM?

A

DR2

DQ6

29
Q

What is the high risk HLA class 2 allele?

A

Chromosome 6

–>DQ2/DQ8 and DR3/DR4

30
Q

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

A

DQ2/DQ8

DR3/DQ2

DR4/DQ8

31
Q

What genotype is most common in children dx before 5?

A

DR3/DR4

32
Q

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

A

Asp57

33
Q

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

A

Rheumatoid Arthritis

Type 1 DM

autoimmune thyroid

34
Q

What autoimmunity is seen in CTLA 4 gene dysfunction?

A

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

35
Q

What autoimmunity is seen in AIRE gene dysfunction?

A

Diabetes

Adrenal autoimmunity

Parathyroid autoimmunity

36
Q

What autoimmunity is seen in FAS gene dysfunction?

A

Splenomegaly
Lymphadenopathy
Adrenal autoimmunity

37
Q

What autoimmunity is seen in FoxP3 gene dysfunction?

A

Immune dysregulation

Polyendorinopathy

Enteropathy

***essentially widespread autoimmunity d/t deficient # Treg cells

38
Q

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

A

AIRE

–>normally protective against Type 1 DM development

39
Q

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

A

risk of Type 1 DM increases 2 fold

–>associated with lower insulin mRNA synthesis (reduced tolerance d/t low presentation)

40
Q

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

A

CTLA-4 gene

–>normally maintains tolerance

41
Q

Is Type 1 DM risk factors purely genetic?

A

NO–> monozygotic risk same in 1 and 2 DM

increasing risk 3%/year too high to be d/t genes alone

42
Q

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

A

INVERSE

decreased breastfeeding–> increased risk

43
Q

What is the relationship with cow milk and Type 1 DM

A

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

44
Q

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

A

Wheat gluten

45
Q

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

A

increase risk

46
Q

What viruses are implicated in development of Type 1 DM?

A 
Mumps
Rubella
Cytomegalovirus
Enterovirus
Retrovirus
47
Q

What chemicals cause direct destruction of beta cells?

A

N-nitroso compunds
Alloxan
smoked meat/foods

48
Q

Describe the processing, presentation and activation of autoantigen by APCs

A

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

49
Q

What are the islet cell autoantibodies (ICAs)?

A

GAD65
IA-2
Insulin autoantibodies (AA)

–>presence confirms Type 1 DM

50
Q

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

A

months to years

—>used to predict disease course

51
Q

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

A

no, only course of disease development

52
Q

What destroys beta cells?

A

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

53
Q

How are Th1 and Th2 in Type 1 DM?

A

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

54
Q

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

A

Asthma

–> both have dysregulation of Tregs

55
Q

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

A

CTLA 4

GIGU (37 decks)

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