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GIGU Quiz 2 > 5. Immune Mechanisms of Diabetes > Flashcards

5. Immune Mechanisms of Diabetes Flashcards

1
Q

With normal insulin metabolism what immunological molecules predmoniate

A
  • Low serum IL-1B
  • High serum IL-1 receptor antagonist
  • M2 Macrophages (alternatively activated)
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2
Q

In T2DM Insulin Resistance what occurs in adipocytes

A
  • Increased lipolysis

- Increased macrophage accumulation

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3
Q

What are the major triggers / risk factors for T2DM

A
  • Microbiome
  • Diet
  • Energy Expenditure
  • Early life influences
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4
Q

In LEAN adipocytes what anti-inflammatory molecules are present

A
  • Treg cells
  • Th2 cells
  • M2 macrophages (alternatively activated)
  • Eosinophils
  • iNKT cells
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5
Q

In OBESE adipocytes what pro-inflammatory molecules are present

A
  • Th1 cells
  • M1 macrophages (classically activated)
  • CD8+ T cells (cytotoxic)
  • B cells
  • Dendritic, Mast and Neutrophils
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6
Q

What interleukins are found in lean vs obese adipocytes

A

Lean: IL-4, IL-10, IL-13
Obese: IL-1B, IL-6, IFN-y, FFA, TNF-a

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7
Q

The presence of what interleukin is well documented for its role in adipose inflammation and insulin resistance

A

IL-6 (released by M1 macrophages)

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8
Q

How does FFA induce adipose inflammation

A
  • FFA (palmitate) is a ligand for TLR4 on adipocytes
  • Leading to pro-inflammatory cytokine and chemokine production as well as differentiation of M1 macrophages

(Inflammatory state leads to sustained B-cell dysfunction)

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9
Q

In a normal weight insulin sensitive person what molecules do we want to see

A
  • M2 macrophages (alternative)
  • Treg cells
  • IL (4,10,13)
  • Th2 response
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10
Q

In an obese insulin resistance person what molecules do we see

A
  • M1 macrophages (classically)
  • Mast cells
  • B2 cells
  • TNF-a, IFN-y, IgG2c antibodies
  • Th1 response
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11
Q

What is the relationship between T2DM and beta cell dysfunction

A
  • T2D never develops without beta cell dysfunction

- This indicates the need for beta cell protection before the onset of T2DM

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12
Q

In T1DM what type of hypersensitivity is present and what cells mediate the destruction of B-cells

A
  • T cell mediated (Type IV hypersensitivity)

- CD8+ Cytotoxic T cells kill beta cells in this case

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13
Q

Around 20 genes are associated with T1DM, what are the four she emphasized and the two interleukins

A
  1. HLA
  2. INS (inslun gene)
  3. AIRE
  4. CTLA-4

IL-2 and IL-10

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14
Q

How do HLA class II alleles on chromosome 6 impact T1DM

A
  • DQ2/DQ8 found in more than 90% of individuals with T1DM
  • DR3/DR4 most common in children under age 5 (50%)
  • Lack Asp57
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15
Q

What is special about the HLA Class II for T1DM

A

There is a protective allele

DR2/DQ6 confers PROTECTION

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16
Q

What do these genes control; PTPN22, CTLA4, AIRE, FOXP3

A

PTPN22- Tyrosine Phosphatase
CTLA4- T cell regulation
AIRE- Thymic expression of self-proteins
FOXP3- Tregs cells

17
Q

What happens if FOXP3 gene is faulty

A

Immune dysregulation, polyendocrinopathy, enteropathy

Widespread autoimmunity

18
Q

What happens when there is a mutation in AIRE

A

AIRE expression and presentation of insulin in thymus to developing T cells is critical to protecting against development of T1DM

19
Q

What is there to know about the Insulin Gene

A
  • Class I (26-63 VNTR in promoter region) is associated with lower insulin mRNA synthesis
  • Reduction in tolerance to insulin due to low presentation
20
Q

What is there to know bout the CLTA-4 Gene

A

Defect in CTLA-4 expression on Tregs and activated T cells DECREASES ability to down-regulate immune responses and maintain tolerance

21
Q

How do we know that T1DM has environmental factors in addition to genetic

A

T1DM incidence is increasing by 3% per year which is too high to be attributed only to genetic factors

22
Q

What are some environmental risk factors associated with T1DM

A
  • C sections
  • High birth weight
  • Low transplacental trasmission of anitbodies
  • Birth order
  • Lack of breastfeed or early exposure to cow milk
  • Low Vitamin D intake
23
Q

What disease state is associated with T1DM and what are the two mechanisms viruses use to destroy Beta cells

A

Celiac Disease

-Direct Cytotoxicity and Molecular Mimicry

24
Q

What can be used to predict disease course in DM

A

Islet Cell Auto-antibody Production appears MONTHS to YEARS in advance of metabolic changes

-Their presence confirms a diagnosis of T1DM

25
Q

What are some examples of Islet Cell Auto-antibodies (ICAs)

A
  • Glutamic Acid Decarboxylase (GAD65)
  • Insulinoma Antigen-2 (IA-2, tyrosine phosphatase)
  • Insulin auto-antibodies (IAA)
26
Q

The auto-antibodies in T1DM play what role in pathogenesis

A

They may affect time course of the disease development but do not impact the pathogenesis

27
Q

Why is asthma more prevalent in T1Dm children than non-diabetic children

A

Common pathway for both is dysregulation of Tregs

28
Q

What might you use as a therapeutic to mitigate the loss of Tregs

A

CTLA-4

GIGU Quiz 2 (16 decks)

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