5. Immune Mechanisms of Diabetes Flashcards
With normal insulin metabolism what immunological molecules predmoniate
- Low serum IL-1B
- High serum IL-1 receptor antagonist
- M2 Macrophages (alternatively activated)
In T2DM Insulin Resistance what occurs in adipocytes
- Increased lipolysis
- Increased macrophage accumulation
What are the major triggers / risk factors for T2DM
- Microbiome
- Diet
- Energy Expenditure
- Early life influences
In LEAN adipocytes what anti-inflammatory molecules are present
- Treg cells
- Th2 cells
- M2 macrophages (alternatively activated)
- Eosinophils
- iNKT cells
In OBESE adipocytes what pro-inflammatory molecules are present
- Th1 cells
- M1 macrophages (classically activated)
- CD8+ T cells (cytotoxic)
- B cells
- Dendritic, Mast and Neutrophils
What interleukins are found in lean vs obese adipocytes
Lean: IL-4, IL-10, IL-13
Obese: IL-1B, IL-6, IFN-y, FFA, TNF-a
The presence of what interleukin is well documented for its role in adipose inflammation and insulin resistance
IL-6 (released by M1 macrophages)
How does FFA induce adipose inflammation
- 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)
In a normal weight insulin sensitive person what molecules do we want to see
- M2 macrophages (alternative)
- Treg cells
- IL (4,10,13)
- Th2 response
In an obese insulin resistance person what molecules do we see
- M1 macrophages (classically)
- Mast cells
- B2 cells
- TNF-a, IFN-y, IgG2c antibodies
- Th1 response
What is the relationship between T2DM and beta cell dysfunction
- T2D never develops without beta cell dysfunction
- This indicates the need for beta cell protection before the onset of T2DM
In T1DM what type of hypersensitivity is present and what cells mediate the destruction of B-cells
- T cell mediated (Type IV hypersensitivity)
- CD8+ Cytotoxic T cells kill beta cells in this case
Around 20 genes are associated with T1DM, what are the four she emphasized and the two interleukins
- HLA
- INS (inslun gene)
- AIRE
- CTLA-4
IL-2 and IL-10
How do HLA class II alleles on chromosome 6 impact T1DM
- DQ2/DQ8 found in more than 90% of individuals with T1DM
- DR3/DR4 most common in children under age 5 (50%)
- Lack Asp57
What is special about the HLA Class II for T1DM
There is a protective allele
DR2/DQ6 confers PROTECTION
What do these genes control; PTPN22, CTLA4, AIRE, FOXP3
PTPN22- Tyrosine Phosphatase
CTLA4- T cell regulation
AIRE- Thymic expression of self-proteins
FOXP3- Tregs cells
What happens if FOXP3 gene is faulty
Immune dysregulation, polyendocrinopathy, enteropathy
Widespread autoimmunity
What happens when there is a mutation in AIRE
AIRE expression and presentation of insulin in thymus to developing T cells is critical to protecting against development of T1DM
What is there to know about the Insulin Gene
- Class I (26-63 VNTR in promoter region) is associated with lower insulin mRNA synthesis
- Reduction in tolerance to insulin due to low presentation
What is there to know bout the CLTA-4 Gene
Defect in CTLA-4 expression on Tregs and activated T cells DECREASES ability to down-regulate immune responses and maintain tolerance
How do we know that T1DM has environmental factors in addition to genetic
T1DM incidence is increasing by 3% per year which is too high to be attributed only to genetic factors
What are some environmental risk factors associated with T1DM
- 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
What disease state is associated with T1DM and what are the two mechanisms viruses use to destroy Beta cells
Celiac Disease
-Direct Cytotoxicity and Molecular Mimicry
What can be used to predict disease course in DM
Islet Cell Auto-antibody Production appears MONTHS to YEARS in advance of metabolic changes
-Their presence confirms a diagnosis of T1DM
