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
What are some examples of Islet Cell Auto-antibodies (ICAs)
- Glutamic Acid Decarboxylase (GAD65)
- Insulinoma Antigen-2 (IA-2, tyrosine phosphatase)
- Insulin auto-antibodies (IAA)
The auto-antibodies in T1DM play what role in pathogenesis
They may affect time course of the disease development but do not impact the pathogenesis
Why is asthma more prevalent in T1Dm children than non-diabetic children
Common pathway for both is dysregulation of Tregs
What might you use as a therapeutic to mitigate the loss of Tregs
CTLA-4
