Immune Mechanisms of Diabetes Flashcards
Lean vs obese adipose tissue and inflammation
Lean adipose tissue:
Treg cells, Th2, iNKT cells, M2 macrophages and eosinophils
Obese adipose tissue:
Th1, M1 macrophages, CD8+ T cells, B cells, Dendritic cells, mast cells neutrophils
IL-6 role in T2DM
Acute inflammatory response
Role in adipose inflammation and insulin resistance
Increases GLP1 in pancreas/intestine
Increases lipolysis in adipose and muscle
Increases GLUT4 in muscle
FFA induction of adipose inflammation
FFA Palmitate is ligand for TLR4 on adipocytes
Binding leads to pro-inflammatory cytokine and chemokine production, recruitment of M1 macrophage
Inflammatory state leads to sustained B cell dysfunction
T2DM and beta cell dysfunction/insulin resistance
Now believed that insulin resistance is largest factor for hyperglycemic state early in disease state, and eventually beta cell dysfunction becomes the ultimate causative factor
T1DM is what type of hypersensitivity
Type IV- CD8 T cell mediated
Autoantibodies are produced but are not thought to contribute to disease strongly
High risk HLA class II alleles in T1DM
Chromosome 6
DQ2/DQ8 (90%+) and DR3/DR4 (most common in children diagnosed before 5)
AIRE mutation T1DM
AIRE expression and presentation of insulin in thymus to developing T cells is critical to protect against development of T1DM
AIRE is necessary for thymic expression of self proteins (i.e. insulin)
CTLA4 and T1DM
Chromosome 2
Defect in CTLA4 expression on Tregs and activated T cells decreases ability to down regulate immune responses
Insulin gene VNTR and T1DM
Chromosome 11
Class I VNTR (lowest amount of repeats) is associated with lower insulin mRNA synthesis
Reduction in tolerance to insulin and precursors due to low presentation
Breast feeding and T1DM vs cow milk
Decreased breast feeding is associated with higher risk for T1DM - breast milk has high amounts of insulin
Early exposure to ow milk may contribute to development of T1DM as cow milk contains much less insulin than breast milk
Wheat gluten and T1DM
T1DM risk increased in CD patients because wheat gluten is a potent diabetogen
Vitamin D and T1DM
Vitamin D deficiency causes increased risk for T1DM
Infections and T1DM
Mumps Rubella Cytomegalovirus Enteroviruses and retroviruses These caused increased risk for T1DM b/c of molecular memory or direct cytotoxicity
Islet cell auto-antibody production
Ab production occurs months to years in advance of metabolic changes from Beta cell destruction and can be used to predict disease course Auto Abs include: GAD65 IA-2 tyrosine phosphatase Insulin Auto Abs IAAs
Auto-antibody prediction facts
Presence of 2 or more Auto-Abs is highly predictive of future T1DM
Transferring Auto-antibodies to another person would not cause T1DM
Auto Abs may affect the time course of the disease development but not the pathogenesis (higher amounts do not correlate with increased/decreased symptoms or insulin levels)
