Immune Mechanisms of Diabetes Flashcards
What do we find in the blood in a person with normal insulin metabolism?
Low serum insulin, glucose, and FFA
Low serum IL-1B
High serum IL1-Ra
Alternatively activated kupffer cells (M2 macrophages which are immunosuppressant-secrete IL-10, TGF-B)
How does obesity affect a patient with T2DM?
Increase in lipolysis
Increase in macrophage accumulation
How does obesity lead to an inflammatory state?
Causes lipolysis which results in a release of FFA
Causes IL-1B and IL-6 to be secreted which causes an inflammatory response
What secretes IL-6?
M1 Macrophages
Activated adipocytes
What does IL-6 cause in adipose tissue?
Increased lipolysis
Increased AMPK
Explain FFA induction of adipose inflammation
1) FFA Palmitate is a ligand for TLR4 on adipocytes
2) Receptor binding leads to inflammation
3) Recruitment of M1 macrophages
4) Inflammation leads to B-cell dysfunction
What immune markers would you find in high quantity in a normal weight/insulin sensitive person?
M2 macrophages
Eosinophils
Tregs
iNKT cells
IL-4, IL-10, IL-13
What type of hypersensitivity is T1DM?
Type 4
What causes T1DM?
Autoantigens form on insulin-producting beta cells and circulate in the blood stream and lymph
What are some genes that make a person at high risk for T1DM?
HLA
PTPN22
INS
AIRE
CTLA-4
What are some high risk HLA class II alleles?
DQ2/DQ8 (in more than 90% of T1DM)
DR3/DR4 (50% of children diagnosed before age 5)
HLA Class II that lacks Asp57
What HLA Class II haplotype confers protection?
DR2/DQ6
How does AIRE play a role in protection against developing T1DM?
AIRE expresses and presents insulin in thymus to developing T cells so that they recongize it as self and do not respond
What Variable Number Tandem Repeats (VNTR) cause an increase in diabetes?
Increase in risk with two class I alleles
What happens with a defect in CTLA-4?
Expression on Tregs and activated T cells decreases ability to down-regulate immune response and maintain tolerance
