Immune Mechanisms of Diabetes Flashcards
what have complementary effects on development of type II diabetes
genetic susceptibility, sedentary lifestyle, high fat diet, and psychological stress
lean adipose tissue has greater amount of this compared to people who are obese
has a greater proportion of M2 to M1 macrophages, M2 can be anti-inflammatory with secretion of IL-10
- has a greater amount of T-regulatory cells
- increase of Th2 CD4+ T cells
obesity leads to what type of cells compared to people with lean adipose tissue
- more M1 macrophages
- more Th1 CD4+ T cells
- increase in CD8+ T cells
- increase in B cells
obesity leads to what kind of macrophages and what kind of cytokines
M1 macrophages which secrete pro-inlammatory cytokines and chemokines: IL-1, TNF-a, IL-6, CCL2, CCL3, CXCL8
lean insulin sensitive tissue leads to what macrophages and cytokines
M2 macrophages, Treg cells
-antiinflammatory cytokines: IL-10, 4, 13
most cases of Type 1 diabetes are characterized by what?
autoantibodies to B cells in pancreas and strong HLA associations
what kind of autoimmune disorder is type 1 diabetes
T cell mediated
-mononuclear cells and CD8+ T cells infiltrate the islets of langerhans
what could be the link between environmental factors, the development of autoimmunity and T1D
gut microbiota
what can lead to T1D, early exposure to breast-feeding or cow milk and why
early exposure to cow milk can lead to T1D
-possibly because cow milk contains much less insulin than breast milk
a higher fiber diet leads to what kind of gut bacteria which leads to what
- prevotella predominate in high fiber diet
- leads to increased butyrate and mucine synthesis (thicker mucus layer)
- anti-inflammatory response
- maintained tight junctions
- Treg differentiation
Gluten, bovine milk, high fat diet leads to what kind of gut bacteria which leads to what
bacteroides–>propionate, succinate, acetate
- mucine degradation
- altered permeability
- inflammation
- decreased insulin sensitivity
- autoimmunity and T1D
lack of what vitamin can lead to T1D because of its role as an immune modulator and suppressant
Vitamin D
immunizations only trigger the Th___ response. so __ is never achieved
Th2
- Th1 never achieved
- decreased in incidence of infectious diseases contrasted with incidence of Type 1 diabetes
viruses can act against B cells of pancreas by what? specific virus examples
direct cytotoxicity
trigger autoimmunity by molecular mimicry
-mumps and rubella
most significant genes associated with TD1 (4 of them)
1) HLA region, chromosome 6, presentation of insulin Ags for CD8+ T cells
2) Insulin gene, chromosome 11, Ag for autoimmune response
3) AIRE, regulator of insulin gene expression in thymus
4) CTLA-4 gene, chromosome 2, regulates autoimmune response
how is central tolerance to insulin established?
in thymus, thymic antigen presenting cells present insulin antigens within class II MHC
-if CD4+/CD8+ precursor recognizes strongly then cell programmed for apoptosis
which HLA alleles are high risk
DQ2/DQ8 in 90% of individuals with T1D
DR3/DR4 most common in children diagnosed with T1D
HLA class II molecules that lack ___ of the beta chain are often found in individuals with T1D
Asp57
HLA Class II haplotypes such as ____/_____ confer dominant protection
DR2/DQ6
Insulin gene and VTNR class 1
insulin gene is mapped to variable number tandem repeat in promoter of insulin gene
-3 classes: class 1: low Ag insulin synthesis so low Agpresentation in thymus = failure of deleting self-reactive CD8 T cells
AIRE and insulin
AIRE is needed to make insulin mRNA in thymus which is then presented to T cells for negative selection. without AIRE central tolerance against insulin fails
CTLA-4 and peripheral tolerance
CTLA-4 on the T regulatory cell binds B7 on the APC
- this prevdnts CD28 on the T cell from binding B7 on APC
- prevents T cell activation
- failure may be seen in T1D
islet cell autoantibodies: specificities of several identified ICA include:
glutamic acid decarboxylase (GAD65)
Insulinoma Antigen-2 (IA-2, tyrosine phosphatases)
Insulin Autoantibodies (IAA)
need presence of ___ or more distinct antibody specificites to higly predict future of T1D
2
