Immune Mechanisms of Diabetes

Question 1

what have complementary effects on development of type II diabetes

Answer 1

genetic susceptibility, sedentary lifestyle, high fat diet, and psychological stress

Question 2

lean adipose tissue has greater amount of this compared to people who are obese

Answer 2

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

Question 3

obesity leads to what type of cells compared to people with lean adipose tissue

Answer 3

• more M1 macrophages
• more Th1 CD4+ T cells
• increase in CD8+ T cells
• increase in B cells

Question 4

obesity leads to what kind of macrophages and what kind of cytokines

Answer 4

M1 macrophages which secrete pro-inlammatory cytokines and chemokines: IL-1, TNF-a, IL-6, CCL2, CCL3, CXCL8

Question 5

lean insulin sensitive tissue leads to what macrophages and cytokines

Answer 5

M2 macrophages, Treg cells

-antiinflammatory cytokines: IL-10, 4, 13

Question 6

most cases of Type 1 diabetes are characterized by what?

Answer 6

autoantibodies to B cells in pancreas and strong HLA associations

Question 7

what kind of autoimmune disorder is type 1 diabetes

Answer 7

T cell mediated

-mononuclear cells and CD8+ T cells infiltrate the islets of langerhans

Question 8

what could be the link between environmental factors, the development of autoimmunity and T1D

Answer 8

gut microbiota

Question 9

what can lead to T1D, early exposure to breast-feeding or cow milk and why

Answer 9

early exposure to cow milk can lead to T1D

-possibly because cow milk contains much less insulin than breast milk

Question 10

a higher fiber diet leads to what kind of gut bacteria which leads to what

Answer 10

• prevotella predominate in high fiber diet
• leads to increased butyrate and mucine synthesis (thicker mucus layer)
• anti-inflammatory response
• maintained tight junctions
• Treg differentiation

Question 11

Gluten, bovine milk, high fat diet leads to what kind of gut bacteria which leads to what

Answer 11

bacteroides–>propionate, succinate, acetate

• mucine degradation
• altered permeability
• inflammation
• decreased insulin sensitivity
• autoimmunity and T1D

Question 12

lack of what vitamin can lead to T1D because of its role as an immune modulator and suppressant

Answer 12

Vitamin D

Question 13

immunizations only trigger the Th___ response. so __ is never achieved

Answer 13

Th2

• Th1 never achieved
• decreased in incidence of infectious diseases contrasted with incidence of Type 1 diabetes

Question 14

viruses can act against B cells of pancreas by what? specific virus examples

Answer 14

direct cytotoxicity
trigger autoimmunity by molecular mimicry

-mumps and rubella

Question 15

most significant genes associated with TD1 (4 of them)

Answer 15

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

Question 16

how is central tolerance to insulin established?

Answer 16

in thymus, thymic antigen presenting cells present insulin antigens within class II MHC

-if CD4+/CD8+ precursor recognizes strongly then cell programmed for apoptosis

Question 17

which HLA alleles are high risk

Answer 17

DQ2/DQ8 in 90% of individuals with T1D

DR3/DR4 most common in children diagnosed with T1D

Question 18

HLA class II molecules that lack ___ of the beta chain are often found in individuals with T1D

Answer 18

Asp57

Question 19

HLA Class II haplotypes such as ____/_____ confer dominant protection

Answer 19

DR2/DQ6

Question 20

Insulin gene and VTNR class 1

Answer 20

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

Question 21

AIRE and insulin

Answer 21

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

Question 22

CTLA-4 and peripheral tolerance

Answer 22

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

Question 23

islet cell autoantibodies: specificities of several identified ICA include:

Answer 23

glutamic acid decarboxylase (GAD65)
Insulinoma Antigen-2 (IA-2, tyrosine phosphatases)
Insulin Autoantibodies (IAA)

Question 24

need presence of ___ or more distinct antibody specificites to higly predict future of T1D

Answer 24

2

Question 25

can type 1 diabetes be transferred using serum from diabetic humans with autoantibodies?

Answer 25

no, Abs may be future predictor

Question 26

does Type 1 diabetes have TH1 or TH2 cells

Answer 26

TH1 cells are autoreactive

-Th2 cells are protective

Question 27

APCs present antigen in class II MHC molecules and secrete ___ which gives TH1 subtype. These Ag-specific CD4 T cells further stimulates ___ which inhibits ___

Answer 27

IL-12, IFN-y

IFN-y inhibtis Th2 cytokine production

Question 28

what other disease is prevelant with T1D and what is it due to?

Answer 28

asthma, failure of T reg cells

Question 29

how do regulatory T cells regulate

Answer 29

1) production of immunosuppressive cytokines IL-10 and TGF-B
2) Reduced ability of APCs to stimulate T cells (CTLA-4)
3) consumption of IL-2 which is a growth factor for other T cells, so this stops this

Question 30

What is another name for Tregulatory cells? (letters and numbers!!!)

Answer 30

CD4+/CD25+

-also FoxP3 txn factor is master regulator in development and function of regulatory T cells

Question 31

loss of Treg can in ___ syndrome leads to neonatal diabetes

Answer 31

IPEX