Immune Mechanisms of Diabetes

Question 1

What is the clinical distinction of T1DM?

Answer 1

insulin dependence, with loss of beta cells

Question 2

What is the etiology of T2DM?

Answer 2

insulin resistance and relative insulin deficiency

Question 3

What is the clinical distinction of T2DM?

Answer 3

oral hypoglycemic agents are effective early in the disease

Question 4

What has complementary effects on the development of T2DM?

Answer 4

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

Question 5

What is the immunological composition of lean adipose tissue?

Answer 5

Contains more:
M2 Mo (anti-inflammatory like)
Th2 CD4 T cells
CD4 Treg cells
Eosinophils

Question 6

What is the immunological composition of obese adipose tissue?

Answer 6

Adipocyte necrosis 
Increase in M1 Mo (pro-inflammatory like) also some M2
Th1 CD4 T cells
CD8 T cells 
Mast cells
B cells 

Reduction of Treg

Question 7

What cytokines do lean insulin sensitive adipose tissue produce?

Answer 7

IL-10, 4, 13: anti-inflammatory

Question 8

What cytokines do obese insulin resistant adipose tissue release?

Answer 8

IL-1B, TNF-a, IL-6, CCL2, CCL3, CXCL8

Question 9

Long-term __________ excess leads to apoptotic and necrotic death of adipocytes

Answer 9

excess

Question 10

_____ is characterized by immune-mediated destruction of pancreatic beta-cells resulting in _______ _______.

Answer 10

T1DM

Insulin deficiency

Question 11

Patients with T1D are prone to ________, dangerously high levels of ______ in the blood.

Answer 11

ketoacidosis

ketones

Question 12

Most cases of T1D are characterized by autoantibody markers of ______ destruction and strong ______ aassociations.

Answer 12

Beta-cell

HLA

Question 13

T1DM is a __________ - mediated autoimmune disorder

Answer 13

T cell-mediated

Question 14

Describe insulitis

Answer 14

the infiltrate of the islets of langerhans by mononuclear cells and CD8 T cells

Associated with onset of T1D

Question 15

What are the leading causes of disability and mortality in young adults with T1D?

Answer 15

Long-term micro- and macro-vascuclar complications of diabetes

Question 16

T1D development involves ____ and ______ factors, such as birth delivery mode, use of antibiotics and diet.

Answer 16

Genetic and environmental

Question 17

What could be the link btwn environmental factors, the development of autoimmunity and T1D?

Answer 17

Gut microbiota

Question 18

Inverse correlation btwn a decrease in ________ and the increase in type 1 D risk

Answer 18

breast-feeding

Question 19

How can cow milk possibly contribute to T1D?

Answer 19

early exposure might compromise immune tolerance to insulin
Milk contains much less insulin than human milk

*inconsistency tho due to variations in composition of milk, genetic variation in cow proteins

Question 20

Describe the microbiota in healthy individuals who eat high-fiber diet

Answer 20

thick mucus layer
anti-inflammatory
Treg
prevotella: butyrate->mucine synthesis->maintained tight junctions

Question 21

Describe the diet and microbiota in T1D

Answer 21

Gluten, Bovine milk, high-fat diet
Increased paracellular permeability
Bacteroides: propionate, succinate, and acetate->mucine degradation->altered permeability 
thin mucus layer
Inflammation
decreased insulin sensitivity
autoimmunity

Question 22

Wheat gluten is a potent ______.

Answer 22

diabetogen

Question 23

The risk of T1D is higher in pts with ______-sensitive enteropathy

Answer 23

gluten

Question 24

Describe the possible relationship of Vit D and T1D

Answer 24

north-south gradient of T1D in Europe, with lower mean sunshine hours in the north

Question 25

What are viruses that have been implicated in T1D?

Answer 25

Mumps and Rebella *streptomyces are also cytotoxic for B cells

Question 26

What other autoimmune diseases are T1D pts are at risk of?

Answer 26

thyroid and addison's disease

Question 27

There are about ____ genes of varying potency associated with susceptibility to T1D. What are the most significant?

Answer 27

18 HLA: MHC gene on Ch. 6 - insulin Ags for CD8 T cells Insulin gene: Ch. 11 - Ag for AutoI response Regulators of insulin gene expression in thymus (AIRE) CTLA-4 gene: Ch. 2 - regulation of autoI response

Question 28

How is central tolerance to insulin established?

Answer 28

In the thymus, insulin-Ags are presented within Class II MHC CD4/CD8 thymocyte with high-avidity recognition of peptide on thymic antigen-presenting cell -> apoptotic cell death = negative selection

Question 29

What are the high risk alleles in T1D?

Answer 29

DQ2/DQ8 (haplotypes DR3/DQ2 or DR4DQ8) found in more than 90% with T1D and DR3/DR4 (heterozygous genotypes most common in children diagnosed before age of 5)

Question 30

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

Answer 30

Asp57

Question 31

HLA class II haplotypes such as ______ confer dominant protection from T1D

Answer 31

DR2/DQ6

Question 32

What class of VTNR polymorphism of insulin is associated with lower insulin mRNA synthesis? What does this result it?

Answer 32

Class I: the central tolerance is broken Low Ag (insulin) synthesis -> low Ag presentation in the thymus -> failure of deleting self-reactive CD8 T cells

Question 33

What is transcription of insulin in the thymus controlled by? What happens if its malfunctioning?

Answer 33

AIRE Break down of central tolerance: medullary thymic epithelial cells fail to induce negative selection by not being able to display insulin peptides to T cells

Question 34

What does CTLA-4 encode?

Answer 34

a glycoprotein that is a CD28 homologue and binds B7 protein (CD80/86) Counter-regulate the CD28-dependent TCR activation of T cells Suppression of T cell activation and activation of apoptosis

Question 35

What are the mechanisms of action of CTLA-4

Answer 35

1. cell intrinsic inhibitory signaling (B7/CTLA-4) inhbiit T cells 2. Blocking and removing B7 on APC; Treg cells have CTLA-4 that bind to/remove B7 on APC making B7 costimulators unavailable to CD28 on T cells to block activation

Question 36

What is sCTLA-4?

Answer 36

soluble recombinant CTLA4 used in clinical trials for autoimmune diseases

Question 37

CTLA4 = CD_____

Answer 37

152

Question 38

In activated T cells, CD152 (CTLA-4) ....

Answer 38

begins to move to the membrane and binds CD80/CD86

Question 39

What is the etiology of type I DM?

Answer 39

Beta cell destruction due to immune or idiopathic cause

Question 40

What can be used to predict T1 DM disease in advance (months to years)?

Answer 40

Islet Cell autoantibodies | Their presence confirms a diagnosis of type IA diabetes

Question 41

What are the specificities of several identified ICA?

Answer 41

ICA = islet cell autoantibody Glutamic acid decarboxylase (GAD65) Insulinoma antigen-2 (IA-2, tyrosine phosphatases) Insulin autoantibodies (IAA)

Question 42

IL-4 induces what type of T cell?

Answer 42

Th2

Question 43

IL-12 induces what type of T cell?

Answer 43

TH1

Question 44

What cytokines do Th1 cells produce?

Answer 44

IFNy, IL-12 | *these inhibit TH2

Question 45

What types of cytokines do TH2 cells produce?

Answer 45

IL-10 and IL-4, IL-5 | *these inhibit TH1 cells

Question 46

TH1 cells with what cytokine induce cytotoxic T cells, Mo, and NK cells?

Answer 46

IFNy

Question 47

Antibody-mediated immunity is mediated by ____ T cells

Answer 47

TH2

Question 48

Cell-mediated immunity is mediated by _____ T cells

Answer 48

TH1

Question 49

Where are T cells activated?

Answer 49

in the Lymph nodes that drain the pancreas

Question 50

Once activated, where do islet specific T cells go?

Answer 50

Traffic to the pancreas where they proliferate and accumulate resulting in organ specific inflammation

Question 51

What type of APCs play an important role in pathogenesis of T1D

Answer 51

Local APCs presenting with Class II MHC and secreting IL-12 They activated CD4 T cells and further stimulate IFN-Gamma

Question 52

What does IFN-gamma enhance?

Answer 52

IL-1Bb, TNF-a and free radical production by Mo | All are toxic to islet beta cells

Question 53

Where can Treg cells act?

Answer 53

Locally in tissues and draining lymph nodes

Question 54

What do Treg cells become activated by?

Answer 54

local APC presenting auto-Ag

Question 55

How do T reg cells suppress APCs?

Answer 55

directly: cell to cell interactions Indirectly: cytokines IL-4, IL-10, TGF-B *reduce ability of APCs to stimulate T cells (CTLA-4?)

Question 56

What immunosuppressive cytokines do Treg cells produce?

Answer 56

IL-10 and TGFB

Question 57

Because of the high level of expression of IL-2 receptor on Treg cells, these cells may be able to do what?

Answer 57

consume IL-2 and deprive other T cell populations of this GF | Results in reduced proliferation and differentiation of IL-2 dependent cells

Question 58

Where are Islet-specific Ags released and presented? What can recognize it?

Answer 58

in pancreatic lymph nodes The can activate damaging CD4 and CD8 T cells But can also activate CD4/CD25 T reg cells which prevent activation of the damaging cells

Question 59

What is a specific marker of natural T reg cells

Answer 59

FoxP3: function as the master regulator in the development and function of Treg cells

Question 60

What autoantigen is most prevalent in children with T1DM?

Answer 60

insulin/proinsulin

Question 61

What autoantigen is most prevalent in adult-onset T1DM?

Answer 61

GAD65