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Endocrine - MSI Spring > Immune Mechanisms of Diabetes > Flashcards

Immune Mechanisms of Diabetes Flashcards

1
Q

What is the clinical distinction of T1DM?

A

insulin dependence, with loss of beta cells

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2
Q

What is the etiology of T2DM?

A

insulin resistance and relative insulin deficiency

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3
Q

What is the clinical distinction of T2DM?

A

oral hypoglycemic agents are effective early in the disease

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4
Q

What has complementary effects on the development of T2DM?

A

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

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5
Q

What is the immunological composition of lean adipose tissue?

A 
Contains more:
M2 Mo (anti-inflammatory like)
Th2 CD4 T cells
CD4 Treg cells
Eosinophils
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6
Q

What is the immunological composition of obese adipose tissue?

A 
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

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7
Q

What cytokines do lean insulin sensitive adipose tissue produce?

A

IL-10, 4, 13: anti-inflammatory

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8
Q

What cytokines do obese insulin resistant adipose tissue release?

A

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

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9
Q

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

A

excess

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10
Q

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

A

T1DM

Insulin deficiency

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11
Q

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

A

ketoacidosis

ketones

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12
Q

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

A

Beta-cell

HLA

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13
Q

T1DM is a __________ - mediated autoimmune disorder

A

T cell-mediated

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14
Q

Describe insulitis

A

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

Associated with onset of T1D

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15
Q

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

A

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

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16
Q

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

A

Genetic and environmental

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17
Q

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

A

Gut microbiota

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18
Q

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

A

breast-feeding

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19
Q

How can cow milk possibly contribute to T1D?

A

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

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20
Q

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

A

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

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21
Q

Describe the diet and microbiota in T1D

A 
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
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22
Q

Wheat gluten is a potent ______.

A

diabetogen

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23
Q

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

A

gluten

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24
Q

Describe the possible relationship of Vit D and T1D

A

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

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25
Q

What are viruses that have been implicated in T1D?

A

Mumps and Rebella

*streptomyces are also cytotoxic for B cells

26
Q

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

A

thyroid and addison’s disease

27
Q

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

A

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

28
Q

How is central tolerance to insulin established?

A

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

29
Q

What are the high risk alleles in T1D?

A

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)

30
Q

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

A

Asp57

31
Q

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

A

DR2/DQ6

32
Q

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

A

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

33
Q

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

A

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

34
Q

What does CTLA-4 encode?

A

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

35
Q

What are the mechanisms of action of CTLA-4

A
  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
36
Q

What is sCTLA-4?

A

soluble recombinant CTLA4 used in clinical trials for autoimmune diseases

37
Q

CTLA4 = CD_____

A

152

38
Q

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

A

begins to move to the membrane and binds CD80/CD86

39
Q

What is the etiology of type I DM?

A

Beta cell destruction due to immune or idiopathic cause

40
Q

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

A

Islet Cell autoantibodies

Their presence confirms a diagnosis of type IA diabetes

41
Q

What are the specificities of several identified ICA?

A

ICA = islet cell autoantibody

Glutamic acid decarboxylase (GAD65)
Insulinoma antigen-2 (IA-2, tyrosine phosphatases)
Insulin autoantibodies (IAA)

42
Q

IL-4 induces what type of T cell?

A

Th2

43
Q

IL-12 induces what type of T cell?

A

TH1

44
Q

What cytokines do Th1 cells produce?

A

IFNy, IL-12

*these inhibit TH2

45
Q

What types of cytokines do TH2 cells produce?

A

IL-10 and IL-4, IL-5

*these inhibit TH1 cells

46
Q

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

A

IFNy

47
Q

Antibody-mediated immunity is mediated by ____ T cells

A

TH2

48
Q

Cell-mediated immunity is mediated by _____ T cells

A

TH1

49
Q

Where are T cells activated?

A

in the Lymph nodes that drain the pancreas

50
Q

Once activated, where do islet specific T cells go?

A

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

51
Q

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

A

Local APCs presenting with Class II MHC and secreting IL-12

They activated CD4 T cells and further stimulate IFN-Gamma

52
Q

What does IFN-gamma enhance?

A

IL-1Bb, TNF-a and free radical production by Mo

All are toxic to islet beta cells

53
Q

Where can Treg cells act?

A

Locally in tissues and draining lymph nodes

54
Q

What do Treg cells become activated by?

A

local APC presenting auto-Ag

55
Q

How do T reg cells suppress APCs?

A

directly: cell to cell interactions
Indirectly: cytokines IL-4, IL-10, TGF-B

*reduce ability of APCs to stimulate T cells (CTLA-4?)

56
Q

What immunosuppressive cytokines do Treg cells produce?

A

IL-10 and TGFB

57
Q

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

A

consume IL-2 and deprive other T cell populations of this GF

Results in reduced proliferation and differentiation of IL-2 dependent cells

58
Q

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

A

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

59
Q

What is a specific marker of natural T reg cells

A

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

60
Q

What autoantigen is most prevalent in children with T1DM?

A

insulin/proinsulin

61
Q

What autoantigen is most prevalent in adult-onset T1DM?

A

GAD65

Endocrine - MSI Spring (15 decks)

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