2-5-16-Immune Mechanisms Of Diabetes (Shnyra)

Question 1

Obesity leads to adipocyte necrosis and an increase in ___ macrophages. There is also a reduction in Treg cells and an increase in ___ cells

Answer 1

M1

B cells, CD4+ TH1, and CD8+ T cells

Question 2

List some of the pro-inflammatory cytokines involved obesity and insulin resistance

Answer 2

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

Anti-inflammatory–> IL-10, IL-4, IL-13

Question 3

Type 1 diabetes is a ___-mediated autoimmune disorder

Answer 3

T cell

Question 4

The onset of T1D is associated with infiltration of the islets of langerhans by ___ cells and the infiltrate is termed Insulitis

Answer 4

Mononuclear cells and CD8+ T cells

Question 5

Describe the relationship between breast-feeding and type 1 diabetes incidences

Answer 5

Studies have shown an inverse correlation between a decrease in breast-feeding and an increase in T1d risk

Early exposure to cow milk in life may contribute to T1d

Question 6

Wheat gluten is a potent ___

Answer 6

Diabetogen

Risk of T1D is higher in pts with gluten-sensitive enteropathy

Question 7

Streptozocin and bafilomycin A1 from streptomyces are cytotoxic for ___ cells

Answer 7

Beta

Question 8

List viruses that have been implicated in T1D:

Answer 8

Mumps
Rubella
CMV
Enteroviruses
Retroviruses

Question 9

The __ region (MHC gene on chromosome 6) presents insulin ags. For CD8+ T cells is associated with susceptibility to T1D

Answer 9

HLA

Question 10

The __ gene (chromosome 11) is an ag for the autoimmune response and is associated with susceptibility to T1D

Answer 10

Insulin

Question 11

___ is a regulator of insulin gene expression in the thymus

Answer 11

AIRE

Question 12

The ___ gene (chromosome 2) is a regulator of the autoimmune response that is associated with susceptibility to T1D

Answer 12

CTLA-4

Question 13

In the thymus, insulin ags are presented within ___ MHC

Answer 13

Class II

Question 14

Which HLA alleles are considered “High risk” in T1D?

Answer 14

HLA-DQ2/DQ8 and DR3/DR4

DQ2/DQ8 found in more than 90% of individuals with T1D

DR3/DR4 most common in children diagnosed with T1D prior to age 5

Question 15

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

Answer 15

Asp57

Question 16

HLA class II haplotypes such as ___ confer dominant protection against T1D

Answer 16

DR2/DQ6

Question 17

This tandem repeat is a polymorphism that is categorized into classes I, II, and III associated with the insulin gene

Answer 17

VNTR core repeat sequence (VNTR polymorphism)

Question 18

The susceptible class I alleles of the insulin VNTR are associated with lower __ synthesis resulting in: low ag synthesis –> low ag presentation in the thymus –> failure of deleting self-reactive CD8 T cells

Answer 18

insulin mRNA

Question 19

Regarding the insulin gene, the central tolerance is broken with class ___ alleles

Answer 19

I

Question 20

The absence or a defect in ___ in the medullary thymic epithelial cell can lead to failure of negative selection and AUTOIMMUNITY. It is a critical transcriptional factor regarding insulin

Answer 20

AIRE

Question 21

___ is the susceptibility locus on chromosome 2 associated with T1D.

Answer 21

CTLA-4

Question 22

CTLA-4 encodes a glycoprotein that is a ___ homologue and binds B7 protein (CD80/86)

Answer 22

CD28

Question 23

The function of ___ is suppression of T cell activation and apoptosis

Answer 23

CTLA-4

Question 24

CTLA-4 on a T cell binds ___ on an APC

Answer 24

B7

Question 25

CTLA-4 competes with __ for binding CD80 leading to cell-cycle arrest that prevents expansion of activated T Cells

Answer 25

CD28

Question 26

Failure of T cells to express the __ gene due to a mutation may contribute to aberrant immune responses seen in T1D

Answer 26

CTLA-4

Question 27

___ can be used to treat autoimmune diseases by outcompeting CD28 on T cells for binding CD80/86 on an APC

Answer 27

sCTLA-4

Question 28

The presence of __ abs can be used to predict/diagnose if an individual has T1D

Answer 28

Islet cell

Question 29

The specificities of several identified Islet Cell Abs (ICA) include:

Answer 29

GAD65 (glutamic acid decarboxylase) IA-2, tyrosine phosphatases IAA (insulin autoantibodies)

Question 30

The presence of __ distinct antibody specificities is highly predictive of future T1D

Answer 30

2 or more When combined with HLA typing, autantibody screening is also useful for predicting disease in general populations

Question 31

T1D is a ___-mediated disease

Answer 31

Th1

Question 32

Regarding the pathogenic role of T cells: T cells are activated in the ___ that drain the pancreas --> Once activated, islet-specific T cells traffic to the pancreas where they ___ and accumulate resulting in organ-specific inflammation --> Local APCs capable of presenting ag in the context of Class II MHC molecules secrete ___ which plays an important role in the pathogenesis of T1D --> These APCs activate ag-specific ___ cells and further stimulates IFN-y --> IFN-y inhibits ___ cytokine production (IL-4/5/10) and enhance IL-1b, TNF-a, and free radical production by macrophages which are all toxic to islet beta cells

Answer 32

Lymph nodes Proliferate IL-12 CD4 T Th2

Question 33

Asthma is more prevalent in children in T1D than non-diabetic children and the common denominator in cases is the failure of regulatory mechanisms controlled by __ cells

Answer 33

Treg

Question 34

Susceptibility to T1D may be greatly enhance when __ cells fail to prevent activation/expansion of auto-reactive T cells

Answer 34

Treg

Question 35

List cytokines secreted by Treg cells that lead to decreased in CD40, CD80/86, and IL-12

Answer 35

IL-4, IL-10, TGF-b

Question 36

What are the effects of Tregs on B cells and NK cells?

Answer 36

Directly suppress B cell activation Inhibit proliferation and differentiation of NK cells

Question 37

What are the "CD's" of Treg cells?

Answer 37

CD4+/CD25+

Question 38

The loss of Tregs in IPEX syndrome leads to ____

Answer 38

Neonatal diabetes

Question 39

IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome) is a rare disease linked to the dysfunction of the transcriptional activator ___

Answer 39

FoxP3

Question 40

___ appears to function as the master regulator in the development and function of regulatory T cells

Answer 40

FoxP3

Question 41

Lean adipose tissue contains a greater proportion of ___ macrophages as well as ___ cells

Answer 41

M2/M1 Treg