7. Immune Mechanisms of Diabetes

Question 1

Which free fatty acid binds to which toll-like receptor?

Where is that toll-like receptor present

Answer 1

Long chain free fatty acid palmitate binds to TLR4.

TLR4 is present on adipocytes.

Question 2

What transcription factor should be always associate with T regulatory cells?

Answer 2

FOXP3

Question 3

What happens as a result of a defect in the FOXP3 gene?

Answer 3

Polyendocrinopathy, and widespread autoimmunity due to a deficiency of regulatory T cells.

“X-linked polyendocrinopathy and enteropathy (IPEX)”

Question 4

Which genetic populations are more likely to develop type II diabetes?

Answer 4

African-Americans.

Hispanics.

Native Americans.

(Pima Native Americans especially.)

Question 5

What are the four high-risk HLA class II alleles for type I diabetes?

Answer 5

DQ2/DQ8

DR3/DR4

Question 6

HLA class II alleles relevant to type I diabetes are found in which chromosome?

Answer 6

Chromosome 6

Question 7

Which HLA class to haplotype confers protection from type II diabetes?

Answer 7

DR2/DQ6

Question 8

What are the three islet cell antigens that we use for staging of type I diabetes?

Answer 8

GAD65 (glutamic acid decarboxylase)

IA-2 (insulinoma antigen-2)

IAA (insulin auto-antibodies)

Question 9

What is the function of AIRE?

Answer 9

Presents self antigens for peripheral tissues in the thymus to immature T cells.

Question 10

What cytokines are used by Tregs to inhibit T cell responses?

Answer 10

IL-10.

TGF-β.

Question 11

What environmental factors were specifically talked about as risk factors for type I diabetes?

Answer 11

↓ Breast-feeding.

↑ Wheat gluten.

↑ Cows milk exposure.

Vitamin D deficiency.

Certain infections.

Certain chemicals (Compounds in smoked meat.)

Question 12

What haplotypes of HLA class II alleles are found in more than 90% of individuals with type I diabetes?

Answer 12

DR3DQ2

DR4DQ8

Question 13

How does a defect in CTLA-4 generate autoimmunity?

Answer 13

CTLA-4 is one of the ways that Tregs down regulate immune response. It’s defect disables Tregs, and results in autoimmunity.

Question 14

What is the function of CD25 (IL-2 receptor, α-chain)?

Answer 14

CD25 allows CD4+ T cells to respond more quickly and significantly to IL-2.

For this class, this is especially important for CD4+ FOXP3+ Treg cells.

(Recall that IL-2 is secreted by CD4+ T cells as a sort of autocrine function.)

Question 15

Which HLA class II alleles are most common in children diagnosed with type I diabetes prior to age 5?

Answer 15

DR3/DR4

Question 16

What bacteria produces compounds that are cytotoxic to β-cells?

Answer 16

Streptomyces.

Question 17

How does type I diabetes lead to a change in the Treg population and effector function?

Answer 17

Leads to FOXP3 expression becoming unstable.

Ex-Tregs, after FOXP3 is lost, may even produce IFN-γ and IL-17.

Question 18

What are the functions of IL-6 on the liver?

Answer 18

↑ Acute phase response.

↑ SOCS-3.

↑ Insulin resistance.

Question 19

What issue with the insulin gene can break central tolerance?

How does this issue break central tolerance?

Answer 19

The region on chromosome 11 that codes for insulin has a variable number tandem repeat region with three polymorphisms. The class I polymorphism is associated with a higher risk for type I diabetes.

The class I polymorphism results in a decrease in insulin mRNA synthesis, and a concomitant decrease in insulin presentation to immature thymocytes – breaking central tolerance.

Question 20

Why does breast-feeding decrease the risk of type I diabetes?

Answer 20

Breast milk contains insulin, which may help to desensitize neonates who might otherwise have an autoimmune event to insulin.

Question 21

How do alternatively activated macrophages respond to insulin under normal conditions?

Answer 21

The increase their IL-1 receptor – but presence of IL-1 overall is decreased.

Question 22

Development of type I diabetes is a risk factor for what non–diabetes related diseases?

Answer 22

Other autoimmune diseases, such as celiac disease (40% chance).

Question 23

Why does a mutation in the AIRE gene specifically lead to type I diabetes in some cases?

Answer 23

A mutation in the AIRE gene can prevent insulin peptides from being expressed appropriately in the thymus to establish tolerance to insulin in the T cells.

Question 24

What costimulatory protein on the antigen presenting cell binds to what other receptor on the T lymphocyte?

Answer 24

The antigen presenting cell presents B7.

The T cell presents CD28.

Question 25

What viruses may be implicated in molecular mimicry leading to type I diabetes via incidental destruction of the beta cells because of similar epitopes?

Answer 25

Mumps.

Rubella.

Cytomegalovirus.

Enteroviruses.

Retroviruses

Question 26

What pro-inflammatory cytokines were discussed as a major portion of the inflammatory state of obesity?

Answer 26

TNF-α

IL-1β

IL-6

(With IL-6 being especially well documented.)

Question 27

Which binds to B7 with a higher affinity, CD28 or CTLA-4?

Answer 27

CTLA-4. This allows activated T cells to turn themselves off.

Question 28

Besides HLA, what genes are often involved in autoimmunity?

Answer 28

CTLA-4 gene.

AIRE gene.

Insulin gene.

FOXP3.

Tyrosine phosphatase gene (PTPN22).

​FAS gene.