7. Immune Mechanisms of Diabetes Flashcards
Which free fatty acid binds to which toll-like receptor?
Where is that toll-like receptor present
Long chain free fatty acid palmitate binds to TLR4.
TLR4 is present on adipocytes.
What transcription factor should be always associate with T regulatory cells?
FOXP3
What happens as a result of a defect in the FOXP3 gene?
Polyendocrinopathy, and widespread autoimmunity due to a deficiency of regulatory T cells.
“X-linked polyendocrinopathy and enteropathy (IPEX)”
Which genetic populations are more likely to develop type II diabetes?
African-Americans.
Hispanics.
Native Americans.
(Pima Native Americans especially.)
What are the four high-risk HLA class II alleles for type I diabetes?
DQ2/DQ8
DR3/DR4
HLA class II alleles relevant to type I diabetes are found in which chromosome?
Chromosome 6
Which HLA class to haplotype confers protection from type II diabetes?
DR2/DQ6
What are the three islet cell antigens that we use for staging of type I diabetes?
GAD65 (glutamic acid decarboxylase)
IA-2 (insulinoma antigen-2)
IAA (insulin auto-antibodies)
What is the function of AIRE?
Presents self antigens for peripheral tissues in the thymus to immature T cells.
What cytokines are used by Tregs to inhibit T cell responses?
IL-10.
TGF-β.
What environmental factors were specifically talked about as risk factors for type I diabetes?
↓ Breast-feeding.
↑ Wheat gluten.
↑ Cows milk exposure.
Vitamin D deficiency.
Certain infections.
Certain chemicals (Compounds in smoked meat.)
What haplotypes of HLA class II alleles are found in more than 90% of individuals with type I diabetes?
DR3DQ2
DR4DQ8
How does a defect in CTLA-4 generate autoimmunity?
CTLA-4 is one of the ways that Tregs down regulate immune response. It’s defect disables Tregs, and results in autoimmunity.
What is the function of CD25 (IL-2 receptor, α-chain)?
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.)
Which HLA class II alleles are most common in children diagnosed with type I diabetes prior to age 5?
DR3/DR4
What bacteria produces compounds that are cytotoxic to β-cells?
Streptomyces.
How does type I diabetes lead to a change in the Treg population and effector function?
Leads to FOXP3 expression becoming unstable.
Ex-Tregs, after FOXP3 is lost, may even produce IFN-γ and IL-17.
What are the functions of IL-6 on the liver?
↑ Acute phase response.
↑ SOCS-3.
↑ Insulin resistance.
What issue with the insulin gene can break central tolerance?
How does this issue break central tolerance?
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.
Why does breast-feeding decrease the risk of type I diabetes?
Breast milk contains insulin, which may help to desensitize neonates who might otherwise have an autoimmune event to insulin.
How do alternatively activated macrophages respond to insulin under normal conditions?
The increase their IL-1 receptor – but presence of IL-1 overall is decreased.
Development of type I diabetes is a risk factor for what non–diabetes related diseases?
Other autoimmune diseases, such as celiac disease (40% chance).
Why does a mutation in the AIRE gene specifically lead to type I diabetes in some cases?
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.
What costimulatory protein on the antigen presenting cell binds to what other receptor on the T lymphocyte?
The antigen presenting cell presents B7.
The T cell presents CD28.
What viruses may be implicated in molecular mimicry leading to type I diabetes via incidental destruction of the beta cells because of similar epitopes?
Mumps.
Rubella.
Cytomegalovirus.
Enteroviruses.
Retroviruses
What pro-inflammatory cytokines were discussed as a major portion of the inflammatory state of obesity?
TNF-α
IL-1β
IL-6
(With IL-6 being especially well documented.)
Which binds to B7 with a higher affinity, CD28 or CTLA-4?
CTLA-4. This allows activated T cells to turn themselves off.
Besides HLA, what genes are often involved in autoimmunity?
CTLA-4 gene.
AIRE gene.
Insulin gene.
FOXP3.
Tyrosine phosphatase gene (PTPN22).
FAS gene.
