Lecture 8: Immunological Mechanisms of Diabetes Flashcards
In lean, insulin-sensitive individuals, what does normal insulin secretion cause tissue macrophages and Kupffer cells to do?
- Express and release soluble IL-1 receptor antagonist (IL-1Ra), leading to suppression of IL-1β
- IL-1Ra is a anti-inflammatory, regulatory, cytokine
In insulin resistance how does the role of classically activated tissue macrophages and Kupffer cells switch?
- Necrosis of the stressed beta cells is sensed causing macrophages to take on pro-inflammatory phenotype
- Increased production/serum levels of inflammatory IL-1β and decreased anti-inflammatory IL-1Ra
Obesity is characterized by chronic activation of which pathways; and that this is causally linked to?
Obesity is characterized by chronic activation of inflammatory pathways and inflammtion in obesity is causally linked to insulin resistance
Under lean conditions, adipocytes are secreting which factors, which promote which macrophage phenotype; this phenotype secretes?
- IL-13. IL-4, SCFA’s (anti-inflammatory)
- Promote alternative activation of macrophages (M2)
- M2 macrophages secrete anti-inflammaotry IL-10
Obesityy induces changes in adipocyte metabolism and gene expression, resulting in increased lipolysis and release of what factors; what do the activated macrophages produce?
- Pro-inflammatory LCFA’s and MCFA’s and factors that recruit and activate M1 macrophages, such as MCP-1 and TNF-α
- Activated M1’s produce large amounts of pro-inflammtory mediators such as TNF-α and IL-1 β
How is palmitate responsible for Islet inflammation and β-cell dysfunction?
- Palmitate, a very long chain fatty acid, is sensed by β-cells via the TLR4/MyD88 pathway
- Leads to recruitment of inflammaotry monocytes to islets by producing chemokines.
- Recruited monocytes differentiate into M1 macrophages that play a pivotal role in β-cell dysfunction
Type 1 DM is mediated by what and considered what type of disorder?
- T cell-mediated autoimmune disorder
- Onset of T1DM associated w/ infiltration of the islets of Langerhans by mononuclear cells and CD8+ T cells, this infiltrate is termed Insulitis
What are the most significant genes associated w/ T1DM?
- HLA region (MHC gene on chromosome 6): presentation of insulin Ag for CD8+ T cells
- Insulin gene (chromosome 11): Ag for autoimmune response
- Regulators of insuline gene expression in the thymus (AIRE)
- CTLA-4 gene (Chromosome 2): regulation of auto immune response
Which HLA alleles are the high-risk alleles found in more than 90% of individuals w/ T1DM?
HLA DQ2/DQ8
Heterozygous genotypes of which HLA alleles are most common in children w/ TD1 prior to the age of 5?
HLA DR3/DR4
HLA class II molecules that lack ________ of the beta chain are often found among indivuals w/ T1D?
Lack Asp57 of the beta chain
Which HLA class II halotypes confer dominant protection from T1D?
HLA DR2/DQ6
How can the insulin gene play a role in development of T1D; mapped to which region; which class of alleles causes problems?
- Mapped to a region containing the variable number of tandem repeat (VNTR) in the promoter region
- The susceptible class I alleles of the insulin VNTR are associated with lower insulin mRNA synthesis resulting in:
- Low Ag (insulin) synthesis
- Low Ag presentation in the thymus
- Failure of deleting self-reactive CD8 T cells
* The central tolerance is BROKEN w/ class I alleles
What controls transcriptional expression of insulin in the thymus and why is this important; what occurs if this system malfunctions?
- AIRE
- Malfunctioning of AIRE results in lower levels of insuin mRNA in the thymus
- Absence of insulin results in failure of deleting insulin-reactive T cells and the CENTRAL TOLERANCE is broken
- AIRE is a critical factor in the induction of central tolerance against insulin
What is the function of the CTLA-4 gene on chromosome 2?
- CTLA-4 encodes a glycoprotein that is a CD28 homologue and binds B7 protein (CD80/86)
- CTLA-4 (CD152) may counter-regulate the CD28-dependent TCR activation of T cells by competing with CD28 for binding CD80/CD86
- CTLA-4 (CD152) functions to suppress T cell activation and activate apoptosis
Failure of T cells to express th CTLA-4 gene due to a mutation may contribute to?
Aberrant immune responses seen in T1D
What has been used in clinical trials for treatments of autoimmune diseases and may show promise for T1D patients?
- Soluble recombinant CTLA4 (sCTLA4)
What are the 2 ways that CTLA-4 (CD152) can act?
1) Direct engagement of CTLA-4 on a T cell may deliver inhibitory signals that terminate further activation of that cell (cell-intrinsic function of CTLA-4)
2) CTLA-4 on Treg or responding T cells binds to B7 (CD80/86) molecules on APCs or removes these molecules from the surface of the APCs, making the B7 costimulators unavailable to CD28 and blocking T cell activation
A variety of studies have shown what correlation between breast-feeding and type 1 diabetes; what is the link to cow milk?
- Inverse correlation between a decrease in breast-feeding and the increase in type 1 diabetes risk
- Early exposure to cow milk in life may contribute to T1D
- Immune tolerance to insulin may also be compromised by early exposure to cow milk which contains much less insulin than does human milk
Which autoantibodies are detected in individuals with T1D; and when do they start to appear; clinical importance?
- Islet Cell Autoantibodies (ICA) are detected in individuals w/ T1D are present w/ increased frequency among individuals recently diagnosed w/ T1D
- Appear in advance (months to years)
- Their presence confirms a diagnosis of type 1A diabetes
What are the 3 specific identified islet cell autoantibodies (ICA) that have been identified?
1) Glutamic Acid Decarboxylase (GAD65)
2) Insulinoma Antigen-2 (IA-2, tyrosine phosphatases)
3) Insulin AutoAntibodies (IAA)
How do the number of autoantibodies present correlate w/ clinical outcomes of T1D?
- Presence of 2 or more distinct antibody specifcities is highly predictive of future T1D
- When combined w/ HLA typing, autoantibody screening is also useful for predicting disease in general populations
T1D is mediated by what type of T-cells; how does this response occur from presentation to β-cell death?
- Th1-mediated
- β-cell death in the islets causes DC’s to pick up Ag’s which can then activate CD4+ T cells
- DC’s also cross-present Ag to β-cell Ag-specific CD8+ T cells so that they upregulate their cytotoxic properties
- CTLs can kill β-cells through release of granules containing perforin and granzymes, as well as through Fas-FasL interaction
- CD4+ T cells also activate islet antigen-specific B cells so that they differentiate into Ab-producing plasma cells (memory cells)
Through which 3 mechanisms are Treg cells able to suppress immune responses?
1) Production of immunosuppressive cytokines IL-10 and TGF-β
2) Reduced ability of APC’s to stimulate T cells through CTLA-4 binding to B7
3) Consumption of IL-2 because Treg cells express high levels of CD25+, an IL-2 receptor
What is the importance of FOXP3?
Serves as the master regulator in the the development and function of Treg cells
An activated autoimmune cytotoxic T lymphocyte can become functional upon interaction with an antigen‐presenting cell expressing?
- CD8+ T cells recognize antigen that is presented by MHC class I
- Naive CD8+ Th cells become activated only in the presence of a costimulatory signal mediated by B7 (CD80/86) present on the surface of professional APCs such as DCs.
