2-5-16-Immune Mechanisms Of Diabetes (Shnyra) Flashcards
Obesity leads to adipocyte necrosis and an increase in ___ macrophages. There is also a reduction in Treg cells and an increase in ___ cells
M1
B cells, CD4+ TH1, and CD8+ T cells
List some of the pro-inflammatory cytokines involved obesity and insulin resistance
IL-1b, TNF-a, IL-6, CCL2, CCL3, CXCL8
Anti-inflammatory–> IL-10, IL-4, IL-13
Type 1 diabetes is a ___-mediated autoimmune disorder
T cell
The onset of T1D is associated with infiltration of the islets of langerhans by ___ cells and the infiltrate is termed Insulitis
Mononuclear cells and CD8+ T cells
Describe the relationship between breast-feeding and type 1 diabetes incidences
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
Wheat gluten is a potent ___
Diabetogen
Risk of T1D is higher in pts with gluten-sensitive enteropathy
Streptozocin and bafilomycin A1 from streptomyces are cytotoxic for ___ cells
Beta
List viruses that have been implicated in T1D:
Mumps Rubella CMV Enteroviruses Retroviruses
The __ region (MHC gene on chromosome 6) presents insulin ags. For CD8+ T cells is associated with susceptibility to T1D
HLA
The __ gene (chromosome 11) is an ag for the autoimmune response and is associated with susceptibility to T1D
Insulin
___ is a regulator of insulin gene expression in the thymus
AIRE
The ___ gene (chromosome 2) is a regulator of the autoimmune response that is associated with susceptibility to T1D
CTLA-4
In the thymus, insulin ags are presented within ___ MHC
Class II
Which HLA alleles are considered “High risk” in T1D?
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
HLA class II molecules that lack ___ of the beta chain are often found among individuals with T1D
Asp57
HLA class II haplotypes such as ___ confer dominant protection against T1D
DR2/DQ6
This tandem repeat is a polymorphism that is categorized into classes I, II, and III associated with the insulin gene
VNTR core repeat sequence (VNTR polymorphism)
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
insulin mRNA
Regarding the insulin gene, the central tolerance is broken with class ___ alleles
I
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
AIRE
___ is the susceptibility locus on chromosome 2 associated with T1D.
CTLA-4
CTLA-4 encodes a glycoprotein that is a ___ homologue and binds B7 protein (CD80/86)
CD28
The function of ___ is suppression of T cell activation and apoptosis
CTLA-4
CTLA-4 on a T cell binds ___ on an APC
B7
CTLA-4 competes with __ for binding CD80 leading to cell-cycle arrest that prevents expansion of activated T Cells
CD28
Failure of T cells to express the __ gene due to a mutation may contribute to aberrant immune responses seen in T1D
CTLA-4
___ can be used to treat autoimmune diseases by outcompeting CD28 on T cells for binding CD80/86 on an APC
sCTLA-4
The presence of __ abs can be used to predict/diagnose if an individual has T1D
Islet cell
The specificities of several identified Islet Cell Abs (ICA) include:
GAD65 (glutamic acid decarboxylase)
IA-2, tyrosine phosphatases
IAA (insulin autoantibodies)
The presence of __ distinct antibody specificities is highly predictive of future T1D
2 or more
When combined with HLA typing, autantibody screening is also useful for predicting disease in general populations
T1D is a ___-mediated disease
Th1
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
Lymph nodes
Proliferate
IL-12
CD4 T
Th2
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
Treg
Susceptibility to T1D may be greatly enhance when __ cells fail to prevent activation/expansion of auto-reactive T cells
Treg
List cytokines secreted by Treg cells that lead to decreased in CD40, CD80/86, and IL-12
IL-4, IL-10, TGF-b
What are the effects of Tregs on B cells and NK cells?
Directly suppress B cell activation
Inhibit proliferation and differentiation of NK cells
What are the “CD’s” of Treg cells?
CD4+/CD25+
The loss of Tregs in IPEX syndrome leads to ____
Neonatal diabetes
IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome) is a rare disease linked to the dysfunction of the transcriptional activator ___
FoxP3
___ appears to function as the master regulator in the development and function of regulatory T cells
FoxP3
Lean adipose tissue contains a greater proportion of ___ macrophages as well as ___ cells
M2/M1
Treg
