Immune Mechanisms of Diabetes Flashcards
What is the clinical distinction of T1DM?
insulin dependence, with loss of beta cells
What is the etiology of T2DM?
insulin resistance and relative insulin deficiency
What is the clinical distinction of T2DM?
oral hypoglycemic agents are effective early in the disease
What has complementary effects on the development of T2DM?
genetic susceptibility, sedentary lifestyle, high-fat diet, and psychological stress
What is the immunological composition of lean adipose tissue?
Contains more: M2 Mo (anti-inflammatory like) Th2 CD4 T cells CD4 Treg cells Eosinophils
What is the immunological composition of obese adipose tissue?
Adipocyte necrosis Increase in M1 Mo (pro-inflammatory like) also some M2 Th1 CD4 T cells CD8 T cells Mast cells B cells
Reduction of Treg
What cytokines do lean insulin sensitive adipose tissue produce?
IL-10, 4, 13: anti-inflammatory
What cytokines do obese insulin resistant adipose tissue release?
IL-1B, TNF-a, IL-6, CCL2, CCL3, CXCL8
Long-term __________ excess leads to apoptotic and necrotic death of adipocytes
excess
_____ is characterized by immune-mediated destruction of pancreatic beta-cells resulting in _______ _______.
T1DM
Insulin deficiency
Patients with T1D are prone to ________, dangerously high levels of ______ in the blood.
ketoacidosis
ketones
Most cases of T1D are characterized by autoantibody markers of ______ destruction and strong ______ aassociations.
Beta-cell
HLA
T1DM is a __________ - mediated autoimmune disorder
T cell-mediated
Describe insulitis
the infiltrate of the islets of langerhans by mononuclear cells and CD8 T cells
Associated with onset of T1D
What are the leading causes of disability and mortality in young adults with T1D?
Long-term micro- and macro-vascuclar complications of diabetes
T1D development involves ____ and ______ factors, such as birth delivery mode, use of antibiotics and diet.
Genetic and environmental
What could be the link btwn environmental factors, the development of autoimmunity and T1D?
Gut microbiota
Inverse correlation btwn a decrease in ________ and the increase in type 1 D risk
breast-feeding
How can cow milk possibly contribute to T1D?
early exposure might compromise immune tolerance to insulin
Milk contains much less insulin than human milk
*inconsistency tho due to variations in composition of milk, genetic variation in cow proteins
Describe the microbiota in healthy individuals who eat high-fiber diet
thick mucus layer
anti-inflammatory
Treg
prevotella: butyrate->mucine synthesis->maintained tight junctions
Describe the diet and microbiota in T1D
Gluten, Bovine milk, high-fat diet Increased paracellular permeability Bacteroides: propionate, succinate, and acetate->mucine degradation->altered permeability thin mucus layer Inflammation decreased insulin sensitivity autoimmunity
Wheat gluten is a potent ______.
diabetogen
The risk of T1D is higher in pts with ______-sensitive enteropathy
gluten
Describe the possible relationship of Vit D and T1D
north-south gradient of T1D in Europe, with lower mean sunshine hours in the north
What are viruses that have been implicated in T1D?
Mumps and Rebella
*streptomyces are also cytotoxic for B cells
What other autoimmune diseases are T1D pts are at risk of?
thyroid and addison’s disease
There are about ____ genes of varying potency associated with susceptibility to T1D. What are the most significant?
18
HLA: MHC gene on Ch. 6 - insulin Ags for CD8 T cells
Insulin gene: Ch. 11 - Ag for AutoI response
Regulators of insulin gene expression in thymus (AIRE)
CTLA-4 gene: Ch. 2 - regulation of autoI response
How is central tolerance to insulin established?
In the thymus, insulin-Ags are presented within Class II MHC
CD4/CD8 thymocyte with high-avidity recognition of peptide on thymic antigen-presenting cell -> apoptotic cell death
= negative selection
What are the high risk alleles in T1D?
DQ2/DQ8 (haplotypes DR3/DQ2 or DR4DQ8) found in more than 90% with T1D
and DR3/DR4 (heterozygous genotypes most common in children diagnosed before age of 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 from T1D
DR2/DQ6
What class of VTNR polymorphism of insulin is associated with lower insulin mRNA synthesis? What does this result it?
Class I: the central tolerance is broken
Low Ag (insulin) synthesis -> low Ag presentation in the thymus -> failure of deleting self-reactive CD8 T cells
What is transcription of insulin in the thymus controlled by? What happens if its malfunctioning?
AIRE
Break down of central tolerance: medullary thymic epithelial cells fail to induce negative selection by not being able to display insulin peptides to T cells
What does CTLA-4 encode?
a glycoprotein that is a CD28 homologue and binds B7 protein (CD80/86)
Counter-regulate the CD28-dependent TCR activation of T cells
Suppression of T cell activation and activation of apoptosis
What are the mechanisms of action of CTLA-4
- cell intrinsic inhibitory signaling (B7/CTLA-4) inhbiit T cells
- Blocking and removing B7 on APC; Treg cells have CTLA-4 that bind to/remove B7 on APC making B7 costimulators unavailable to CD28 on T cells to block activation
What is sCTLA-4?
soluble recombinant CTLA4 used in clinical trials for autoimmune diseases
CTLA4 = CD_____
152
In activated T cells, CD152 (CTLA-4) ….
begins to move to the membrane and binds CD80/CD86
What is the etiology of type I DM?
Beta cell destruction due to immune or idiopathic cause
What can be used to predict T1 DM disease in advance (months to years)?
Islet Cell autoantibodies
Their presence confirms a diagnosis of type IA diabetes
What are the specificities of several identified ICA?
ICA = islet cell autoantibody
Glutamic acid decarboxylase (GAD65)
Insulinoma antigen-2 (IA-2, tyrosine phosphatases)
Insulin autoantibodies (IAA)
IL-4 induces what type of T cell?
Th2
IL-12 induces what type of T cell?
TH1
What cytokines do Th1 cells produce?
IFNy, IL-12
*these inhibit TH2
What types of cytokines do TH2 cells produce?
IL-10 and IL-4, IL-5
*these inhibit TH1 cells
TH1 cells with what cytokine induce cytotoxic T cells, Mo, and NK cells?
IFNy
Antibody-mediated immunity is mediated by ____ T cells
TH2
Cell-mediated immunity is mediated by _____ T cells
TH1
Where are T cells activated?
in the Lymph nodes that drain the pancreas
Once activated, where do islet specific T cells go?
Traffic to the pancreas where they proliferate and accumulate resulting in organ specific inflammation
What type of APCs play an important role in pathogenesis of T1D
Local APCs presenting with Class II MHC and secreting IL-12
They activated CD4 T cells and further stimulate IFN-Gamma
What does IFN-gamma enhance?
IL-1Bb, TNF-a and free radical production by Mo
All are toxic to islet beta cells
Where can Treg cells act?
Locally in tissues and draining lymph nodes
What do Treg cells become activated by?
local APC presenting auto-Ag
How do T reg cells suppress APCs?
directly: cell to cell interactions
Indirectly: cytokines IL-4, IL-10, TGF-B
*reduce ability of APCs to stimulate T cells (CTLA-4?)
What immunosuppressive cytokines do Treg cells produce?
IL-10 and TGFB
Because of the high level of expression of IL-2 receptor on Treg cells, these cells may be able to do what?
consume IL-2 and deprive other T cell populations of this GF
Results in reduced proliferation and differentiation of IL-2 dependent cells
Where are Islet-specific Ags released and presented? What can recognize it?
in pancreatic lymph nodes
The can activate damaging CD4 and CD8 T cells
But can also activate CD4/CD25 T reg cells which prevent activation of the damaging cells
What is a specific marker of natural T reg cells
FoxP3: function as the master regulator in the development and function of Treg cells
What autoantigen is most prevalent in children with T1DM?
insulin/proinsulin
What autoantigen is most prevalent in adult-onset T1DM?
GAD65
