19. Immunological Mechanisms of Diabetes Flashcards by Deleted Deleted

T/F: In the past T2D was thought to be solely d/t insulin resistance, but now this is combined with decreased insulin production and destruction/decrease in production of beta cells

True

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T2D is a multifactorial disease. How have twin studies proved this?

Offspring of a parent with T2D have 40% lifetime risk, increasing to 70% if both parents have T2D.

Environment also important, because in twin studies show 34% concordance rate in monozygotic

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What race has a 10 fold higher prevalence of T2D — 50% of which occurring at age 20?

Pima indians

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Other than the proven genetic component of developing T2D, what are some behavioral/environmental factors contributing to T2D?

Sedentary lifestyle
High fat diet
Pollution (pesticides, herbicides, traffic-related pollutants PM and NO2)

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Pesticides and herbices disturb ____ metabolism and induce insulin _____

Glucose; resistance

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Risk factors that contribute to development of T2D

Body fat - particularly abdominal fat
Insulin resistance
Ethnicity (greater risk in african american, hispanic, and native american children)
Onset of puberty

[these risk factors appear to act in additive fashion)

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High correlations between percentage body fat and _____ _____are found in obese children

Fasting insulin

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What are levels of the following like in a person with healthy pancreatic beta cells:

Serum insulin
Serum glucose
Serum FFA
Serum IL-1B
Serum IL-1Ra

Low Serum insulin
Low Serum glucose
Low Serum FFA
Low Serum IL-1B
High Serum IL-1Ra

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What type of macrophages are found in adipose tissue of healthy people, and what is the important cytokine produced?

What do they secrete into serum?

M2 (alternative) macrophages — anti-inflammatory IL-10

Secrete IL-R1a, which is soluble in serum

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What changes occur in the macrophages of adipocytes and kupffer cells (liver macrophages) in diabetic conditions? How does this perpetuate the diabetic disease state?

They take on M1 phenotype - produce pro-inflammatory IL-1

Inflammation is perpetuated by decreased secretion of IL-1R antagonist in serum, so that more and more inflammation occurs

This eventually reaches the pancreatic beta cells which will be killed by necrosis

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_____ is characterized by chronic activation of inflammatory pathways

It is increasingly recognied that inflammation in this condition are causally linked to insulin ______

Obesity; resistance

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In lean, insulin-sensitive individuals, normal insulin secretion is sufficient to:

Induce robust uptake of glucose from circulation by _____ and ______ tissue

Inhibit _____ release from adipose tissue

Suppress hepatic ______

Skeletal m; adipose

FFA

Gluconeogenesis

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The adipose tissue macrophages and kupffer cells in a healthy individual have an alternative bias, resulting in expression of _____ receptor antagonist and suppression of ______

The resulting serologic state is characterized by relatively low concentrations of insulin, glucose, FFAs, and inflammatory mediators, and high levels of regulatory cytokines

IL-1 (IL1-Ra); IL-1B

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Adipose tissue obesity is a chronic _____ disease leading to a predominance of _____-like macrophages

Inflammatory; M1

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What mediators are released by lean, insulin-sensitive adipocytes to favor the development of anti-inflammatory M2 macrophages?

Short-chain FA
IL-13
IL-4

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What mediators are released by obese, insulin-resistant adipocytes to favor the development of pro-inflammatory M1 macrophages?

Long- and Medium-chain FAs
Chemokines
MCP-1
TNF-alpha

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The IL-10 secreted by M2 macrophages activates _____ to secrete more anti-inflammatory mediators that promote further M2 production, while simultaneously inhibiting the action of ____ macrophages

Adipocytes; M1

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What mediators are released from M1 macrophages to perpetuate the diabetic disease state set up by obese, insulin-resistance adipocytes?

TNF-a
IL-1B
IL-6
Resistin
NO

[further induce insulin resistant state]

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Besides the mediators released by obese, insulin-resistant adipocytes, what 2 things activate M2 macrophages?

LPS

IFN-y

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The ______ pathway leads to islet inflammation and beta cell dysfunction

Palmitate-TLR-4

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A long chain FA _______ induces beta cell dysfunction in vivo at least partly by activating inflammatory processes in _____

Beta cells sense this molecule via the ______ pathway and recruit inflammatory monocytes to islets by producing ______

The recruited monocytes differentiate into _____ macrophages that play a pivotal role in beta cell dysfunction

Palmitate; islets

TLR4/MyD88; chemokines

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T1D is characterized by _______-mediated destruction of pancreatic beta cells resulting in insulin _______

Immune; deficiency

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Patients with T1D are prone to ______, a dangerously high level of ____ in the blood

Most cases are characterized by _______ markers of beta-cell destruction and strong _____ associations

Ketoacidosis; ketones

Autoantibody; HLA

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Type 1 diabetes is a _______mediated autoimmune disorder; its onset is associated with infiltration of the islets of langerhans by ______ cells and ______ cells

This infiltrate is termed _______

T-cell; mononuclear; CD8 T

Insulitis

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Factors contributing to T1D occur at interface between genetics and environment Islet cell mass ______ MHC I ______ Th1/Th2 ratio ______ All leading to increased beta cell death

Decreases Increases Increases

T/F: T1D patients and their relatives are at increased risk for other autoimmune diseases like thyroid autoimmunity and Addison disease

True

About 18 genes of varying potency are associated with susceptibility to T1D. Of these, the most significant are: The ____ region — the MHC gene on chromosome ____ responsible for Ag presentation The _____ gene on chromosome 11 — Ag for autoimmune response Regulators of insulin gene expression in the thymus = ______ The _____ gene on chromosome 2 = regulation of autoimmune response

HLA; 6 Insulin AIRE CTLA-4

Central tolerance to insulin is established in the ______ when insulin-Ags are presented within ______ MHC

Thymus; class II [high-avidity recognition of peptide-MHC complexes on thymic APCs leads to negative selection and apoptotic cell death]

HLA alleles ____ and _____ are high-risk for developing T1D; the former are found in more than 90% of individuals with T1D

DQ2/DQ8; DR3/DR4 [typically found in those who develop T1D early in life]

Heterozygous genotypes _______ are most common in children diagnosed with T1D prior to age 5 (50%)

DR3/DR4

HLA class II molecules that lack _____ of the beta chain are often found among individuals with T1D HLA class II haplotypes such as ______ confer dominant protection against T1D

Asp57 DR2/DQ6

The insulin gene = ______

IDDM2

What is the insulin gene

IDDM2

The antigenic area of the insulin gene IDDM2 is mapped to a region containing the variable number of tandem repeat (VNTR) in the ____ region of the gene. The VNTR polymorphism can be categorized into classes I, II, or III

Promoter

Which class of insulin VNTR polymorphism is associated with lower insulin mRNA synthesis? What does this result in?

Susceptible class I Low Ag (insulin) synthesis, low Ag presentation in thymus, failure of deleting self-reactive CD8 T cells Net result is breakdown of central tolerance with class I alleles

Transcriptional expression of insulin in the thymus is controlled by ______

AIRE

Malfunctioning if AIRE results in what?

Lower levels of insulin mRNA in the thymus

Transcriptional expression of insulin in the thymus is controlled by AIRE. Malfunctioning of AIRE results in lower levels of insulin mRNA in the thymus The absence of insulin results in failure of deleting insulin-reactive T cells and _________ ______ breaks down

Central tolerance [Thus AIRE is a critical factor in the induction of central tolerance against insulin]

______ = susceptibility locus on chromosome 2 to be associated with T1D

CTLA4 (IDDM12)

CTLA4 encodes a glycoprotein that is a ______ homologue and binds _____ protein

CD28; B7 (CD80/86)

CTLA4 may counterregulate the CD28-dependent TCR activation of T cells; what does this mean for its function?

CTLA4 functions to suppress T cell activation and leads to activation of its apoptosis

What is the normal MOA of CTLA4?

Engagement of CTLA4 on a T cell may deliver inhibitory signals that terminate further activation of that cell CTLA4 on regulatory or responding T cells binds B7 molecules on APCs or removes these molecules on surface of the APCs, making the B7 costimulators unavailable to CD28 and blocking T cell activation

CTLA4 typically functions in later immune responses in order to cause contraction of effector mechanisms and leads to cell cycle arrest. Failure of T cells to express the CTLA4 gene due to mutation may contribute to aberrant immune responses seen in _____

T1D

The soluble form of _____ has been used in clinical trials for tx of autoimmune diseases

sCTLA4

How does breastfeeding vs. cow’s milk affect T1D risk?

A variety of studies have shown an inverse correlation between a decrease in breastfeeding and the increase in T1D risk

Early exposure to cow milk in life may contribute to T1D. Why?

Immune tolerance to insulin might be compromised in early exposure to cow milk which contains much less insulin than does human milk [however, inconsistencies in variations in composition of cow milk, genetic cow variation, and variations in milk-sensitivities in diabetes-prone patients]

_______ _____ is a potent diabetogen, and thus the risk of T1D is higher in patients with _____-sensitive enteropathy

Wheat gluten; gluten

Other environmental factors linked with T1D include _______, an immune modulator and suppresant. This theory is based on the north-south gradient of T1D with lower mean sunshine hours in the north

Vitamin D

What are some chemicals that can cause destruction of beta cells?

``` N-nitroso compounds Streptozocin Alloxan Compounds in smoked meat/foods Drinking water ``` [no detailed investigation of these associations]

Infection also plays a role in T1D. ______ and _____ from Streptomyces are cytotoxic for T cells Bacteria may also act as ______ for the immune response to food Ags

Streptozocin; bafilomycin A1 Adjuvants

Viruses may act against beta cells in what 2 ways?

Direct cytotoxicity Triggering of an autoimmunity by molecular mimicry

What are 2 viruses that have been implicated in T1D?

Mumps Rubella [also cytomegalovirus, enteroviruses, retroviruses]

In terms of the role infections play in development of T1D, Approximately 20% of children born with ______ ultimately develop T1D

Rubella

What test is used to detect loss of first phase insulin response to diagnose T1D?

IVGTT - Intravenous glucose tolerance test

The level of _____ in the blood can show how much insulin is being made by the pancreas. Absence of this compound is considered overt diabetes

C-peptide

________ are detected in individuals with T1D with INCREASED frequency among individuals recently diagnosed with T1D

Islet cell autoantibodies (ICAs)

T/F: autoantibody production to islet cells begins at the onset of metabolic changes of T1D

False; autoantibody production appears months to years in advance of the metabolic changes of T1D and can be used to predict the disease

The presence of ICA’s confirms a diagnosis of type ____ diabetes

What are 3 of the specificities of identified ICA?

Glutamic acid decarboxylase (GAD65) Insulinoma Ag-2 (IA-2, tyrosine phosphatases) Insulin autoantibodies (IAA)

Genetic predisposition and environmental exposure interact with an impaired immune system to break tolerace towards pancreatic insulin-producing beta cells. Initial beta cell detruction leads to release of beta-cell-specific auto-Ags, such as ______, _____, and _____, among others. Upon auto-Ag recognition, auto-reactive T cells expand, migrate to the pancreas causing ______, and induce progressive beta-cell destruction In healthy individuals, these autoreactive T cells are controlled by _____ cells. However, in T1D patients this regulatory counterpart is impaired causing a significant imbalance of this immune control mechanism. In addition, aut-Ag activated ____ cells produce beta-cell-specific auto-Abs. When patients present with clinical symptoms caused by insufficient beta cell mass and subsequent aberrant glucose regulation, this auto-Ab profile allows for specific dx of immune-mediated T1D

Pro-insulin, GAD65, IA-2; insulitis Treg; B

Despite the utility of auto-Abs for diagnostic purposes, their pathogenic contribution is controversial. Why?

T1D cannot be transferred using serum from diabetic humans - plasmapheresis provides little therapeutic benefit T1D was reported in a 14 y/o male with X-linked agammaglobulinemia (so he was unable to generate those auto-abs)

T/F: the presence of 2 or more distinct antibody specificities is highly predictive of future T1D

True (5 year risk = 28-66%)

What is the only confirmed pathogenic role of auto-Abs in T1D?

Auto-Abs may affect the time course of disease development

When combined with _____ typing, autoantibody screening is also useful for predicting disease in general populations

HLA

Initiation of immune response in T1D: Beta cell death in islets can occur both physiologically and as result of infection _____ cells are always present in the islets and can take up released beta cell antigen; these cells can then activate ____ cells

Dendritic; CD4 T

Dendritic cells cross present Ag to beta cell antigen specific _____ so that they upregulate their cytotoxic properties

CD8

CTLs can kill beta cells through the release of cytolytic granules containing ____ and ____ as well as through ____:____ interaction

Perforin; granzymes; Fas:FasL

CD4 T cells activated by dendritic cells with beta cell antigen can also activate antigen specific B cells so that they differentiate into antibody-producing plasma cells These immune mechanisms can be tempered by ______ cells

Treg

T cells are activated in the ____ ____ that drain the pancreas Once activated, islet specific T cells traffic to the pancreas where they proliferate and accumulate, resultin gin organ-specific ______

Lymph nodes; inflammation

Local APCs capable of presenting Ag in the context of _______ MHC molecules and secreting ______ play an important role in pathogenesis of T1D These APCs activate Ag-specific _____ cells and further stimulates ____

Class II; IL-12 CD4 T; IFN-y

What is the role of IFN-y in T1D pathogenesis?

Inhibits Th2 cytokine production (IL-4, IL-5, IL-10) and enhance IL-1B, TNF-a, and free radical production by macrophages, which are all toxic to islet beta cells

A counter regulatory role for Th1/Th2 subsets would suggest that T1D would not occur with _______; however, this condition is more prevalent in children with T1D than non-diabetic children. The common denominator between the above condition and T1D is the failure of regulatory mechanisms controlled by _____ cells

Asthma Treg

Susceptibility to T1D may be greatly enhanced when ____ cells fail to prevent activation/expansion of autoreactive T cells Islet specific pathogenic clones of T cells are found in healthy individuals, but T1D is prevented and ________ self tolerance is maintained by Treg cells

Treg Peripheral

Function of Treg cells

Treg cells can act locally in tissues and draining LNs Treg cells can become activated by local APC presenting Auto-Ag Treg cells suppress APCs directly through cell-cell interactions or indirectly via cytokines or chemokines Alternatively, Treg cells might act directly on T cell effectors

Regulatory T cells appear to suppress immune responses at multiple steps. They may also directly suppress ____ cell activation and inhibit the proliferation and differentiation of ____ cells

B; NK

Several mechanisms of suppression by Treg cells have been proposed, what are the 3 major theories?

Production of immunosuppressive cytokines IL-10 and TGF-b Reduced ability of APCs to stimulate T cells Consumption of IL-2

Islet-specific Ags are released and presented in pancreatic lymph nodes. The Ags can activate damaging CD4 and CD8 T cells. The Ags can also activate ___+/___+ Treg cells, which prevent activation of both CD4+ and CD8+ T cells

CD4; CD25

T/F: Treg cells are shown to prevent diabetes in non-obese diabetic mice (NOD mice)

True

Regulatory T cells are important. The loss of Tregs in _____ syndrome leads to neonatal diabetes. This syndrome involves immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome linked to the dysfunction of the transcriptional activator _______, a specific marker of natural Treg cells

IPEX FoxP3