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Endo/Repro Exam 1 > Immunological Mechanisms of Diabetes > Flashcards

Immunological Mechanisms of Diabetes Flashcards

1
Q
  • Early stages of T2D are characterized by _
  • Later stages of T2D are characterized by _
  • What are some complications that can result from elevated blood sugar levels?
A
  • Hyperinsulinemia
  • Insulin secretion decrease
  • Renal failure, CAD, blindness, stroke
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2
Q
  • In healthy individuals, there is expression of _ antagonist and suppression of _
A
  • IL-1
  • IL-1Beta (pro-inflammatory cytokines)
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3
Q

_ are the predominant macrophages active in healthy individuals (induced by IL-3 and IL-4)

What other cell types are expressed in a healthy/lean person?

They secrete what cytokines?

A
  • M2 macrophages
  • Treg, Th2, Eosinophils
  • Secrete anti-inflammatory cytokines:
    • IL-10 (which suppresses M1 activation)
    • TGF-Beta
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4
Q
  • _ are the predominant macrophages in patients with obesity (are induced by LPS and IFNgamma and inhibited by IL-10_
  • What other cell types are present in these patients?
  • What cytokines do these secrete?
A
  • M1 macrophages
  • Th1 cells, CTLs, Neutrophils
  • Secrete pro-inflammatory cytokines
    • TNF
    • IL-12
    • IFNalpha
    • IFNbeta
    • IL-6
    • IL-15
    • IL-18
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5
Q
  • _ free fatty acids are more common in healthy patients
  • _ free fatty acids are more common in obese patients
A
  • Short chain
  • Medium/Long chain
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6
Q

_ inflammation in obesity can lead to insulin resistance and T2D

A

Adipose tissue

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7
Q
  • How does glucotoxicity, lipotoxicity, and beta cell death contribute to T2D
A
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8
Q

_ is a FFA recognized by TLRs (TLR2/TLR4) and produces cytokines that are precursors for M1 macrophages and lead to increased inflammation, increased Ag presentation, and activation of CTLs that ultimately leads to destruction of Beta Pancreatic Islets

A
  • Palmitic acid (long chain)
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9
Q
  • What are environmental factors in the development of T2D?
A
  • Sedentary lifestyle
  • High Fat Diet
  • Pollution
    • Pesticides/Herbicides
    • Traffic related pollutants (Diesel, PM, NO2)
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10
Q
  • What is the role of microflora in the development of T2D?
  • What are the two mechanisms by which this happens
A
  • Increase in Firmicutes/Bacteriodetes ratio (esp decrease in bacteriodetes) aids in development of obesity
  • Why is this important?
    • Gut microbiota facilitate energy harvest (increase in adipocytes, FFA production, leading to insulin resistance and inflammation)
    • Initiate inflammatory response
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11
Q
  • Fecal transplantations are potential future treatments for T2D in the fact that they induce _ producing intestinal bacteria into the recipient of the transplant
A
  • Butyrate-producing bacteria
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12
Q

T1D is an AID characterized by _ cell mediated destruction of beta cells in the pancreas via the production of auto-Abs

Diabetes was considered a _ condition until insulin was available for therapy

_ was the youngest nobel prize winner for his work (worked alongside Macleod)

A
  • T cell
  • Terminal
  • Banting
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13
Q
  • Patients with T1D are more likely to develop _
  • Most cases of T1D ate characterized by _ markers of beta cell destruction and strong _ associations
  • _ cell mediated AID
A
  • Ketoacidosis
  • Autoantibody, HLA
  • TH1
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14
Q
  • Insulinitis
A
  • Infiltration of mononuclear and CD8+ T cells into islets of Langerhans
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15
Q
  • Summary of physiological contributions to T1D
A
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16
Q
  • Role of infections in T1D development
A
  • Bacteria act as adjuvants
  • Viruses:
    • Enteroviruses
    • Mumps
    • Rubella
    • Cytomegalovirus
    • Retrovirus
  • Viruses can act against b cells by:
    • Direct cytotoxicity
    • Triggering of autoimmunity by molecular mimicry
17
Q
  • Tolerance to insulin may be compromised by stopping _ too soon and inducing _ too early
A
  • Breast-feeding (breast milk contains a lot of insulin)
  • Cows milk (much less insulin)
18
Q
  • What are some other environmental factors that contribute to the development of T1D?
A
  • Wheat gluten
  • Gluten-sensitive enteropathy
  • Lack of Vitamin D
  • Psychological stress
19
Q
  • Role of Microflora in T1D:
    • ​_ is more common in patients with T1D
    • T1D patients often present with _ of the intestinal mucosa which leads to a decrease in the _ producer genera in the gut
      • ​Normally helps with _ synthesis and _ formation
      • Lack of this in T1D patients leads to an increased _
A
  • Celiac Disease
  • Chronic inflammation, butyrate
  • Mucin synthesis, tight junction formation
  • Gut permeability
20
Q
  • What are the most important genes determining T1D susceptibility?
A
  • Insulin gene-Ag for autoimmune response
  • Regulators of insulin gene expression in thymus (AIRE)
  • HLA region (DR/DQ)-presentation of insulin Ags for CD8+ T Cells
  • CTLA-4 gene-regulation of autoimmune response
21
Q
  • How is central tolerance established?
A
  • Negative selection when doiuble positive CD4+/CD8+ T cell binds self peptides presented in thymus within Class I and Class II MHC with a high enough affinity to receive an apoptotic signal
22
Q
  • Genetic mechanisms (allelic variation, alternative splicing, epigenetic regulation) of gene expression can lead to suboptimal expression of _ cell auto-Ags and lead to imperfect tolerance
  • Can lead to mismatched expression patterns in _ and _
  • _ cells are involved in negative selection of self-reactive T cells (these cells also transcribe an important protein _, that acts as a transcription factor)
A
  • Islet cell auto-Ags
  • Pancreas-Thymus
  • Thymic epithelial cells
  • AIRE
23
Q

_ is a protein transcribed by T epithelial cells and is important in negative selection of self reactive T cells

If not present, can lead to autoimmunity

A
  • AIRE
24
Q

Role of AIRE in development of T1D:

Transcriptional expression of _ is controlled by AIRE

Malfunctioning of AIRE results in _ in the thymus

This causes a failure in deletion of _ and breaking of central tolerance

A
  • Insulin
  • Lower levels of Insulin mRNA
  • Insulin reactive T cells
25
Q
  • Insulin Gene (IDDM2) and the development of T1D
    • ​Mapped to a region contraining the _ in _ region of insulin gene
    • _ polymorphism is categorized into three classes (I,II,III)
    • _ alleles are . associated with lower insulin mRNA synthesis
      • ​Leads to low Ag (insulin) synthesis
      • Low Ag presentation in the thymus​
      • Failure to delete self-reactive T cells
      • Break of central tolderane
A
  • VNTR, promoter
  • VNTR
  • Class I
26
Q
  • Role of HLA in T1D:
    • ​HLA _/_ and _/_ are high risk alleles
    • Which alleles are most common?
    • Which alleles are most common in children
    • These HLA Class II molecules lack _ of beta chain
    • HLA Class II haplotypes like _/_ confer dominant protection
A
  • DQ2/DQ8 and DR3/DR4
  • DQ2/DQ8 ( I went 2 DQ and 8 a blizzard)
  • DR3/DR4 (children like going to the DR at ages 3/4)
  • Asp57
  • DR2/DR6
27
Q
  • _ is a susceptability locus to be associated with T1D
  • It encodes a glycoprotein that is an inhibitory CD28 homologue and binds _ protein
  • May counter regulate the CD28 dependent TCR activation of T Cells
  • Function is _ and activation of apoptosis
  • Decreased expression may contribute to T1D
A
  • CTLA4
  • B7
  • suppression of T cell activation
28
Q

Immunopathogenesis of T1D

A
  • Beta cell death occurs
  • DCs present in islets and take up released Beta Cell Ag
  • Release of proinflammatory cytokines (Type 1 IFNs) can activate DCs and promote antigen presentation to T cells
  • T cells (pancreas specific) activated
  • T cells move to pancreas where they proliferate and accumulate to result in pancreatic inflammation
  • APCs present Ag to Class II MHC molecules and secrete IL-12
  • IFN gamma further stimulated by activation of CD4 cells
  • Th2 is inhibited and enhancement of IL-1beta, TNF-alpha and free radical production by macrophages occurs
29
Q
  • _ is more prevalent in children with T1D than non-diabetic children
  • Both occur d/t failure of regulatory mechanisms controlled by _
  • Susceptibility to T1D is enhanced if _ fail to prevent activation/expression of _ T cells
  • _ from individuals with T1D are less able to control proliferation and cytokine production by _ T Cells
A
  • Asthma
  • Tregs
  • Tregs, autoreactive T cells
  • Tregs, effector T cells
30
Q
  • MOA of Tregs:
    • Suppress _ cell activation and inhibit proliferation and differentiation of _ cells
    • Produce _ cytokines (IL-10 and TGF-Beta)
    • _ ability of APCs to stimuate T Cells
    • Consume _ (deprives other T cells of this growth factor, leading to reduced proliferation and differentiation of T cells dependent on this cytokine)
A
  • B cell, NK cells
  • Immunosuppressive cytokines (IL-10, TGF-Beta)
  • Decrease ability of APCs to stimulate T cells
  • Consume IL-2
31
Q
  • Role of microflora in T1D
A
  • Change the bacterioidetes/firmicutes ration
    • Modifies balance of Treg (Th1 and Th17) in GALT
    • Defect in FoxP3 and Tregs
32
Q
  • AutoAbs in T1D:
    • _ are present with increased frequency among those diagnosed with T1D
    • _ compared to metabolic changes associated with T1D and can be used to predict disease and confirm diagnosis
  • What are the identified AutoAbs?
  • What is the pathogenic role of auto-Abs in T1D?
A
  • ICA (Islet Cell Autoantibodies)
  • Appear early
  • Identified auto-Abs:
    • ​GAD65 (Glutamic acid decarboxylase)
    • IA-2, tyrosine phosphatase (Insulinoma Antigen 2)
    • IAA (Insulin Autoantibodies)
  • May affect time course of T1D development
33
Q
  • Pathogenic Role of Auto-Abs
A
34
Q
  • Diagnostic role of Auto-Abs
A

Endo/Repro Exam 1 (12 decks)

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