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Endo Repro Midterm > Immune Mechanisms of Diabetes > Flashcards

Immune Mechanisms of Diabetes Flashcards

1
Q

T2D and obesity behavioral and environmental triggers

LO1

A

Microbiome

  • delivery mode
  • antibiotic usage
  • diet: processed foods

Diet

  • total calorie intake
  • macronutrients
  • micronutrients
  • vitamins
  • high fat diet

Energy Expenditure

  • basal metabolism
  • exercise
  • sedentary behavior
  • ambient temperature

Early life influences

  • maternal disease
  • placental function
  • maternal nutrition
  • postnatal growth

Other

  • particulate matter
  • NO2
  • pesticide
  • sleep debt
  • endocrine disruptors
  • chronic inflammation
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2
Q

T2D and obesity genetic risk factors

LO1

A
  • ethnicity: greater risk for african american, hispanic, and native american
  • Pima Native Americans: 10 fold higher prevalence than general population
  • offspring with 1 T2D parent: 40% risk
  • offspring with 2 T2D parents: 70% risk
  • monozygotic twins: 34%
  • dizygotic twins: 16%
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3
Q

What are the differences in LEAN adipose tissue vs OBESE adipose tissue?

LO2

A

LEAN: more Treg cells, Th2 cells, NK T cells, M2 macrophages, and eosinophils –> more IL-4, IL-13, IL-10, and adiponectin (all antiinflammatory)

OBESE: more Th1 cells, M1 macrophages, CD8+ T cells, B cells, dendritic cells, mast cells, and neutrophils due to increased migration from blood –> more leptin, elastase, IFN gamma, TNF alpha, IL1beta, and IL-6 (all inflammatory)

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4
Q

What is the effect of IL-6 in T2D?

LO3

A

acute inflammatory response; role in adipose inflammation and insulin resistance well documented

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5
Q

What is the effect of IL-6 on the pancreas?

LO3

A

increase GLP-1

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6
Q

What is the effect of IL-6 on the intestine?

LO3

A

increase GLP-1

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7
Q

What is the effect of IL-6 on adipose tissue?

LO3

A

increase lipolysis and AMPK

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8
Q

What is the effect of IL-6 on muscle?

LO3

A

increase GLUT4 translocation and lipolysis

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9
Q

What is the effect of IL-6 on the liver?

LO3

A

increase acute-phase response, SOCS-3, and insulin resistance

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10
Q

What does use of IL-6 in clinical settings increase the patient’s risk for?

LO3

A

risk of inflammation, cancer, and rheumatoid arthritis

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11
Q

What is the process for FFA induction of adipose inflammation?

LO2

A
  • long chain FFA palmitate is a ligand for TLR4 present on adipocytes
  • receptor/ligand binding leads to pro-inflammatory cytokine and chemokine production
  • recruitment and differentiation of M1 macrophages
  • inflammatory state leads to sustained beta cell dysfunction
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12
Q

What are the innate immune responses that increase in obesity?

LO3

A

M1 macrophages

Mast cells

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13
Q

What are the innate immune responses that decrease in obesity?

LO3

A

M2 macrophages

eosinophils

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14
Q

What are the adaptive immune responses that increase in obesity?

LO3

A

B2 cells
CD8+ T cells
INF gamma Th1 cells

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15
Q

What are the adaptive immune responses that decrease in obesity?

LO3

A

Treg

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16
Q

What cytokines increase in obesity?

LO3

A

TNF alpha
IFN gamma
IgG2c antibodies
Th1 response

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17
Q

What cytokines decrease in obesity?

LO3

A

IL-4
IL-10
IL-13
Th2 response

18
Q

What are histological changes in T2D?

LO3

A

islet hyalinization: central hyaline deposits replace dead beta cells in late stages

19
Q

Describe T1D

LO4

A
  • true autoimmunity
  • T cell mediated –> Type IV hypersensitivity
  • T cell mediated destruction of of beta cells resulting in insulin deficiency
  • autoantibody production used as markers of beta-cell destruction
  • strong HLA associations
  • prone to ketoacidosis
  • insulitis: lymphocytic infiltrate within islets
20
Q

What is insulitis?

LO4

A

lymphocytic infiltrate within islets

21
Q

What are complications of T1D?

LO4

A
  • kidney failure
  • cardiovascular disease
  • diabetic retinopathy
  • foot ulcers
22
Q

Describe the mechanism of T1D

LO4

A
  • genetic predisposition and environmental factors lead to autoantigen formation on insulin-producing beta cells and circulate in the blood stream and lymphatics.
  • Processing and presentation of autoantigen by antigen presenting cells.
  • Activation of Th1 lymphocytes –> IFN gamma and IL-2
  • IFN gamma –> activation of macrophages with release of IL-1 and TNF alpha
  • IL-2 –> activation of autoantigen specific T cytotoxic CD8 cells
  • Activation of Th2 lymphocytes –> IL-4 –> activation of B lymphocytes to produce islet autoantibodies and antiGAD65 antibodies
  • all lead to destruction of beta cells with decreased insulin secretion
23
Q

Genetics of T1D: familial clustering and concordance

LO5

A
  • mother: 2-3% lifetime risk
  • father: 5-6% lifetime risk
  • both: 30% lifetime risk
  • sibling: 6% lifetime risk
  • general public: 0.4% risk
  • monozygotic twins: 30-50%
  • dizygotic twins: 10%

patients and relatives at increased risk for other autoimmune diseases

24
Q

What are genes associated with T1D?

LO5

A

HLA alleles DQ2/DQ8 and DR3/DR4
INS-insulin gene
AIRE
CTLA-4

25
Q

What are the high risk HLA alles for T1D?
-chromosome

LO5c

A
  • chromosome 6
  • DQ2/DQ8 and DR3/DR4
  • DQ2/DQ8 halotypes DR3DQ2 and DR4DQ8 found in >90%
  • heterogenous genotypes DR3/DR4 are most common in children diagnosed prior to age 5
  • HLA class II lacking Asp57 of beta chain are common amongst T1D
26
Q

What halotype confers protection against T1D?

LO5c

A

HLA Class II halotype DR2/DQ6

27
Q

Role of AIRE mutation in T1D

LO5e

A
  • AIRE expression and presentation of insulin in thymus to developing T cells is critical to protecting against development of T1D
  • AIRE is necessary to express self antigen (for insulin) in the thymus, where self proteins would not normally be expressed
28
Q

Insulin gene’s role in T1D

LO5d

A

chromosome 11 IDDM2

  • VNTR in promotor region
  • relative increase in risk 2 fold with two class I alleles –> lower insulin mRNA synthesis
  • reduction in tolerance to insulin and precursors due to low presentation
29
Q

CTLA-4 gene role in T1D

LO5f

A
  • chromosome 2 IDDM12
  • defect in CTLA-4 expression on Tregs and activated T cells decreases ability to down regulate immune response and maintain tolerance
30
Q

What are perinatal and intrauterine environmental risk factors for T1D?
LO5

A
  • decreased by transplacental transmission of antibodies
  • increased by cesarean deliveries
  • increased by higher birthweight
  • interplay between maternal age and birth order
31
Q

What are postnatal environmental risk factors for T1D?

LO5

A
  • decreased by breastfeeding
  • increased by cow milk exposure
  • decreased by vitamin D intake
  • decreased by childhood infections
  • increased by obesity
  • viral infections
  • other dietary factors
32
Q

What is the difference between breast milk and cow’s milk?

LO5b

A

breast milk contains more insulin –> exposure so that the body does not destroy insulin

33
Q

What is the relationship between breast feeding and T1D?

LO5b

A

inverse correlation between decreased breast-feeding and increased T1D

34
Q

What are dietary risk factors for T1D?

LO5a

A
  • gluten is a potent diabetogen –> T1D risk increased in CD patients
  • vitamin D deficiency –> increased risk of T1D if living with little sunlight
35
Q

How do viruses increase the risk of T1D?

  • mechanisms
  • viruses

LO5

A
  • direct cytotoxicity
  • molecular mimicry –> cells that destroy infection also destroy beta cells
  • mumps
  • rubela
  • cytomegalovirus
  • enteroviruses
  • retroviruses
36
Q

What chemicals cause direct destruction of beta cells?

LO5

A
  • N-nitroso compounds
  • Alloxan
  • compounds in smoked meat/foods
37
Q

What compounds from streptomyces are cytotoxic to beta cells?

LO5

A
  • streptozocin

- bafilomycin A1

38
Q

What is the processing, presentation, and activation process for T1D?

LO6b

A
  • DC present antibodies of damaged beta cell to Th1 and CD8+ T cells
  • CD8+ cells go to pancreas and destroy beta cells by perforin and granzymes to induce apoptosis (main mechanism)
  • through cross presentation Th1 cells interact with B cells to produce autoantibodies
39
Q

What are the roles of autoantibodies in T1D?

LO6a

A

Islet Cell Antigens (ICAs):
glutamic acid decarboxylase GAD65
insulinoma antigen-2 IA-2
insulin auto-antibodies IAA

presence confirms diagnosis of T1D
(presence of 2 or more is highly predictive of future T1D - 5 year risk)

DO NOT INFLUENCE PATHOGENESIS

40
Q

What is the common pathway for asthma and T1D?

LO7

A

Tregs

41
Q

How does T1D influence Tregs?

LO7

A

leads to change in Treg population/effector function, can become unstable and lose Foxp3 expression –> Tregs now express IFN gamma and IL-17

42
Q

What would CTLA-4 do in treatment of T1D?

LO7

A

bind to IL-2 to inhibit inflammation

Endo Repro Midterm (12 decks)

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