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Endo/Repro Exam 1 > 7. Immune Mechanisms of DB > Flashcards

7. Immune Mechanisms of DB Flashcards

1
Q

Type 1 DM can be immune mediated or idiopathic. Immune mediated type 1 DM is d/t what?

A

B-cell destruction.

Both will result in insulin dependence, with a loss of B-cells.

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2
Q

What is Type 2 DM?

A

Insulin resistance and relative insulin deficiency.

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3
Q

What is the clinical distinction for type 2 DM?

A

Oral hypoglycemic agents only work early in the disease process.

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4
Q

What are the mechanisms for T2D?

A
  • B cells loss
  • Decrease in B cell mass
  • Decrease in Insulin-secretion
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5
Q

What are the causes of T2D?

A

Insulin resistance and glucotoxicity cause B-cells to overwork and failure, leading to overt and late T2D.

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6
Q

T2D is caused by ____________ in both the ________ and ______ that results in the development in the disease.

A

Chronic infllmation

Adipose tissue

& pancreas

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7
Q

T2D is characteristized by what 3 things?

A
  1. Hyperglycemia
  2. Insulin resistance
  3. Impairment in insulin secretion
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8
Q

T2D patients. have elevated blood sugar, resulting in what four things?

What contributes to the development of the disease?

A
  • Renal failure, CAD, blindness and stroke.
  • Genetic and lifestyle factors.
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9
Q

In patients that are normal-weight and nondiabetic, insulin secretion will result in

____ serum insulin

____ serum glucose

____ serum FFA

_____ IL-1B

_____ IL-1R ANT

A

Low

Low

Low

Low

HIGH

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10
Q

Insulin-sensitive individuals (norma), normal insulin secretion will do what:

_______ uptake of glucose from the circulation by skeletal. m and adipose tissue.

________ FFA release from adipose tissue

________ hepatic gluconeogenesis.

A

increase

inhibit

supress

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11
Q

In insulin-sensitive individuals, when insulin is secreted, how do adipose tissue macrophasges and kupffer cells react?

A
  1. Express IL-1 receptor antagonic
  2. Supress IL-1B
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12
Q

What is obesity characterized by and why is it linked to T2D?

A

Obesity causes chronic activation of inflammatory pathways.

Inflammation in obesity is linked to insulin resistance.

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13
Q

As we go from lean -> onset. of obsity ->chronic obesity, what changes?

A

we will start to express more immune cells in our adipose tissue;.

When we are lean, we have mostly [m2 macrophages, T-reg cells, Th2 cells and eosinophils].

  • In chronic obesity, we. have mostly [m1 macrophages, Th1 cells, CTLs and neutrophils].
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14
Q

Obesity causes changes in adipocyte metabolism and gene expression.

Under lean-conditions (insulin-sensitive), what do adipocytes secrete?

A

Adipocytes will secrete

  1. Anti-inflammatory FFA (short-chain), IL-13 and IL-4.
  2. Those will then cause alternative activation of M2 MO, which secrete anti-inflammatory cytokines like IL-10, which will also inhibit M1 MO activation.
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15
Q

Obesity causes changes in adipocyte metabolism and gene expression.

Under obesity-conditions (insulin-resistant), what do adipocytes secrete?

A

Adipocytes will secrete

  • Proinflammatory FFA (long and medium-chain FA)
  • MCP-1 and TNF-alpha, which activate M1 MO.

M1 MO will then release pro-inflammatory mediatorys such as TNF-alpha, IL-1B, IL6, NO that act on adipocytes to cause insulin-resistance.

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16
Q

In T2D who are insulin-resistance, how do B-cells die?

A

Stressed beta cells will release insulin into bloodstream; resulting in:

    1. high serum insulin
    1. High serum glucose
    1. High serum FA
    1. High serum IL-1B
    1. Low serum IL-1Ra

That will result in glucotoxicity, lipotoxicity. and IL-1B toxicity -> [recruitment of MO, islet inflammation, increase antigen presentation and B-cell specific CTL licesnsing] -> B cell death.

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17
Q

In obsese patients, adipose tissues release __________, a _____- chain FFA. What happens next?

A

Palmitate, a long-chain FFA.

  • B-cells in the pancreas sense palmitate via the TLR4-myD88 and recruit inflammatory monocytes to islets via chemokines.
  • Monocytes–> M1 MO.
  • M1 MO will -> increase inflammation, increase Ag presentation, activate cytoxic T-cells.
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18
Q

M2 MO and M1 are counterbalancings. M1 produces TNF and IL12, which stimulates NK cells to make INF-y.

M2 MO produces IL-10, which inhibit M1 MO.

IL-1 makes TNF and IFN-y –> + activate M1

Th2–> IL10, 4, 5 13. IL4, 13 and 10 will + M2 MO

A
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19
Q

T2D is a multifactorial disease, arising from the presence of T2D risk alleles and a disease-conducive environment. 52 common varients have been identified.

The lifetime risk for developing T2D if one parent has T2D is ____, and _____ when both parents have T2D.

A

40%

70%

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20
Q

What is the concordance rate of T2D in MZ twins and DZ twins?

A

MZ- 34%

DZ- 16%

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21
Q

________ have a 10 fold higher prevalence of T2D than general U.S population.

A

PIMA INDIANS

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22
Q

Twin studies show an important role in environmental and behavorial factors in developing T2D. Senendary life-styles and high fat diets can also cause it.

What is an environmental risk-factor?

A

Pollution; trafffic pollution. and pesticides, herbicides.

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23
Q

What is the role of microflora in T2D?

A

Weight gain–> increase intestinal microbiota (firmicutes/ bacteroidetes ratio) -> inflammation and insulin resistance.

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24
Q

There is a ______ relationship between intestinal microbiota and metabolic health.

A

recipricol.

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25
Q

What can be a Tx for insulin resistance and type 2 DM?

A

Faecal transplation (butyrate producing bacteria)

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26
Q

What is T1D?

A

Chronic autoimmune disease where by T-cells destroy pancreatic B-cell, causing insulin deficiency.

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27
Q

Insulin is one of the key target Ags recognized by auto-reactive T-cells, which destroy our B-cells. In 1965, pancreatic islet. inflammation was a hallmark of recent onset T1D. This was then followed by what?

A

Auto-antibodies, which became the first biomarker of T1D, which target insulin.

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28
Q

In the 1980s, it was established that T1D is d/t what?

A

Autoreactive T-lymphocytes and auto-antibodies that target insulin.

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29
Q

DB was considered a terminal condition before insulin was available for therapy.

In Jan 11, 1922, a 14yo boy became the 1st recipient of insulin.

A
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30
Q

Patients with T1D are prone to ________ and most cases are characterized by _____________ markers of what?

A

Patients with T1D are prone to ketoacidosis and most cases are characterized by auto-ab markers that. cause B-cell destruction and strong HLA associations.

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31
Q

At the time clinical sx of T1D show, _____ of the B-cells are destroyed.

Onset of T1D is associated with __________ infiltrating of the islets of langerhans.

A

60-80%.

Mononuclear cells and CD8+ Tcells (insulitis)

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32
Q

Physiological contributions to T1D fall in what three cateogies?

A

1. Bone marrow and thymus

2. Immune system

3. B-cells of the pancrease

33
Q

What environmental factors contribute to T1D?

These factors and what, contribute to T1D?

A
  • 1. Diet
  • 2. Virus
  • 3. Toxins and stress.

These factors, in combination with genes, can cause a decrease in islet mass and increase in MHC 1 -> Increase in Th1/Th2 cells -> B cell death -> type 1 DN.

34
Q

Concordance rate of T1D in MZ twins is what? What does this suggest?

What supports this?

A

30-50% , this suggests there genes are not the only important cause.

  • Incidence is increasing by 3% per year, thus, we cant soelely blame genes.
  • Epidemiological and animal studies show a indirect link to environment
  • 350 fold variation in the incidence of T1D in different countries around da world
35
Q

What are prenatal triggers to T1D?

A

1. Maternal enteroviral infection******

2. Older maternal age.

36
Q

What are postnatal triggers to T1D?

A

1. Enteroviral infections ***

  1. Infant weight gain
  2. Serious life events
37
Q

What are promoters of progression to T1D?

A
  • 1. Overweight or increased height velocity
  • 2. Puberty
  • 3. Insulin resistance
  • 4. Psychological stress
38
Q

What are the protective factors for T1D?

A
  • Higher omega 3 FA
  • Introduction of solid foods while breastfeeding and after 4 months.
39
Q

What viruses are implicated in T1D?

A
  1. Enteroviruses
  2. Mumps
  3. Rubella
40
Q

Viruses attack B-cells through what mechanisms?

A

1. Direct cytotoxicity

2. Trigger autoimmunity by molecular mimicry

41
Q

Breast-feeding vs. Cow milk in T1D.

A
  • Breastfeeding will decrease risk for Type 1 DB because it contains a high amount of insulin.
  • Cow milk contains much less, so early exposure can lead to T1D because they will make auto-ab.
  • It is good to introduce cow milk and cereal SLOWLY.
42
Q

are the breastfeeding and cow milk studies consistent?

A

there is some inconsistency d/t

    1. differences in composition of milk
    1. genetic variation in cow proteins
    1. differences in milk-sensitive db prone patients.
43
Q

What are other environmental factors for T1D?

A
  1. Wheat gluten. Risk of T1D is higher in pts that have gluten-sensitive enteropathy.
  2. Decreased Vit. D.
  3. Psychological stress.
44
Q

Many T1D patients have celiac disease (CD).

What is the role of microflora in T1D patients?

A

T1D patients often present with chronic inflammation of the intestinal mucosa, even in the absence of CD. Often seen in the mucosa is a absence of butyrate-producer genera (role: increase mucin and tight junctions)

  • also have deficiency of mucin-degrading genera -> increases gut permeability.
45
Q

There is familial clustering of T1D.

The risk of developing T1D before 20 yo is ____ % in the sibling of an affected patient and ___% in the general population

A

6%

0.4%

46
Q

What is the concordance in in MZ and DZ twins T1D?

A

MZ: 30-50%

DZ: 10%

47
Q

What genes determine T1D susceptility?

A

There is NO specific DB gene, but a wrong combination of normal polymorphisms.

48
Q

T1D is a _________ autoimmune disease; thus, patients have _________ risk for other diseases (________ and _________).

A

T1D is a MULTIFACTORIAL autoimmune disease; thus, patients have increased risk for othre diseases (thyroid autoimmunity and Addisons disease).

49
Q

About ___ genes are associated with susceptibility to T1D.

What are the 4 most significant?

A

18.

  1. Insulin gene on chromosome 11- Ag for autoimmune response
  2. Regulators of insulin gene expression in the thymus (AIRE)
  3. HLA-DR3/DR4 and HLA-DQ2/DQ8 genes on chromosome 6, which present insulin antigens to CD8+ cells
  4. CTLA-4 gene on chromosome 2, which is involved in regulation of an autoimmune response.
50
Q

thymic expression and presentation of self-molecules isdone so by thymic epithelial cells that are involved in the negative selection of self-reactive T-cell. They are controlled by

A

AIRE (autoimmune regulator transcrption factor)

51
Q

How is central tolerance established?

A

Negative selection (apoptosis of self-reactive cells) occurs when

double positive CD4/CD8+ T cells bind self- peptides in the thymus within Class I and Class II MHC with high enough enough affinity to cause apoptosis.

52
Q

AIRE protein does what?

A

AIRE controls auto-antigen expression in the thymus.

AIRE expression and presentation of insulin in thymus is important to protecting against the development of T1D.

53
Q

Transcriptional expression of insulin in the thymus is controlled by _____.

Malfunctioning of this causes what?

A

AIRE.

Malfunctioning of AIRE causes lower levels of insulin mRNA in the thymus. Absence of insulin -> failure of deleting insulin-reactive T cells -> breaks Central tolerance.

54
Q

The insulin gene on chromosome 11 is mapped to a region that contains ____________ in what region of the gene?

A

a variable number of tandem repeats in the promoter region of the gene.

55
Q

The insulin gene on chromosome 11 is mapped to a region that contains variable number of tandem repeats in the promotor region of the gene. The VNTR can have what three polymorphisms?

Which is ass. with T1 DB.

A

Class 1

Class 2

Class 3.

The class 1 VNTR makes patients susceptible to type 1 diabetes by decreasing insulin mRNA synthesis -> low insulin presentation in the thymus -> failure to delete self-reactive CD8 T-cells -> breaks central tolerance.

56
Q

HLA alleles DQ_/DQ_ and DR_/DR_ are high-risk alleles.

HLA class __ molecules that lack ______ of the ____ chain are found in ppl with T1D.

A

HLA alleles DQ2/DQ8 and DR3/DR4 are high-risk alleles.

HLA class II molecules that lack Asp57 of the beta chain are found in ppl with T1D.

57
Q

What types confer dominant protection?

A

DR2/DR6

58
Q

What is CTLA4?

A

CTLA4 gene on chromosome 2 is assx with T1D. Fx of it is to suppress T-cell activation and cause apoptosis of it.

CTLA4 encodes a glycoprotein that is an inhibitor CD28 homologue and binds B7.

59
Q

CTLA can inhibit T cell activation in two ways:

1. Bind and deliver inhibitory signals, inhibiting T-cell activation (cell-intrinsic CTLA-4 function.

2.

A

Blocks and removes B7 cells on APC, making it unavailable to co-stimulation to CD28, and blocks T-cell activation (cell-extensic CTLA-4 fx)

60
Q

B7 has higher affinity for CTLA4 or CD28?

A

CTLA-4

61
Q

In T1D, B-cells of the pancreas can die due to physiology or as a result of infection.

DC’s are always present in the islet and can do what?

1. B cell with infection of bad B cell

2. Release of pro-inflammatory cytokines (IFN-y).

What happens next?

A
  1. DCs are activated and present the B cells ANT to T cells.
  2. CD4 (Th1 cells) are activated in the LN that drain the panceras.
  3. Once activated, they go to the pancreas, proliferate and cause inflammation
62
Q

What. does the activated CD4 cell then do?

A
  1. Activated CD4+ T cell can then do two things: Actcated Treg cells or Teffector cells.
  2. Normally: CD4+ T cell will release IL10, TGF-B and IL2 to activate the CD4+, CD25+ and FoxP3 Treg cell, which will release IL10 and inhibit CD4+ effector cells. It will also consume IL2 and TNF alpha to reduce infection and inflammation.
  3. In Pts with Type1 DB: CD4+ will release IL12, +CD4+ effector cells
  4. Teff -> makes Th2 cells (which makes antiinflammtory cytokines) and Th17, Th1 (makes pro-inflammatory cytokines).
  5. I_FN-y_ inhibits Th2 cytokine production (IL4, 5 and 10)
  6. Proinflammatory cytokines can then do two things:
  • A. +CD8 and and cytoxic macorphages -> release IL1-B, TNF-alpha and free radicals and kill B cells via FasL granzyme perforin
  • B. Directly kill B-cells
63
Q

Counter regulatory role for Th1 and Th2 subsets would suggest that T1D would not occur in patients with astha. However, kids with T1D are more prone to have asthma.

Why?

A

Foxp3+ Tregs fail to prevent making auto-reactive T-cell, creating T-effector cells.

64
Q

What do T-reg cells do?

A

Treg act in tissues and draining LN.

  • They are activated by a APC that presents a auto-antigen. They supress APC directly by cell to cell interaction or indirectly by cytokines.
  • They also act directly on Teffs.
65
Q

T-reg cells can suppress immune responses, B-cell activation and diferentiation of NK cells.

How do T-regs supress?

A
    1. Make IL-10 and TGF-B (make immunosupressive agents)
    1. bind CTLA-4 to B7 on APC, preventing APCs to activate T cells
    1. Consume IL2 and and TNF alpha deprive other T-cells of this growth factor, reducing proliferation and differentiation.
66
Q

Describe the microflora in T1D patients

A
  • Altered hange the [bacteroidetes/firmicutes ratio] –> alter balance of Treg/Th1 and Th17 in GALT.
  • T1D pts also have a defect in Foxp3 T-reg cells.

More firmicutes (SFB, Lactobacillis bifudus) TH17, TH1 cells -> inflammation -> autoimmunity.

Also defect in FOXP3

67
Q

PPl just recently diagnosed with T1D will see an increase in ___________.

This change appears in advance and can be used to PREDICT the dz. If they are present, it CONFIRMS the dz.

A

Islet cell autoantibodies (ICA)

68
Q

What kind of ICAs do we have?

A
  1. GAD65 (glutamic acid decarboxylase)
  2. IA-2 (insulinoma antigen-2), tyrosine phosphotases
  3. IAA (insulin autoantibodies)
69
Q

Is there a pathogenic contribution of ICAs to DIA?

A

Questionable.

  1. cannot be transferred using serum
  2. plasmapheris is littler therapeutic help in pts with T1D
  3. T1D reported in a male with X-linked agammaglobinemia
70
Q

What is the pathogenic role of auto-abs in T1D?

A

Auto-ab may affect the time course of T1D development

71
Q

The presence of ___ autoantibidies is highly predictive of future T1Dwith a 5 year risk of more than 40%

The presence of ___ autoantibidies is highly predictive of future T1Dwith a 5 year risk of more than 60%

A

2

3

72
Q

HLA typing + autoantibody screning is useful for what?

A

predicint disease in general populations.

73
Q

____ have been the focus of most strategies of immunotherapy. for T1D

A

T cells

74
Q

Define obesity as a key factor in adipose tissue inflammation.

A

When adipose tissue cells get larger, they can cut off blood supply leading to some necrosis.

This necrosis leads to a pro-inflammatory region that summons TNF-α, IL-1β and IL-6.

75
Q

. Describe and compare immune mechanisms of type 1 diabetes (T1D) and T2D.

A

Type I diabetes is an autoimmune attack on β-cells leading to insulin deficiency.

Type II diabetes is insulin resistance and chronic inflammation.

76
Q

AIRE is responsible for

A

displaying insulin and other B cell epitopes to T cells to ensure that they are not reactive to it. Defective AIRE can lead to auto reactive T cells.

77
Q

Define T1D as an autoimmune disease:

a. Role of autoantibodies in T1D

A

Autoantibodies attack beta cells, specifically glutamic acid decarboxylase (GAD65), insulinoma antigen-2 (IA-2), and insulin auto-antibodies (IAA).

78
Q

b. Role of cell-mediated immune responses (CD4+ Th1 cells and CD8+ T cells)

A
  • CD8+ T cells utilize perforin and granzymes to trigger cell death in cells presenting type I diabetes related autoantigens.
  • CD4+ Th1 cells interact with B cells to activate them and cause autoantibody production.

Endo/Repro Exam 1 (14 decks)

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