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ENRE > Immunological Mechanisms of Diabetes > Flashcards

Immunological Mechanisms of Diabetes Flashcards

1
Q

What causes T2D in general?

A

chronic inflammation in both adipose tissue and pancreas both genetic and lifestyle factors contribute to it

associated with obesity

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2
Q

In a normal person, what immunological things does insulin do?

A

promotes release of IL1Ra (anti-inflammatory)

inhibits IL-1beta (inflammatory)

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3
Q

How does obesity contribute to T2DM?

A

characterized by chronic activation of inflammatory pathways –> inflammation causally linked to insulin resistance

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4
Q

What inflammatory mediators are present in chronic obesity?

A

M1 macrophages

Th1 cells

CTLs

Neutrophils

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5
Q

What immune mediators that are anti-inflammatory are predominant in lean people?

A

M2 macrophages

Treg cells

Th2 cells

eosinophils

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6
Q

What Free fatty acids predominate in T2D pts?

Normal, lean ppl?

A

long and medium-chain FAs = bad

short-chain FAs = good

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7
Q

How are M1 macrophages activated in T2D ppl?

A

LPS IFN-gamma –> M1 –> TNFalpha, IL-1beta, IL-6, resistin, NO, etc –> insulin resistant

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8
Q

How are M2 macrophages acitvated and what do they do to lean ppl?

A

IL-4, IL-3 –> M2 –> IL-10 –> promotes insulin sensitivity via short chain FFAs, IL-13 and IL-4

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9
Q

What type of fat is bad in obese people and what does it do?

A

visceral fat

induces inflammatory cascades –> leukocyte-endothelial interaction –> coupled angiogenesis and adipogenesis and adipocyte dell death

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10
Q

What is MCP-1?

A

factor that helps recruit and activate macrophages

seen in obesity

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11
Q

What things contribute to beta cell death in T2D?

A

high serum IL-1beta

low serum IL-1Ra

glucotoxicity

lipotoxicity

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12
Q

What is the significance of palmitic acid?

A

long-chain FFA released by obese adipose tissue –> TLR4/MyD88 –> chemokines –> m1 macrophages recruited and inflammation ensues –> beta cell dysfunction

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13
Q

What are the genetics of T2D?

A

multifactorial disease related to 52 common risk variants

40% of dev if 1 parent has T2D

70% of developing if 2 parents have it

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14
Q

How is pollution related to T2D?

A

chronic exposure to organic land pollutants –> disturbs glucose metabolism and induces insulin resistance

chronic exposure to traffic-related pollutants (particulate matter and NO2) –> assoc w/ higher rates of T2D

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15
Q

What is the link btw gut microflora and insulin resistance?

A

increase in the firmicutes/bacteroidetes ratio linked to insulin resistance

recent studies w/ fecal transplants show butryate-producing intestial bacteria protect against T2D

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16
Q

What is the immune cause of T1D?

A

autoauntibodies that attack beta islet cells

cytotoxic T cells also attack insulin

Type IV hypersensitivity

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17
Q

When was insulin first used to treat a Type 1 diabetic?

A

Jan 11, 1922

nobel prize to Frederick Grant Banting and John James Richard Macleod

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18
Q

What is insulitis?

A

infiltration of islets by mononuclear cells and CD8 T cells

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19
Q

What are some phys contributions from the bone marrow and thymus toward T1D?

A

defective thymic selection

potential for self-Ags presented in incorrect register of MHC binding

Aire and VNTR expression in thymus

defects in lymphocyte precursors

genetic susceptibility

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20
Q

What are some phys contributions of beta cells toward T1D? (7)

A

expression of class 1 MHC

production of cytokines and chemokines

free-radical sensitivity

ptential to present high quantities of self-Ag via MHC II

susceptibility to viral tropism and inability to resolve inflammation

limited replication potential

rate of immune destruction influenced by metabolic activity

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21
Q

What is the concordance rate for T1D in monozygotic twins?

A

30-50% = suggests non-genetic influences

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22
Q

What are some key environmental factors being studied in T1D?

A

incidence is increasing abt 3% each year

evidence linking the environment ant T1D in himans is indirect

350 fold variation in indicence of T1D in different countries

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23
Q

What are the most significant pre and post-natal triggers for T1D?

A

pre: maternal enteroviral infection, older maternal age
post: enteroviral infection, infant weight gain, serious life events

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24
Q

What are the main promoters of progression of T1D?

A

overweight or increased height velocity

puberty

insulin resistance

psychological stress

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25
Q

What are the main pre and post-natal protective factors against T1D?

A

high vitamin D intake in pregnancy

breastfeeding until 4 mos

higher omega-3 fatty acids

*no known factors slowing progression

26
Q

What is the role of infections in T1D development?

A

bacteria may act as adjuvants for the immune response

virues have been implicated in T1D –> may act against beta cells thru cytotoxicity or triggering autoimmunity via molecular mimicry

27
Q

What are the viruses linked to T1D?

A

enteroviruses

mumps

rubella

cytomegalovirus

retroviruses

28
Q

What is the link btw milk and T1D?

A

early exposure to cow milk in life may contribute to T1D

cow’s milk has less insulin –> immune tolerance to insulin might get compromised

*inconsistency in results

29
Q

How is gluten linked to T1D?

A

risk of T1D is higher in pt’s w/ gluten-sensitive enteropathy

high prevalence of celiac disease in diabetics

butyrate-producing microflora scarce in T1D pts

30
Q

What genes determine T1D susceptibility?

A

multifactorial autoimmune disease

T1D pts and their relatives are at increased risk for other autoimmune diseases

may be no specific diabetes gene, but only wrong combos of normal polymorphisms

31
Q

What are the most significant genes associated with T1D?

A

insulin gene = Ag for autoimmune response

AIRE = regulator of insulin gene expression in the thymus

HLA region = presentation of insulin Ags for CD8 t cells

CTLA-4 gene = regulation of autoimmune response

32
Q

How is central tolerance established?

A

when double positive CD4/CD8 T cell binds self peptides presented by thymic epithelial cells –> apoptosis signal

33
Q

What is AIRE?

A

autoimmune regulator transcription factor

controls thymic expression and presentation of self-molecules (insulin) to do central tolerance

malfunctioning –> lower levels of insulin mRNA in thymus

bad tolerization to islet cell molecules–> autoreactive T cells

34
Q

How is the insulin gene (IDDM2) related to T1D?

A

variable number of tandem repeats in promoter region = class I, II, and III polymorphisms

class I = lowest number of repeats –> assoc w/ lower insulin mRNA synthesis –> low Ag presentation in thymus –> failure of deleting self-reactive CD8 T cells

35
Q

What are the high risk HLA alleles for T1D?

A

DQ2/DQ8 and DR3/DR4 = high risk

DQ2/DQ8 in 90% of ppl with T1D

DR3/DR4 = most common in kids diagnosed before age 5 (50%)

36
Q

What are the HLA class II negative and protective factors to know?

A

HLA class II molecules that lack Asp57 of beta chain often found in T1D individuals

DR2/DQ6 = dominant protection

37
Q

What is the link btw CTLA-4 and T1D?

A

CTLA4 = susceptibility locus assoc w/ T1D

encodes glycoprotein that is an inhibitory CD28 homologue and binds B7 protein

may counter-regulate CD28-dependent TCR activation of T cells –> activates apoptosis of self-reactive ones

38
Q

What does CTLA4 do on Teff or Treg cells?

A

binds to B7 or APCs or removes them –> reduced B7 costimulation –> inhibition of T cell activation

*this is good if self-reactive

39
Q

How does beta cell death occur?

A

DCs are always present in islets and can take up beta cell Ag –> proinflammatory cytokines my activate this self presentation to T cells

can be due to viral infection or stress

T cells then are activated in LNs that drain pancreas –> proliferate to cause organ-spec inflammation

40
Q

How do T helper cells contribute to T1D?

A

Th17 and Th1 –> proinflammatory cytokines

41
Q

What type of local APCs are important in T1D pathogenesis?

A

local APCs that can present self Ag on class II MHc

secrete IL-12

42
Q

How is IFN-gamma important in t1D?

A

released by Self-reactive CD4 T cells

inhibits Th2 cytokine production (IL-4, IL-5, IL-10)

enhances IL-1beta and TNF-alpha and free radical production

43
Q

What is interesting about T1D and asthma?

A

T1D = Th1 dominant disease

Asthma = Th2 dominant

you would think you would have one or the other, but high prevalence of asthma in T1 diabetics

bc failure of FOXP3 tregs to work

44
Q

How do Tregs stop autoimmunity?

A

suppress APCs directly through cell-cell interactions

release IL-10 and TGF-beta

might act directly on Teffs

consume IL-2 –> deprives other T cells of it

45
Q

How might gut bacteria be linked to autoimmunity?

A

diet, infections, antibiotics –> might alter bacteriodetes/firmicutes ration –> modifies balance of Treg: Th1/th17 ratio

46
Q

What is the controversy of the role of Auto-Abs?

A

might just affect the time course of development

plasmapheresis doesn’t help

if you transfer blood serum from T1D animal to an unaffected animal –> no result in t1d

but if you transplant T cells from T1D animal –> induces T1D in another

47
Q

What is the diagnostic value of autoantibodies in T1D pts?

A

one Ab = 5-10% 5 year risk

2 Abs = 40% 5 year risk

3 Abs = 60% 5 year risk

48
Q

What is CD25?

A

IL-2 receptor

49
Q

Where does central B cell tolerance occur?

A

in the bone marrow

can do receptor editing, apoptosis, or anergy

50
Q

What is the regulatory receptor on B cells?

A

Fc receptor that recognizes IgG or IgM

51
Q

How does obesity affect glucose uptake?

A

makes it much less efficient

not using muscles is a major component

52
Q

How does obesity itself initiate inflammation?

A

adipocytes become engorged with lipids –> pinch off the blood supply –> can cause small areas of necrosis –> inflammation

53
Q

What does TNF do?

A

increases vascular permeability

associated w/ M1 macrophages

54
Q

How is IL-6 related to T2D?

A

initiates inflammatory response

role in T2D and insulin resistance is well documented

get inflammation/CRP in liver

stimulates GLP-1 and lipolysis

55
Q

Where does palmitate bind?

A

TLR4 on adipocytes

(TLR4 present on macrophages and adipocytes)

56
Q

What cytokines do Th2, Tregs, and M2 macrophages promote and are seen in lean people?

A

IL-4

IL-10

IL-13

57
Q

What type of hypersensitivity is T1D?

A

type IV

T-cell mediated

58
Q

If both parents have t1D, what is a child’s risk of getting it?

A

30%

59
Q

What are autoantibodies in T1D to?

A

islet cell antigens (ICAs):

GAD65

IA-2

IAA (insulin autoantibodies)

60
Q

What cytokine is associated w/ activation of auto-Ag specific CD8 T cells?

A

IL-2

ENRE (21 decks)

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