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Host Defense Exam 2 > Bone & Fat Immunology > Flashcards

Bone & Fat Immunology Flashcards

1
Q

define bone homeostasis

A

bone formation and remodeling - a dynamic, ever changing process orchestrated by osteoblasts, osteoclasts, hormones, and immune cells

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2
Q

What do osteoblasts and osteoclasts differentiate from?

A

hematopoietic precursor –> preosteoclast –> osteoclast

mesenchymal stem cell –> preosteoblast –> osteoblast

mesenchymal stem cell –> chondrocyte

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3
Q

How do preosteoblasts modulate bone homeostasis?

A

produce RANKL which increases hematopoietic precursor and preosteoclast differentiation

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4
Q

How do mature osteoblasts modulate bone homeostasis?

A

produce osteoprotogerin which inhibits RANKLs stimulation of preosteoclast differentiation

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5
Q

What does RANK stand for?

A

Receptor Activator of Nuclear factor kB

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6
Q

What family are RANK and RANKL part of?

A

TNF-alpha superfamily

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7
Q

What does RANK and RANKL signaling regulate?

A

formation of multi-nucleated osteoclasts from their precursors

multinucleated osteoclast formation and survival in normal bone remodeling and in a variety of pathological situations

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8
Q

What does osteoprotogerin (OPG) do?

A

protects the skeleton from too much bone resorption by binding RANKL and preventing it from binding to its receptor, RANK (a soluble decoy)

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9
Q

What is an important determinant of bone mass and skeletal integrity?

A

RANKL/OPG ratio

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10
Q

What mediates communication between OB, OC, and immune cells?

A

RANK-RANKL

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11
Q

What promotes OC survival and proliferation, and what releases it?

A

OB release M-CSF which promotes OC survival and proliferation

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12
Q

What expresses RANK?

A

expressed on Pre-OC and OC

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13
Q

What kind of signal is RANKL?

A

a cytokine

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14
Q

What determines bone formation?

A

ratio between OPG and RANKL

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15
Q

What can lead to a bone pathology?

A

any condition that alters or promotes OC dominance

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16
Q

How does Wnt modulate bone homeostasis, and what regulates it?

A

Wnt promotes MSC and preosteoblast differentiation, and inhibits formation of chondrocytes

Wnt also suppress osteoclast-mediated bone resorption by down regulate expression of RANKL, and upregulation of OPG

DKK-1 is negative regulator of WNT/beta catenin pathway, preventing formation of mature osteoblasts

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17
Q

What produces OPG?

A

OB/Osteocytes

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18
Q

What external sources can express RANKL?

A

many innate and adaptive immune cells, including monocytes, neutrophils, DCs, T and B cells

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19
Q

What external sources can induce RANKL, and what does it promote?

A

proinflammatory cytokines IL1, IL6, IL8, TNF-alpha and especially IL17 induce RANKL and promote OC differentiation

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20
Q

What external sources inhibit OC differentiation?

A

anti-inflammatory cytokines such as IL4, IL10

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21
Q

What do sex hormones do?

A

maintain bone homeostasis

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22
Q

What does a Th1 response do in bone?

A

associated with INF-gamma and activation of macrophages. The result is pro-clastogenic and bone resorption

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23
Q

What does a Th17 response do in bone?

A

potent OC activators

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24
Q

What inhibits Th17 response in bone?

A

a normal Th1/Th2 balance

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25
Q

What is greatly increased in the synovium of joints in rheumatoid arthritis?

A

IL23

26
Q

discuss the etiology and result of rheumatoid arthritis

A

Th17 cells infiltrate the synovium, release IL17 which activates neighboring OC which proliferate.

The RANK/RANKL/OPG balance is pro-bone loss and causes bone erosions and loss of joint function

27
Q

How does PTH modulate bone homeostasis?

A

Chief cells synthesize PTH in response to low Ca which promotes the expression of RANKL and M-CSF by osteoblasts.

RANKL promotes osteoclast differentiation and maturation.

M-CSF promote osteoclast differentiation and function

28
Q

What is a drug that treats rheumatoid arthritis, and how does it work?

A

Denosumab: soaks up RANKL preventing osteoclast proliferation

29
Q

What sex hormone promotes normal OB and OC function, and when is this altered?

A

estrogen

post-menopause can result in an altered OPG/RANKL state

30
Q

What is pannus?

A

inflammatory synovial tissue that is a source of cytokines that mediate bone loss

31
Q

Adipose tissue is the largest what?

A

endocrine organ

32
Q

What does adipose tissue produce?

A

wide array of hormones that act like cytokines and vice versa

33
Q

What is white adipose tissue (WAT)?

A

super endocrine organ that is critical for homeostasis

34
Q

What does WAT produce?

A

hormones, chemokines, cytokines

35
Q

What does WAT regulate?

A

energy storage and expenditure, body mass, and immune responses

36
Q

What is WAT composed of?

A

pre-adipocytes, adipocytes, stromal/vascular cells, and macrophages

37
Q

What are the WAT communicators?

A

macrophages

38
Q

What are the 2 major types of macrophages and what do they do?

A

M1 is pro-inflammatory

M2 is anti-inflammatory

39
Q

What are the macrophage-derived cytokines in WAT and what do they do?

A

Osteopontin: pro-inflammatory and a potent chemotactic signal for monocytes and macrophages

Resistin: antagonist of adiponectin

IL1, IL6, IL8, TNF-alpha

40
Q

What kind of cytokines do adipocytes release, and what do they do?

A

Adipocytes produce adipocytokines that act like cytokines & hormones and have broad spectrum effects

41
Q

What are some adipocytokines and what do they do?

A

leptin: pro-inflammatory
adiponectin: anti-inflammatory

macrophage inhibitory cytokine is TNF-like, but promotes adiponectin release

visfatin: pro-inflammatory and pro-angiogenic

42
Q

What occurs in normal (non-obese) WAT?

A

yin/yang relationship between inflammatory and anti-inflammatory adipocytokines with a net effect of slightly anti-inflammatory milieu in health

43
Q

What occurs in obese WAT?

A

WAT becomes proinflammatory by recruiting large amounts of macrophages and monocytes into it

portal vein carries the problem to the liver and into atheromatous plaques

44
Q

How do macrophages regulate adipogenesis?

A

through WNT5a and TNF-like cytokines

45
Q

What is SFRP5, and what does it do?

A

Secreted Frizzled-Related Protein 5

membrane receptor for WNT proteins

SFPR5 is increased in obesity and metabolic syndromes

46
Q

What, in theory, should lead to weight loss?

A

suppression of inflammation

47
Q

What can a fatty artery be described as?

A

local obesity

48
Q

What does cholesterol in an atherosclerotic plaque do?

A

attract M1 (pro-inflammatory) macrophages

49
Q

What do macrophages attracted to an atherosclerotic plaque do?

A

secrete the chemokine CCL2 which attracts monocytes and prevents them from leaving

50
Q

What cytokines do M1s produce?

A

Th1 response: IL1,6,8,TNF-alpha

51
Q

What cytokines do M2s produce?

A

Th2 response: IL4,10,13

52
Q

What is adiponectin?

A

anti-inflammatory - insulin sensitizer

53
Q

What else does leptin do?

A

appetite control at the level of the CNS

54
Q

What are the most abundant adipocytokines?

A

leptin and adiponectin

55
Q

What actively suppresses immune responses in the brain?

A

microglia, IL10, and TGF-beta

56
Q

discuss the two subsets of microglia in the brain

A

one migrates early in development, had DC and macrophage characteristics, and act like M2 macrophages. They are highly branched and display little MHC

the other subset is perivascular and are derived from circulating monocytes

57
Q

What are the innate immune cells of the CNS?

A

microglia

astrocytes: participates with endothelial cells to maintain BBB
oligodendrocytes: participates in myelinating axons in CNS (dif from schwann cells in PNS)

58
Q

What happens when the glial system is activated?

A

neuroinflammation: PAMPS and DAMPS activation leads to M2 to M1 conversion, the secretion of pro-inflammatory cytokines, the upregulation of MHC, and changes in morphology

59
Q

What do CD8 and Th17 activated glia produce and what does that result in?

A

IFN-gamma, TFN-alpha, and IL17 act on endothelial cells and astrocytes. This result in the activation of NF-kB which drives IL6 production. IL6 acts on astrocytes and endothelial cells in an autocrine fashion to amplify the NK-kB response and IL6 production

60
Q

How do neurons stabilize the inflammatory response?

A

by secreting neurotransmitters

61
Q

What are some clinical implications of neuroinflammation?

A

Pro- inflammatory cytokines, especially IL-6, have potent effects on neural function and survival

May be important cause of delirium, long term traumatic brain damage

Host Defense Exam 2 (11 decks)

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