Regional and System Specific Immunology

Question 1

Osteoclasts differentiate from what stem cell?

Answer 1

Hematopoietic stem cell, through the pathway of the common myeloid progenitor

Question 2

Osteoblasts are derived from what stem cell?

Answer 2

Mesenchymal stem cell

Question 3

What signalling is important for the differentiation of a mesenchymal stem cell to the osteoblast?

Answer 3

Wnt

Question 4

How does TNF alpha affect the differentiation of a preosteoblast to a mature osteoblast?

Answer 4

TNF alpha is part of the negative regulatory pathway of osteoblast maturation.

TNF-alpha —> DKK-1 –> inhibition of osteoblast maturation

Question 5

What cells secrete osteoprotegerin?

Answer 5

Mature osteoblasts

Question 6

What is the effect of osteoprotegerin?

Answer 6

Osteoprotegerin inhibits the maturation of osteoclasts (through competitive binding to the RANKL receptor) and protects the bone from excessive bone resorption

Question 7

What does “RANK” stand for?

Answer 7

Receptor associated NFkappa B

Question 8

Where is RANKL produced?

Answer 8

The preosteoblasts

Question 9

What is the role of RANKL?

Answer 9

RANKL induces the differentiation of osteoclasts from their precursors

Question 10

What cells express RANK?

Answer 10

Pre-osteoclasts and osteoclasts

Question 11

What factor is secreted by osteoblasts to that promotes the survival and proliferation of osteoclasts?

Answer 11

M-CSF

Question 12

How does low calcium lead to increased bone resorption?

Answer 12

Low Ca2+ –> release of PTH from chief cells of parathyroid –> PTH binding to osteoblasts –> release of RANKL –> induction of osteocyte differentiation in myeloid pathway

In addition, PTH binding to osteoblasts initiates the expression of M-CSF and downregulates the expression of OPG

Question 13

What type of cytokines induce RANKL expression and promote OC differentiation?

Answer 13

Pro-inflammatory cytokines

IL-1, IL-6, IL-8, TNF-alpha and especially IL-17

Question 14

What type of cytokines inhibit osteoclast differentiation?

Answer 14

Anti-inflammatory cytokines

IL4 and IL10

Question 15

What is the resulting of a dominant Th1 response in and around bone?

Answer 15

INF gamma activates macrophages –> pro-clastogenic and bone resorption

Question 16

Which cell types are the most potent OC activators?

Answer 16

Th17

Question 17

What balance is required for the inhibition of IL-17 production?

Answer 17

Th1/Th2 response balance

Question 18

What is the role of IL-23 in rheumatoid arthritis?

Answer 18

IL-23 promotes IL-17 production by Th17 cells –> activation and proliferation of neighboring OC cells –> bone erosion and loss of joint function

Question 19

How does Denosumab work to help with rheumatoid arthritis?

Answer 19

Denosumab is a (mab) that binds to neutralize RANKL. This prevents the differentiation and proliferation of osteoclasts to prevent joint erosion

Question 20

What happens in postmenopausal women that leads to weak bones?

Answer 20

Loss of E2 —> dysregulated OPG/RANKL ratio –> increased bone resorption

(Favor RANKL and osteoclast maturation)

Question 21

Why is any stimulus that increases inflammation in adipose tissue a bad thing?

Answer 21

Because adipose tissue is the largest endocrine organ that produces a wide array of hormones that act like cytokines. White adipose tissue is critical for homeostasis

Question 22

Differentiate M1 from M2 macrophages

Answer 22

M1: pro-inflammatory
M2: anti-inflammatory

Question 23

What is osteopontin?

Answer 23

A pro-inflammatory and potent chemotactic signal for monocytes and macrophages. It is produced by macrophages in white adipose tissue

Question 24

What is resistin?

Answer 24

Adipose tissue specific- antagonist of adiponectin

Question 25

Is leptin pro or anti-inflammatory?

Answer 25

Leptin is pro-inflammatory

Question 26

Is adiponectin pro or anti-inflammatory?

Answer 26

Adiponectin is anti-inflammatory

Question 27

What are the effects of visfatin?

Answer 27

Visfatin is pro-inflammatory and pro-angiogenic

Question 28

What are the effects of macrophage inhibitory factor cytokine?

Answer 28

Macrophage inhibitory factor cytokine is TNF-like but promotes adiponectin release

Question 29

What is the ratio of pro-and anti- inflammatory adipocytokine production in normal (non-obese) white adipose tissue?

Answer 29

There is a balance, with a net- effect of slightly anti-inflammatory production

Question 30

What happens to the ratio of pro vs anti inflammatory adipocytokines in obese WAT?

Answer 30

The balance shifts to become more pro-inflammatory. Expanding fat in adipocytes triggers a very dangerous signaling problem that makes WAT very pro-inflammatory by recruiting a large number of monocytes and macrophages to it

Question 31

Which T cells are predominantly found in adipose tissue?

Answer 31

Tregs

Question 32

How do macrophages regulate adipogenesis?

Answer 32

WNT5a and TNF=like cytokine production

Question 33

How is SFPR5 affected by obesity and metabolic syndrome?

Answer 33

SFRP5 (frizzled) receptor for WNT signaling is increased in obesity and metabolic syndrome

Question 34

Name two ways adipocytes counteract the pro-inflammatory signaling by macrophages

Answer 34

1) Adipocytes secreted SFRP5 to counteract the WNT5a signaling by macrophages 2) Adipocytes secrete Adiponectin to counteract the TNF secretion by macrophages

Question 35

Why is there a net pro-inflammatory production of cytokines in obese WAT?

Answer 35

Obese WAT leads to increased macrophage infiltration. This leads to an overproduction of TNF, IL-6 and CCL2 (all pro-inflammatory) cytokines and chemokines that has a positive feedback of more pro-inflammatory responses

Question 36

What is the status of the innate immune responses is brain?

Answer 36

Innate immune responses in the brain are held in active suppression by microglia and IL-10 and TGFbeta

Question 37

What are the two different subsets of microglia in the CNS?

Answer 37

1) migrate early in development, have DC and M2 macrophage characteristics. Highly branched and display little MHC 2) Perivascular and derived from circulating monocytes

Question 38

What happens to the M2 macrophages upon infection in the brain?

Answer 38

Activation of the glial system by DAMPS/PAMPS converts the M2 to M1 and then they secrete pro-inflammatory cytokines. They upregulate their MHC and change their morphology

Question 39

Which cells of the CNS are responsible for stabilizing the pro-inflammatory positive feedback loops?

Answer 39

Neurons- through secretion of specific neurotransmitters

Question 40

Which pro-inflammatory cytokine is most important effects on neural function and survival/

Answer 40

IL-6