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Prof. Kwon's Cytokines and Signalling, First Steps

The gap left behind by
'a cytokine switches it on'

Every immunology course repeats the same sentence โ€” IFN-ฮณ matures the DC, IL-12 pushes Th1, TGF-ฮฒ switches to IgA. All pointing at the same thing, and none of them saying what it is.
These twenty lessons are that gap. And they start by showing it is not easy: across ten thousand tumours the cytokine axes do not separate at all. Axes the textbook calls opposites move together.
Lessons 11 to 13 work out why โ€” and what kind of data you have to bring in before the question can be answered.

๐Ÿ“ก cytokines๐Ÿ”— JAK-STAT๐Ÿ›‘ SOCS feedback ๐ŸŒ€ cytokine storm๐Ÿ Python๐Ÿ”ฌ TCGAยทGSE268555๐Ÿ‡ฌ๐Ÿ‡ง English
Start lesson 1 โ†’

How you'll learn

๐ŸงฎAlways show the control

An IFNGโ€“STAT1 correlation of 0.61 only means something next to the 0.20 you get with ACTB. Every correlation here prints its control, because the floor is not zero.

๐Ÿ’ฅShow it break

In lesson 11 not one cytokine axis separates โ€” there is not a single negative correlation. We show that as it is, then spend two lessons working out why.

๐Ÿ”ฌChange the data, ask again

Lesson 12 establishes that bulk cannot answer it in principle; lesson 13 asks the same question of single cells. No method can create information the data does not hold.

๐Ÿ“Set the threshold first

Before drawing the cytokine map in lesson 19 we write both thresholds down first. Pick your cutoffs after seeing the result and you can draw anything.

Full curriculum

01
์‚ฌ์ดํ† ์นด์ธ โ€” ์„ธํฌ๊ฐ€ ์„œ๋กœ์—๊ฒŒ ๋ณด๋‚ด๋Š” ๋ง
๋ฉด์—ญํ•™์˜ ๋‹ค๋ฅธ ๋ชจ๋“  ๊ณผ๋ชฉ์ด '์‚ฌ์ดํ† ์นด์ธ์ด ์ผ ๋‹ค' ๊ณ  ๋งํ•˜๊ณ  ์ง€๋‚˜๊ฐ„ ์ž๋ฆฌ
โœ“
02
์•„์ฃผ ์กฐ๊ธˆ, ์•„์ฃผ ๊ฐ€๊นŒ์ด โ€” ์‚ฌ์ดํ† ์นด์ธ์ด ๋‹ฟ๋Š” ๊ฑฐ๋ฆฌ
ํ”ผ์ฝ”๋ชฐ ๋†๋„๋กœ ์ผํ•œ๋‹ค ยท ๊ทธ๋ฆฌ๊ณ  ๋Œ€๊ฐœ ๋ช‡ ์‹ญ ๋งˆ์ดํฌ๋กœ๋ฏธํ„ฐ๋ฅผ ๋ชป ๋„˜๋Š”๋‹ค
โœ“
03
ใ€์‹ค์Šตใ€‘ ์ข…์–‘ 10,071๊ฐœ์™€ ์„ธํฌ 37,585๊ฐœ๋ฅผ ์—ฐ๋‹ค
TCGA ๋ฒ”์•” 32์ข… ยท GSE268555 ๋งˆ์šฐ์Šค ์ข…์–‘ ๋ฉด์—ญ์„ธํฌ
โœ“
04
ใ€์‹ค์Šตใ€‘ ๋ˆ„๊ฐ€ ๋ฟœ๋‚˜ โ€” ํ‰๊ท ์ด ์ง€์šฐ๋Š” ๊ฒƒ
Il12b ๋Š” ์„ธํฌ 0.08%๋งŒ ๋งŒ๋“ ๋‹ค ยท ๊ทธ ์„ธํฌ์—์„œ๋Š” ํ‰๊ท ์˜ 1,296๋ฐฐ
โœ“
05
ํ•˜๋‚˜๊ฐ€ ์—ฌ๋Ÿฟ์—๊ฒŒ, ์—ฌ๋Ÿฟ์ด ํ•˜๋‚˜๋ฅผ
๋‹ค๋ฉด์„ฑ ยท ์ค‘๋ณต์„ฑ ยท ํ˜‘๋™ ยท ๊ธธํ•ญ โ€” ์‚ฌ์ดํ† ์นด์ธ์„ ํ•˜๋‚˜์”ฉ ๋ชป ๋ณด๋Š” ์ด์œ 
โœ“
06
์ˆ˜์šฉ์ฒด โ€” ๋ถ€ํ’ˆ์„ ๋‚˜๋ˆ  ์“ด๋‹ค
ฮณc ์‚ฌ์Šฌ ํ•˜๋‚˜์— ์—ฌ์„ฏ ์‚ฌ์ดํ† ์นด์ธ ยท gp130 ํ•˜๋‚˜์— ์—ด ๋‚จ์ง“
โœ“
07
JAK-STAT โ€” ๊ฐ€์žฅ ์งง์€ ์‹ ํ˜ธ ๊ฒฝ๋กœ
๋ง‰์—์„œ ํ•ต๊นŒ์ง€ ๋‹จ๋ฐฑ์งˆ ๋‘ ์ข…๋ฅ˜ ยท ์ค‘๊ฐ„ ๋‹จ๊ณ„๊ฐ€ ์—†๋‹ค
โœ“
08
ใ€์‹ค์Šตใ€‘ ์‚ฌ์Šฌ์ด ์ •๋ง ์ด์–ด์ ธ ์žˆ๋‚˜
IFNGโ€“์ˆ˜์šฉ์ฒด 0.21 ยท IFNGโ€“STAT1 0.61 โ€” ๊ฐ€์šด๋ฐ๊ฐ€ ์™œ ์•ฝํ•œ๊ฐ€
โœ“
09
๋„๋Š” ์žฅ์น˜ โ€” ์ผค ๋•Œ ์ด๋ฏธ ๋Œ ์ค€๋น„๋ฅผ ํ•œ๋‹ค
SOCS ยท CIS ยท USP18 โ€” ์‹ ํ˜ธ๊ฐ€ ์ž๊ธฐ๋ฅผ ๋„๋Š” ๊ฒƒ์„ ํ•จ๊ป˜ ์ผ ๋‹ค
โœ“
10
ใ€์‹ค์Šตใ€‘ ๋ธŒ๋ ˆ์ดํฌ๊ฐ€ ์•ก์…€์„ ๋”ฐ๋ผ๊ฐ€๋Š”๊ฐ€
STAT2โ€“USP18 0.578 ยท STAT3โ€“SOCS3 0.423 ยท STAT1โ€“SOCS1 0.288
โœ“
11
ใ€์‹ค์Šตใ€‘ ์ถ•์ด ๊ฐˆ๋ฆฌ์ง€ ์•Š๋Š”๋‹ค โ€” ์ด ๊ฐ•์˜์—์„œ ๊ฐ€์žฅ ์ค‘์š”ํ•œ ๊ฐ•
์ถ• ์•ˆ์ชฝ ์ƒ๊ด€ 0.322 ยท ์ถ• ์‚ฌ์ด 0.221 ยท ๊ทธ๋ฆฌ๊ณ  ๋ชจ๋“  ์ถ• ์Œ์ด ์–‘์˜ ์ƒ๊ด€
โœ“
12
๋ฒŒํฌ๊ฐ€ ๋ชป ํ•˜๋Š” ์ผ โ€” ์„ž์ธ ๊ฒƒ์„ ๋ชป ํ‘ผ๋‹ค
ํ•œ ์ค„์— ์—ฌ๋Ÿฌ ์„ธํฌ๊ฐ€ ์„ž์—ฌ ์žˆ๋‹ค ยท ๊ทธ๋ž˜์„œ '์–‘' ๊ณผ '์ƒํƒœ' ๊ฐ€ ์—‰ํ‚จ๋‹ค
โœ“
13
ใ€์‹ค์Šตใ€‘ ๋‹จ์ผ์„ธํฌ๋กœ ๊ฐ™์€ ์งˆ๋ฌธ์„ ๋‹ค์‹œ ๋ฌป๋Š”๋‹ค
๊ณฑํ•ด์ง€๊ธฐ ์ „์˜ ๊ฐ’์„ ๋ณธ๋‹ค ยท ๊ทธ๋Ÿฌ๋ฉด ์ถ•์ด ๊ฐˆ๋ฆฌ๋‚˜
โœ“
14
๊ฐ™์€ ์‚ฌ์ดํ† ์นด์ธ, ๋‹ค๋ฅธ ๊ฒฐ๊ณผ โ€” ๋งฅ๋ฝ์ด ๋œป์„ ์ •ํ•œ๋‹ค
TGF-ฮฒ ๋Š” Treg ๋„ Th17 ๋„ ๋งŒ๋“ ๋‹ค ยท IL-6 ํ•˜๋‚˜๊ฐ€ ๊ฐˆ๋ฆผ๊ธธ์„ ์ •ํ•œ๋‹ค
โœ“
15
์‚ฌ์ดํ† ์นด์ธ ํญํ’ โ€” ๋˜๋จน์ž„์ด ํ’€๋ ธ์„ ๋•Œ
์–‘์˜ ๋˜๋จน์ž„์ด ์Œ์˜ ๋˜๋จน์ž„์„ ์ด๊ธฐ๋Š” ์ˆœ๊ฐ„ ยท ๊ทธ๋ฆฌ๊ณ  ์™œ ๋˜๋Œ๋ฆฌ๊ธฐ ์–ด๋ ค์šด๊ฐ€
โœ“
16
์‚ฌ์ดํ† ์นด์ธ์„ ์•ฝ์œผ๋กœ ์ค€๋‹ค โ€” IL-2 ์˜ ์ข์€ ์ฐฝ
๊ฐ™์€ ๋ถ„์ž๊ฐ€ ๋‚ฎ์€ ๋†๋„์—์„œ๋Š” ๋ฉด์—ญ์„ ๋„๊ณ  ๋†’์€ ๋†๋„์—์„œ๋Š” ์ผ ๋‹ค
โœ“
17
์‚ฌ์ดํ† ์นด์ธ์„ ๋ง‰๋Š” ์•ฝ โ€” ์ด์ชฝ์€ ํฌ๊ฒŒ ์„ฑ๊ณตํ–ˆ๋‹ค
์ฃผ๋Š” ๊ฒƒ๋ณด๋‹ค ๋ง‰๋Š” ๊ฒƒ์ด ํ›จ์”ฌ ์ž˜ ๋๋‹ค ยท ๊ทธ ์ด์œ ๊ฐ€ ์žˆ๋‹ค
โœ“
18
ใ€์‹ค์Šตใ€‘ ์น˜๋ฃŒ๊ฐ€ ์‚ฌ์ดํ† ์นด์ธ ํŒ์„ ๋ฐ”๊พธ๋‚˜
๋ณ‘์šฉ ์น˜๋ฃŒ์—์„œ Ifng 4๋ฐฐ ยท Cxcl9 2๋ฐฐ ยท Il1b ์ ˆ๋ฐ˜ โ€” ๋งˆ์šฐ์Šค๊ฐ€ ๋„ท์ด๋ผ๋Š” ๊ฒƒ์„ ์•ˆ๊ณ 
โœ“
19
ใ€์‹ค์Šตใ€‘ ์ข…์–‘ ํ•˜๋‚˜์˜ ์‚ฌ์ดํ† ์นด์ธ ์ง€๋„๋ฅผ ๊ทธ๋ฆฐ๋‹ค
๋ˆ„๊ฐ€ ๋ฌด์—‡์„ ๋ฟœ๊ณ  ๋ˆ„๊ฐ€ ๊ทธ๊ฒƒ์„ ๋“ฃ๋Š”๊ฐ€ โ€” 20๊ฐ• ๋ถ„๋Ÿ‰์„ ํ•œ ๊ทธ๋ฆผ์œผ๋กœ
โœ“
20
์ •๋ฆฌ โ€” ๋งํ•  ์ˆ˜ ์žˆ๋Š” ๊ฒƒ๊ณผ ๋งํ•  ์ˆ˜ ์—†๋Š” ๊ฒƒ
20๊ฐ•์—์„œ ๊ณ„์‚ฐํ•œ ๊ฐ’๊ณผ, ๊ทธ ๊ฐ’์ด ๋‹ฟ์ง€ ๋ชปํ•˜๋Š” ๊ณณ
โœ“