Ulcerative colitis question - please help

[Phloston]

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According to UWorld question - ID#1597 [441137], a guy with a biopsy that suggests ulcerative colitis returns two weeks later, not having received treatment, with a second biopsy that shows an amelioration of pathology and decreased inflammation. The question then asks for which cytokine is most likely responsible. Answer choices were TNF-alpha, IL-1, IL-4, IL-5, IL-10, IL-12.

Answer = IL-10

62% answered correctly

I put IL-12, which 11% chose.

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My reasoning was that FA, on p. 355, states that ulcerative colitis is a Th-TWO-mediated process, which is upregulated by IL-4, -5 and -10, -13, and downregulated by IFN-gamma.

IL-12 is the closest answer because IFN-gamma and IL-12 positively regulate one another and increase the ratio of Th1/Th2-driven inflammation.

Now here's an added element of complexity: UWorld attaches two articles to the bottom of the page. I opened up the second one, which led me to PubMed, and I read the article myself. It specifically says that Crohn's disease patients have decreased IL-10 expression and that ulcerative colitis patients have increased IL-10 expression.

UWorld's explanation is that IL-10 is a general suppressor of inflammation (which is correct) and that it upregulates the Th-2 response (which is correct). However, UC is a Th2-reaction!

Does anyone have any input here?

 

[Myxedema]

From Robbins Basic Pathology, 9th Edition, p. 589:

Mucosal immune responses: ...emerging data suggest that TH17 T cells also contribute to disease pathogenesis. Consistent with this, certain polymorphisms of the IL-23 receptor confer protection from Crohn disease and ulcerative colitis (IL-23 is involved in the development and maintenance of TH17 cells). The protection afforded by IL-23 receptor polymorphisms, together with the recognized effectiveness of anti-TNF therapy in some patients with ulcerative colitis, seems to support roles for TH1 and TH17 cells.

Some data suggest that the pathogenic immune response in ulcerative colitis includes a significant TH2 component. For example, mucosal IL-13 production is increased in ulcerative colitis, and, to a lesser degree, Crohn disease. However, the pathogenic role of TH2 cells in IBD pathogenesis remains controversial. Polymorphisms of the IL-10 gene as well as IL-10R, the IL10 receptor gene, have been linked to ulcerative colitis but not Crohn disease, further emphasizing the importance of immunoregulatory signals in IBD pathogenesis.

UC is a disease with a complex pathogenesis. Not only Th17 subtype is involved, but both Th1 and Th2 seem to be involved as well. There are also additional defects in innate immune system (such as Toll-like receptors), enteric cells and even the microbial content of the gut.

At any rate, I believe this question is not about the pathogenesis of UC. Of the given answer choices, only IL-10 supresses immune activity. IL-12 directs cell-mediated immunity; it can only indirectly inhibit humoral immunity through IFN-gamma.

 

[gravitywave]

At any rate, I believe this question is not about the pathogenesis of UC. Of the given answer choices, only IL-10 supresses immune activity. IL-12 directs cell-mediated immunity; it can only indirectly inhibit humoral immunity through IFN-gamma.

correct, the question is not asking about UC, it's asking about your general knowledge of immunomodulatory properties of cytokines.

 

[Phloston]

I feel like IL-10 would be a good answer for any inflammation that's not Th2-mediated. I just don't think it's correct to say that increasing it mitigates UC; the mechanism is more complicated with UC, as IL-10 induces the inflammation.

 

[ijn]

You're over-thinking this question to your own detriment. A variant of this question is pretty common on the practice CBSEs and NBMEs, as well as STEP 1. If you get a question that asks about decreasing inflammation, then they want you to answer IL-10 or TGF beta. If a question asks you about increasing inflammation, then they want you to answer IL-1, IL-6, TNF-alpha. Just give them the Pavlovian response that they're asking for.

 

[Charles_Carmichael]

I feel like IL-10 would be a good answer for any inflammation that's not Th2-mediated. I just don't think it's correct to say that increasing it mitigates UC; the mechanism is more complicated with UC, as IL-10 induces the inflammation.

IL-10 is an anti-inflammatory cytokine (along with TGF&#946😉. I don't have GI path till next semester, but if I had to guess, I would think that the elevated levels of IL-10 that you might see in ulcerative colitis do not contribute to the disease process. Rather, they're elevated in response to the increased inflammation (in an attempt to decrease the inflammation). That's just a guess btw, so don't think I'm telling you the actual mechanism there.

If anything, your pick of IL-12 doesn't make sense, since IL-12 is proinflammatory (by promoting differentiation of T-cells into the Th1 subtype and increasing production of proinflammatory cytokines, such as IFNγ, TNFα, etc). I can't imagine that promoting inflammation in an inflammatory disorder would ameliorate the symptoms. The only anti-inflammatory cytokine listed among the answer choices is IL-10.

You're over-thinking this question to your own detriment. A variant of this question is pretty common on the practice CBSEs and NBMEs, as well as STEP 1. If you get a question that asks about decreasing inflammation, then they want you to answer IL-10 or TGF beta. If a question asks you about increasing inflammation, then they want you to answer IL-1, IL-6, TNF-alpha. Just give them the Pavlovian response that they're asking for.

This.

 

[Phloston]

IL-10 is an anti-inflammatory cytokine (along with TGF&#946😉. I don't have GI path till next semester, but if I had to guess, I would think that the elevated levels of IL-10 that you might see in ulcerative colitis do not contribute to the disease process. Rather, they're elevated in response to the increased inflammation (in an attempt to decrease the inflammation). That's just a guess btw, so don't think I'm telling you the actual mechanism there.

If anything, your pick of IL-12 doesn't make sense, since IL-12 is proinflammatory (by promoting differentiation of T-cells into the Th1 subtype and increasing production of proinflammatory cytokines, such as IFNγ, TNFα, etc). I can't imagine that promoting inflammation in an inflammatory disorder would ameliorate the symptoms. The only anti-inflammatory cytokine listed among the answer choices is IL-10.

Ulcerative colitis is Th2-mediated. IL-10 strengthens Th2 reactions. IL-10 mRNA is increased in UC because that's the driving force; it's not an attempt at suppression. UWorld is wrong. They over-generalized here. I read their attached articles myself. Btw, UWorld isn't impeccable. I'm ~2/3 through it at the moment, and I've encountered errors here and there.

 

[Charles_Carmichael]

Ulcerative colitis is Th2-mediated. IL-10 strengthens Th2 reactions. IL-10 mRNA is increased in UC because that's the driving force; it's not an attempt at suppression. UWorld is wrong. They over-generalized here. I read their attached articles myself. Btw, UWorld isn't impeccable. I'm ~2/3 through it at the moment, and I've encountered errors here and there.

/shrug

One of the first review articles to pop up on PubMed with my search parameters of "il10 AND ulcerative colitis" suggests that loss of IL-10 function/defects in IL-10 signaling plays an important role in UC pathogenesis and that there's renewed interest in IL-10-based therapy:

"Now that IL10 has been robustly implicated in UC GWA studies, IL10-based therapy is being revisited. A novel drug delivery mechanism is being tested, using the genetically engineered, recombinant IL10-producing Lactococcus lactis. Currently, both oral and rectal preparations are being assessed in Phase II trials in patients with UC."

http://www.ncbi.nlm.nih.gov/pubmed/21319274

Either way, I think ijn hit the nail on the head and that you just over-thought this question. Happens to the best of us, mate. It was simply asking you to pick out which one of the answer choices was an anti-inflammatory cytokine.

 

[Phloston]

"Now that IL10 has been robustly implicated in UC GWA studies, IL10-based therapy is being revisited. A novel drug delivery mechanism is being tested, using the genetically engineered, recombinant IL10-producing Lactococcus lactis. Currently, both oral and rectal preparations are being assessed in Phase II trials in patients with UC."

http://www.ncbi.nlm.nih.gov/pubmed/21319274

That's so odd. I just don't get it then.

 

[Corbac]

According to UWorld question - ID#1597 [441137], a guy with a biopsy that suggests ulcerative colitis returns two weeks later, not having received treatment, with a second biopsy that shows an amelioration of pathology and decreased inflammation. The question then asks for which cytokine is most likely responsible. Answer choices were TNF-alpha, IL-1, IL-4, IL-5, IL-10, IL-12.

Answer = IL-10

62% answered correctly

I put IL-12, which 11% chose.

------

My reasoning was that FA, on p. 355, states that ulcerative colitis is a Th-TWO-mediated process, which is upregulated by IL-4, -5 and -10, -13, and downregulated by IFN-gamma.

IL-12 is the closest answer because IFN-gamma and IL-12 positively regulate one another and increase the ratio of Th1/Th2-driven inflammation.

Now here's an added element of complexity: UWorld attaches two articles to the bottom of the page. I opened up the second one, which led me to PubMed, and I read the article myself. It specifically says that Crohn's disease patients have decreased IL-10 expression and that ulcerative colitis patients have increased IL-10 expression.

UWorld's explanation is that IL-10 is a general suppressor of inflammation (which is correct) and that it upregulates the Th-2 response (which is correct). However, UC is a Th2-reaction!

Does anyone have any input here?

IL- 10 is produced by TH2 cells and this is another reason to ameliorate the UC besides what was already said.
IL- 12 and IFN gamma main activity is to stimulate CMI .
IFN gamma also inhibits TH2

 

[gravitywave]

That's so odd. I just don't get it then.

USMLE is a single best answer test. this means that sometimes the best answer is still a crappy one, strictly speaking.

of those six answer choices, five are clearly pro-inflammatory and only one has anti-inflammatory properties, at least at the level of understanding expected of second year medical students. the fact that the patient has UC is utterly irrelevant. on the other hand, the fact that he did not receive any treatment between biopsies is relevant, as otherwise you could make a case for him having had infliximab or something like that in the interim.

the primary value of UW is not in the content (although the content is gold) - it's in showing you how to think about these questions. if you fight the way the test is written, all the knowledge in the world isn't going to help you on test day.

 

[Kaputt]

According to UWorld question - ID#1597 [441137], a guy with a biopsy that suggests ulcerative colitis returns two weeks later, not having received treatment, with a second biopsy that shows an amelioration of pathology and decreased inflammation. The question then asks for which cytokine is most likely responsible. Answer choices were TNF-alpha, IL-1, IL-4, IL-5, IL-10, IL-12.

Answer = IL-10

62% answered correctly

I put IL-12, which 11% chose.

------

My reasoning was that FA, on p. 355, states that ulcerative colitis is a Th-TWO-mediated process, which is upregulated by IL-4, -5 and -10, -13, and downregulated by IFN-gamma.

IL-12 is the closest answer because IFN-gamma and IL-12 positively regulate one another and increase the ratio of Th1/Th2-driven inflammation.

Now here's an added element of complexity: UWorld attaches two articles to the bottom of the page. I opened up the second one, which led me to PubMed, and I read the article myself. It specifically says that Crohn's disease patients have decreased IL-10 expression and that ulcerative colitis patients have increased IL-10 expression.

UWorld's explanation is that IL-10 is a general suppressor of inflammation (which is correct) and that it upregulates the Th-2 response (which is correct). However, UC is a Th2-reaction!

Does anyone have any input here?

Ulcerative colitis is an extremely complicated disease that is poorly understood at the molecular level. Step 1 isn't going to ask you about the pathogenesis of UC, and they really just care that you know it's an inflammatory disease. They will ask you basic questions about cytokines, and a monstrously high-yield concept is that IL-10 and TGF beta are anti-inflammatory cytokines. This question would be a gimme on the real test, no offense, which is why it's probably not a good idea to cloud your knowledge base with excruciating minutiae. Rein it in, buddy. This isn't an exam for immunology PhDs.

 

[theTruth_97]

i just ran into this question on Uworld and while I got the question right in the explanation I noticed something that I think is odd: why does IL-10 increase IL-4 and IL-5 release from TH-2 when it is supposed to be an anti-inflammatory cytokine?.....isn't that effect counter intuitive?

 

[seminoma]

i just ran into this question on Uworld and while I got the question right in the explanation I noticed something that I think is odd: why does IL-10 increase IL-4 and IL-5 release from TH-2 when it is supposed to be an anti-inflammatory cytokine?.....isn't that effect counter intuitive?

IL-10 is a pro-TH2 and anti-TH1 cytokine. In terms of anti-inflammatory, shutting down TH1 (even in the face of activating TH2) is a net anti-inflammatory effect. IL-4 and IL-5 (B cells, IgE, IgA, eos) are much less pro-inflammatory than IFN-gamma from TH1 --> IL-1, 6, 8 and TNF-a from macrophages.