pH And Complement?

[dyspareunia]

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What does low pH have to do with increasing complement activity (as in PNH)?

 

[Brain Bucket]

a valid message.

 

[Modeselektor]

I would guess at altering protein structure/binding affinity

 

[CherryRedDracul]

I would guess at altering protein structure/binding affinity

Could be this. I think the jury is still out on the mechanism because while most people have hemolysis associated with PNH at night, not all day, and they can have it during various parts of the day.

 

[NeuroLAX]

Sooo, the acidosis causes activation of complement, which is bad for people with PNH because the most common defect is a defect in the enzyme (PIGA) needed to make GPI, which normally anchors proteins that are protective against the complement system? No GPI leads to complement activation and lysis?

That's what I came up with after reading Wiki and this: http://www.jleukbio.org/content/69/4/522.full

I would guess at altering protein structure/binding affinity

The above article mentioned that as a possible mechanism.

 

[dyspareunia]

Sooo, the acidosis causes activation of complement, which is bad for people with PNH because the most common defect is a defect in the enzyme (PIGA) needed to make GPI, which normally anchors proteins that are protective against the complement system? No GPI leads to complement activation and lysis?

That's what I came up with after reading Wiki and this: http://www.jleukbio.org/content/69/4/522.full



The above article mentioned that as a possible mechanism.

Didn't read the article, but what you typed is the mechanism for complement activation and lysis. I'm not sure why acidosis causes complement activation though.

 

[NeuroLAX]

Didn't read the article, but what you typed is the mechanism for complement activation and lysis. I'm not sure why acidosis causes complement activation though.

It may not be completely understood. The above article mentions protein structure alteration as a possible mechanism. This article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781874/pdf/9927235.pdf, offers an additional hypothesis, suggesting that acidosis-mediated complement activation may be due to inactivation of complement protease inhibitors.

 

[Brain Bucket]

a valid message.

 

[dyspareunia]

It may not be completely understood. The above article mentions protein structure alteration as a possible mechanism. This article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781874/pdf/9927235.pdf, offers an additional hypothesis, suggesting that acidosis-mediated complement activation may be due to inactivation of complement protease inhibitors.

So basically we know that acidosis inhibits inhibitors, but we don't know why or how..

Just based off of the quote ' defect in the enzyme (PIGA) needed to make GPI, which normally anchors proteins that are protective against the complement system', I'm guessing we're probably talking about Factors H and I. This would likely be a case of the dysfunction of an inhibitor...therefore resulting in an increased chance of activation.

Originally, I'd guessed it was simply the case of factors B and D having a more favourable conformation, leading to greater spontaneous formation of C3bBb.

Right, I understand there's dysfunction of inhibitors (like DAF) leads to increased activation of complement. But, what acidosis has to do with it was what I was trying to figure out. It seems the mechanism is unknown though so I guess it's just something to memorize.

 

[Brain Bucket]

a valid message.

 

[DeeJay2728]

Are they CD55 and CD59?

 

[dyspareunia]

Are they CD55 and CD59?

DAF is CD55, but I'm not sure about 59

 

[NeuroLAX]

Are they CD55 and CD59?

DAF is CD55, but I'm not sure about 59

CD59 is another GPI-anchored protein: MAC-IP/MIRL/protectin.

 

[DeeJay2728]

A lower ph will cause your RBCs to swell, any alteration in RBC membrane can activate complement. Ham test shows increased osmotic fragility.

 

[dyspareunia]

A lower ph will cause your RBCs to swell, any alteration in RBC membrane can activate complement. Ham test shows increased osmotic fragility.

Remind me why lower pH causes RBC swelling (besides the fact that lower pH apparently activates complement)? I thought the Ham test showed complement lysis due to MAC formation? Not necessarily increased osmotic fragility, but increased complement-mediated lysis.

 

[DeeJay2728]

I believe RBC swelling is due to increased Chloride influx (exaggerated Bohr effect, I guess). If anyone knows exact mech, please share. Ham test does show lysis due to MAC formation, and a positive test confirms the lack of CD55/59. RBCs placed into an acidic environment will cause structural changes, I'm not sure if it's the increase of chloride inside the RBC that allows/makes it easier for sodium to come in, or if the increased chloride influx opens voltage gated sodium channels. I'm trying to find more information about the Chloride exchanger. If you find anything please share, my OCD is getting to me!!