“Why does HAE localize in certain area of the body; ie feet vs face or gut?”

Aug 18, 2015

Dr C: This is a fascinating question. I don’t think that we will be able to provide a definitive answer, but we can speculate. As our readers know, bradykinin has been established as the mediator of swelling in HAE. Current understanding suggests that bradykinin is generated in the blood, and then acts on specific bradykinin receptors on endothelial cells, which are the cells that line the blood vessels. Bradykinin causes gaps between the endothelial cells to “open up”, allowing fluid to leak out of the blood vessel thereby causing swelling of the tissue. It would seem, therefore, that attacks of HAE would cause swelling all over the body, right?

Dr. Z: That’s correct. The fact that the swelling is localized rather than generalized presents a dilemma that could be pointing to something that we don’t understand. It’s possible that bradykinin is activated in a local environment and acts only where it’s activated. We’d have to assume, in this case, that the bradykinin is immediately degraded before it reaches other parts of the body. Alternatively, it’s possible that bradykinin is actually activated in the tissue and the changes we see in the blood are secondary.

Dr. C: Another possibility is that there are differences in bradykinin receptors at different sites in the body. The bradykinin receptor that is normally present on cells is called the B2 receptor. We know that there is a second type of bradykinin receptor that is not normally present but can be induced when there is trauma, inflammation, and infection. This receptor is rather confusingly called the B1 receptor. One of our research projects involves looking at whether there is evidence that attack location and severity may be related to whether the B1 bradykinin receptor is expressed.

Dr. Z: I should point out that many attacks start in one location and then go on to involve another location. One possibility that could account for this would be that B1 receptors become induced in the second area during the attack,possibly through activation of B2 receptors. Couldn’t the presence of the B1 receptor also explain why attacks of angioedema go on for so long?

Dr. C: Yes. The B1 receptor appears to just keep signaling until the cell stops making it. This is unlike the B2 receptor, which quickly loses the ability to signal when bradykinin binds to it. One of the reasons that Bruce and I are interested in this hypothesis, is that if true it would suggest that drugs that target the B1 receptor might be effective for the treatment of HAE.

Dr Z: I think that it’s also possible that there are differences in the endothelial cells at specific sites that determine whether bradykinin is able to open up these gaps. It’s much harder to study blood vessels than blood, so our understanding of this issue isn’t very good at the moment.

Dr. C:  Thank you Bruce this was quite an interesting ‘speculation session’. Hopefully this will be helpful for our readers. We look forward to our next ‘Question of the Week’.

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