Natural rheumatism blockers?

Stijff, painful limbs, difficulty in moving, intense fatigue:  these are all very common symptoms of patients suffering from rheumatoid arthritis, a form of rheumatism characterised by chronic inflammation of the joints.  Leendert Trouw, from the Rheumatology Department of the Leiden University Medical Centre (LUMC), has been awarded a Veni subsidy to research how joint inflammation is maintained.  'I think that in time we will probably be better able to block chronic inflammation of the joints of rheumatism patients.' 

Autoimmunity
Reumatoid arthritis is an auto-immune condition.  A characteristic of auto-immune diseases is that the immune system regards the body's own cells and substances as foreign, which sets in motion a rejection process aimed at the body's own tissue. 'When a joint becomes inflamed, this leads to an accumulation of immune cells,' explains Trouw.  'As these immune cells die off, DNA is released.  This so-called extra-cellular DNA in turn activates the complement system, a collection of proteins which cause a further immune reaction. This leads to a vicious circle of immune activation.  As a result, the joint remains permanently inflamed.'

Diagram of the process by which joint inflamation in rheumatism patients is maintained.

Protective factors
There are two factors which Trouw suspects protect people both directly and indirectly against immune activity by extra-cellular DNA. These factors are C4BP and factor H. They probably inhibit the immune activation directly by keeping the complement system in check, and indirectly by binding extra-cellular DNA to themselves, thereby preventing activation of the complement system. Trouw: 'How important these factors are precisely in regulating auto-immunity, is not yet known.  This is also the key question in my research.'

In vitro experiments
It is not possible to study the role of C4BP and factor H within the human body itself.  Trouw therefore resorts to in vitro or test tube experiments. 'You can then examine, for example, what happens with the activation of immune cells by free DNA in serum if you remove C4BP and factor H from the serum.  As a researcher, with these kinds of experiments you know exactly which processes you are influencing.'  

In vivo experiments
Research using mice is a further option, explains Trouw.  'We have bred mice in our lab which lack both C4BP and factor H. By comparing these mice with wild mice which do have these factors, we can study their protective mechanism. Our expectation is that if we initiate a joint inflammation in the mice, the first group will develop more serious joint inflammation than the second group.'

Part of the C4BP molecule. The arrow indicates where extra-cellular DNA can be bonded to the molecule.

Treatment
If C4BP and factor H do indeed prevent the maintenance of the inflammation, according to Trouw, this offers some possibilities for better treatment for rheumatism patients.  The synthetic complement blockers which are being tested in current clinical practice, do have a direct inhibiting effect on the complement system, but are not able to bind extra-cellular DNA in the same way as C4BP and factor H. Stimulation of the complement system by DNA will therefore not be prevented by these means.  Their blocking capability is therefore probably not optimal.  'If we were in future able to increase the concentration of functionality of C4BP and factor H in the blood, this would probably be of greater benefit to patients,' according to Trouw.

Core quality
The Veni laureate says how happy he is to work in an environment in which both clinical research material is available, as well as knowledge about immunological (animal) research.  He commends the combination of these two factors as one of the core qualities of his department. 'There is nothing better than translating clinical observations in patients into experiments in the test tube and with mice, in order to make sure the patient derives the maximum benefit from this research.'  

(12 June 2007/Tristan Lavender)