Expert: Florence M Rollwagen - 8/19/2008

Question
Dear Florence,

            I recently asked this question of another expert and although he said it was one of the most interesting questions he had been asked , unfortunately his knowledge in this area was not enough to give a full answer.

I would be interested to read what you think.



          My question and preamble may be a bit convoluted but i ask you to bare with me for although as a sufferer of Rheumatoid Arthritis (RA)I have read extensively about this disease my understanding is still that of a layman,s and i may have difficulty with context and order. Here goes,I have always believed that RA is the result of an infection(if not directly)then somehow as a consequence of an infection. Recently i read an article about the flu virus and how it can block the interaction of CD200 and it,s receptor CD200R which you may know or have read about and how this interaction can signal the down regulation of the Th1 response and the up regulation of the Th2 response and as a result dampen pro inflammatory macrophages and cytokines and how this blocking effect of the virus continues for some time after the virus has been cleared from the system, this phenomenon in itself would be an interesting piece of research but my interest in this matter as i,m sure you would understand is with the action of CD200 and it,s possible benefits to RA sufferers. Present research is based around a CD200 mimic, a monoclonial antibody called CD200Fc. I have grave concerns about monoclonial antibodies and the risks involved with systemic loading of these antibodies by oral prescription as it would appear to me that you get immunnosuppression where it,s not needed and this could be a reason why risks arise. Considering that in RA inflammation is site specific a better safer means of delivery could and should be developed. Now the point on which my question is based is that CD200 is expressed in mRNA and i should qualify why. Recently while i was in the country side i got several bites by an insect and on reflection my immune system went through what i would say was a normal reaction, itching,swelling,inflammation,dampening of inflammation and healing and this would suggest to me that site specific to these bites i.e. in my epidermis i have active and CD200 expressing mRNA.What i was thinking and i must say that i don,t know if it is even possible , that a persons own CD200 expressing mRNA could harvested and delivered directly to the affected areas. I would be interested in what your thinking on this matter would be. As my question involves genetics i would understand if you feel unable to answer but would be grateful if you could pass it on or recommend an expert.



     Thank you for your time and consideration.



               Yours sincerely.



                     kieran."  

Answer
RA and CD 200

Hi Kieran:  Thanks for your question.

For me to answer fully, you need to do some reading in immunology.  I don’t know how much you’ve already learned, but below are some online immunology textbooks you can look at.  I’m giving you a relatively superficial answer, since I don’t really know what your level of education is (no offense!).  So, my first advice is to read through what I’ve sent and then come back with more specific questions.  In your introductory paragraph you’ve covered about two years of biology classes, so I can’t really answer everything in one session.

See if you can figure out what I’ve written, read the books, then come back with some more specific questions and we can discuss this further.


Most immunologists think that autoimmune diseases (RA and MS, to name two) are the result of an inappropriately elevated immune response following a (silent or inapparent) viral infection.  

The reasons for this lie in the immune system’s ability to distinguish “self” from “non-self”.  In the textbooks that I listed below you can look up the MHC (Major Histocompatibility Complex) and find out how that’s done.  

Now, because “self” clones are deleted in immune maturation, when a virus attacks, the immune system recognizes the complex of “MHC + virus”  as a pathogen and kills the virus infected cells.  This is standard immunology.  For some people with specific MHC haplotypes (genes) the immune response now cannot tell that the virus is gone and continues to attack cells bearing that MHC.  That’s why most autoimmune diseases have a prevalence of certain MHC haplotypes.  

All immune responses generate a balance between Th1 and Th2 responses.  Usually in the laboratory this is analyzed by specific cytokines secreted by each class of cell.  In some cases, this balance is skewed, resulting in allergy, atopy, or autoimmunity.

Work on autoimmune diseases has involved finding ways to shut down the inappropriate immune response using animal models. Great progress has been made, but there is still no way to eliminate just the specific cells responsible for the disease.  These drugs shut down ALL immune responses, and in high dose, can leave the patient vulnerable to infection.  This is a similar situation in what we see with transplant patients and AIDS sufferers, since their ability to respond to infections is progressively limited.  The dose used for autoimmune diseases is much lower, so the risk of infection is less, but still present.

The CD200Fc is an antibody fragment that binds to the RECEPTOR for CD200 on macrophages or other antigen presenting cells.  (look up antibody structure in the books below).

It is possible to “silence” CD200 expression and thereby reduce the local inflammation.  This is done with siRNA (small interfering RNA).  The problem with these local administrations is getting the drug where it needs to be without compromising other (necessary) immune responses.  Because CD200 is involved in all immune responses, shutting off the RA ones without shutting off (for example) the ones for flu is a real problem.

Now your response to the bug bites is what we call an inflammatory response and resides in the innate immune system.  The diseases we’ve been talking about are in the acquired immune system.  These two systems overlap, but are essentially different in too many ways to discuss here.  You can look them up below.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1934540

http://pathmicro.med.sc.edu/book/immunol-sta.htm

http://bcs.whfreeman.com/immunology5e/

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/

I hope this answer has helped you.  Please write back if you have more questions.

FM Rollwagen, PhD