Sunday, October 18, 2009

Plausible disease models

Until now, no good disease models existed to explain to etiology of Chronic Fatigue Syndrome and related disorders. In the 1980's, we called it the yuppie flu, in the 1990's we called it a neuropsychiatric disorder of unknown etiology, then we called Fibromyalgia a pain processing abnormality with hypothalmic disturbances, and for a period of time both conditions became a wastebasket diagnosis. There were no tests available to mainstream medicine that could precisely detect disease markers, although over time various researchers have uncovered slight abnormalities in patient's immune systems.

A good disease model can be explained by the disease pyramid - succeptible host, pathogen, environment, time. My disease model begins with the succeptible host - Man, pathogen - XMRV, environment - stress, and then time. Succeptible host needs some explanation, as does environment, with pathogen and time being constants. I will begin with the host:

Basically, not all human beings are created equal, but being simplistic the prevalence of Fibromyalgia is heavily biased towards women, and chronic fatigue somewhat less. Based on the genome sequence of XMRV, it appears that one gene functions as an androgen responsive element - does it bind androgens and act as a repressor? Further studies will be needed to answer that question, although it provides a plausible explanation. It could also mean that men who have low testosterone levels are more prone to developing disease. Once again, a promising lead that needs to be studied.

Now my model will explain why some people may live symptom free for years. In a state of homeostasis, the immune system efficiently keeps the virus in check.
  • Pregnancy - during pregnancy the balance of the immune system shifts towards Th2, likely from the influence of progesterone, this means that the body's defenses towards viruses are diminished.
  • Stress - Cortisol is a hormone produced by the adrenal glands in response to stress - small amounts are needed to keep the immune system in balance. Larger amounts will generally tend to suppress the Th1 response more than the Th2 response, thus tipping the balance. Emotional stress, sleep deprivation, caffeine, trauma and over-exertion all increase cortisol.
  • Infection - certain infections will favor a Th2 response - extracellular parasites (bacteria, protozoa, etc), and in the process will distract a Th1 response.
But when the balance tips, the XMRV in Nk cells begins to replicate, and infect other Nk cells, and the immune system becomes weakened as Nk cells become depleted, however does not result in a complete immune collapse, as other lymphocytes can partially fill the role of Nk cells, although with much less efficiency. Nk cells are important in recognizing cells infected with herpesviruses (Eppstein-Barr, Cytomegalovirus, HHV-6, Herpes Zoster, and Herpes Simplex 1 & 2), and with diminished numbers, the various viruses that have been identified in Chronic Fatigue and FM sufferers begin to flourish. A futile cycle ensues, where interferon pathways become activated, where RNase-L destroys cellular RNA in an effort to stop viral replication. Likely the fatigue results from chronic interferon activation, in addition to possibly the presence of a viral protein in the blood which acts as an endocrine disruptor. Confidently, I can say that based on this disease model, XMRV is the puppet master of Chronic fatigue. If you can suppress XMRV, Nk cell function will return, and the immune response will now keep herpesviruses in check. Once the immune system becomes competent, or reconstituted you might say, XMRV will be kept in check, until the host defenses are compromised.

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