Potential Role of STAT1 in the Pathogenesis of Chronic Fatigue Syndrome

[Guest guest]

Potential Role of STAT1 in the Pathogenesis of Chronic Fatigue Syndrome

Konstance K. Knox, Ph.D. and R. Carrigan, Ph.D.1

1Institute for Viral Pathogenesis; 10437 Innovation Drive; Suite 417;

Milwaukee, Wisconsin 53226

Project funded by: The National CFIDS Foundation; Needham, Massachusetts

Background

Chronic fatigue syndrome (CFS) is a debilitating illness associated with

persistent severe fatigue and a variety of physical and neuropsychological

signs and symptoms. While the syndrome itself has been recognized for many

years, its etiology and pathogenesis are poorly understood. One of the most

intriguing and potentially important aspects of CFS is the unusual

susceptibility of individuals with it to a variety of infections. Increased

incidences of infections with a variety of viruses (e.g. human herpesvirus

six, Epstein-Barr virus and enteroviruses) and bacteria (e.g. mycoplasma and

chlamydia).1 While this unusual susceptibility to infections is suggestive

of an impaired immune system, no single, consistent immune defect is

observed although a wide variety of deficiencies has been described.1

Recently advances in the understanding of intracellular signal transduction

pathways may have provided a key insight into the immunological defect that

may be operative in CFS. Signal transducers and activators of transcription

(STAT) are a family of transcription factors that play central roles in the

responses of cells to cytokines, molecules that control every aspect of the

immune system. Specifically STAT1 and STAT2 are intimately involved in the

response of cells to type I (alpha and beta) and type II (gamma)

interferons.2 Genetic defects in STAT1 are associated with fatal infections

by both viruses and bacteria.3,4,5

The possible importance of STAT1 in CFS stems from recent observations by a

number of research groups. First, as reviewed by Komaroff,6 the type I

interferon response is abnormal in patients with CFS. In healthy individuals

type I interferon leads to an intracellular antiviral state that is mediated

by the enzyme RNAse L which normally has a molecular weight of 80

kiloDaltons (kDa). However, in patients with CFS the RNAse L induced by type

I interferon is abnormally cleaved into a form of only 37 KDa in weight. The

protease responsible for the abnormal cleavage in unknown, but it is likely

to be closely related to human leukocyte elastase (HLE).7 In work by

Suhadolnik,8 Englebienne9,10 and others, it has been found that patients

with CFS express the 37 kDa form of RNAse L in varying degrees and that this

variation can be expressed by the ratio of the 37 KDA to 80 kDa forms of the

enzyme (termed the " RNAse L ratio " ). In a creative set of studies by

Englebienne, Fremont et al9,10 the RNAse L ratios of a set of CFS patients

were compared with respect to the expression of STAT1 in the patients

peripheral blood mononuclear cells (PBMC).

Remarkably, as the RNAse L ratios increases (higher levels of the abnormal

37 kDa enzyme) the expression of STAT1 protein decreases. When the analysis

is performed in the presence of protease inhibitors, this effect is not

seen, suggesting the STAT1 protein is being proteolytically degraded.10 It

was proposed that the STAT1 protein is degraded by the same protease

responsible for cleavage of the 80 kDa form of RNAse L.9

If these observations and hypothesis prove to be true, the implications for

the pathogenesis of CFS would be of great significance. The loss of STAT1's

signal transduction function would explain the increased susceptibility of

CFS patients to infections and could account for the increased serum levels

of interferons that is seen in some patients with CFS. The increased

interferon levels would result from the homeostatic increased production of

interferon in the face of decreased interferon responsiveness.

continued at

http://www.ivpresearch.org/stat1.htm

_________________________________________________________________

Winterize your home with tips from MSN House & Home.

http://special.msn.com/home/warmhome.armx