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Deficiency in the Expression of STAT1 Protein in a
Subpopulation of Patients with Chronic Fatigue Syndrome (CFS)


Presented at the Seventh International AACFS Conference on Chronic Fatigue Syndrome, Fibromyalgia and other Related Illnesses. Madison, Wisconsin; October, 2004

KK Knox1, A Cocchetto2, E Jordan3, D Leech4 and DR Carrigan1

1 Institute for Viral Pathogenesis; Milwaukee, WI
2 National CFIDS Foundation; Needham, MA; 3 Olean, NY; 4 Albuquerque NM

Background. CFS is a debilitating illness associated with persistent severe fatigue, a variety of physical and neuropsychological signs and symptoms, and frequently, an unusual susceptibility to a variety of infections. The study of intracellular signal transduction pathways may have provided a key insight into the immunological defect operative in CFS patients Signal transducers and activators of transcription (STAT) are a family of proteins that play central roles in the responses of cells to cytokines. Specifically, the protein STAT1 is intimately involved in the response of cells to type I (alpha and beta) and type II (gamma) interferons.

Objectives. The aim of these studies was to evaluate samples of peripheral blood mononuclear cells (PBMC) from CFS patients and healthy control subjects for the expression of STAT1.

Methods. PBMC were purified and lysed in a buffer containing non-ionic detergent, a protease inhibitor cocktail and a combination of two proteosomal protease inhibitors (MG-132 and lactacystin). Samples corresponding to known numbers of PBMC were then subjected to an immunoblotting procedure using a STAT1 specific antiserum (sc-592; Santa Cruz Biotechnology). A quantitation method was developed using densitometric scanning of the protein bands detected by the antiserum. Titration experiments with PBMC from control subjects demonstrated that STAT1 protein detection was quantitatively linear for samples of between 2 X 104 and 1.4 X 105 cells per well in PAGE. Therefore, PBMC samples were screened for STAT1 protein using 105 cells per well. Adequacy of protein in all samples was monitored by staining the immunoblots for actin.

Results. In both CFS patients and controls, five proteins reacting with the sc592 antiserum were identified. Specificity of the antiserum staining was demonstrated by complete blocking of the detection of all five proteins by preincubation of the antiserum with the peptide used for production of the antiserum. STAT1 proteins detected were (1) a minor, inconsistent band of approximately 150 kiloDaltons (kD) (function unknown), (2) a strong band at 91kD (STAT1 alpha splice variant; STAT1-91), (3) a strong band at 84kD (STAT1 beta splice variant; STAT1-84), (4) a strong band at 56kD (function unknown; STAT1-56) and (5) a strong band at 51kD (function unknown; STAT1-51). STAT1-91 and STAT1-84 were not consistently resolved from one another and were analysed together (STAT1-91/84). Results are summarized below:

Subject Group

STAT1-91/84 +  STAT1-56 +

STAT1-56 +
STAT1-51 +

STAT1-51 +

STAT1-91/84 +


92% (25/27)

16% (4/25)

16% (4/25)

0% (0/25)

CFS Patients

68% (17/25)

0% (0/27)

4% (1/27)

4% (1/25)

Conclusions. STAT-1-91/84 represents the form of STAT1 that is involved in the intracellular signaling of both type I and type II interferons. The higher negativity for STAT1-91/84 in the CFS patients (32%) compared to the healthy controls (4%) is highly significant (p < 0.01 by two-sided Fisher's Exact Test). This suggests that a subpopulation of CFS patients may exist who suffer from an abnormally low STAT1 response to interferons. This immunodeficiency may underlie the increased susceptibility to infections seen in many CFS patients.

These studies were supported by the National CFIDS Foundation.  

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