Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) report finding subtle immune abnormalities in people with chronic fatigue syndrome (CFS) that ultimately may explain why they develop the painful muscles and joints, tender lymph nodes and other symptoms associated with the illness.

In the January issue of the Journal of Clinical Immunology, NIAID researchers Stephen E. Straus, MD, Warren Strober, MD, and Janet K. Dale, RN, who with National Cancer Institute contractors Scott Fritz, PhD, and Barbara Gould of Program Resources Inc./Dyncorp, Frederick, Maryland, carried out the study, describe their analysis of immune cells taken from patients with CFS.

Most notably, the CFS patients had significant differences in the number and character of one type of immune cell - T-cells that carry helper molecules, called CD4, on their surfaces. These cells, known as CD4+ T-cells, orchestrate the immune response.

During development, a CD4+ T-cell acquires receptors enabling it to link with a single foreign invader, called an antigen. Thereafter, until the CD4+ T-cell dies, it reacts only with that antigen. CD4+ T-cells circulate in the blood either as 'naive' cells that have not interacted with their antigen; or as 'memory' cells that have interacted with their antigen, and upon re-exposure to that antigen quickly stir the immune system into action. Certain cell surface molecules distinguish the naive cells from the memory cells.

The NIAID investigators found that, as a group, the CFS patients had a significant but slight reduction in the number of these naive T-cells. In addition, whereas the patients had normal numbers of the memory T-cells, a greater-than-average share of them displayed various adhesion molecules. Adhesion molecules act like address labels, enabling circulating T-cells to home and attach to particular tissues.

In summary, these findings suggest that although a greater proportion of CD4+ T-cells had shifted from naive to memory T-cells, sophisticated blood tests did not find excess memory cells because more had developed adhesion molecules, left the circulating blood and entered tissues. The researchers theorise that exposure to infectious agents, or underlying neuroendocrine or neuropsychiatric abnormalities could directly or indirectly trigger this increased maturation of CD4+ T-cells.

Their findings also explain why the CFS patients, as a group, had a slight decrease in total CD4+ T-cells, a decrease matched by the deficit in the naive cell subset. "This decrease does not indicate that CD4+ T-cells are being destroyed, such as happens in AIDS," says Dr Straus, "but that more CD4+ T-cells appear to change location, shifting from the blood into the tissues. These tissue-based cells escape detection by research blood tests."

None of the immunologic differences are large or frequent enough to constitute a meaningful diagnostic test for CFS, Dr Straus says. Their observations do have clinical implications, however.

Finding an increased number of memory cells with adhesion molecules, the investigators speculate, may help explain why CFS patients experience painful muscles and joints, tender lymph nodes and other associated symptoms. In the tissues, CD4+ T-cells release molecules that help regulate the immune response. These molecules can cause mild inflammation and pain. "The same process causes pain in the intestines of people with inflammatory bowel disease," says Dr Strober, another member of the team who is an immunologist and expert in inflammatory bowel disease.

To test the validity of their theory of CFS pain, the researchers are now examining the function of various subsets of T memory cells taken from patients.

Aside from the noted T-cell differences, the investigators found no other immune cell abnormalities in the CFS group. The cells examined included macrophages, which scavenge foreign debris; natural killer (NK) cells, the first line of defence against an invading organism; and B-cells, which produce specific molecules that guard against and can destroy the invader. The researchers note that using frozen cell samples may have affected the NK cell measurements, however, because NK cells may not survive the freezing as well as other cells.

All 18 CFS patients in the study met the full criteria for CFS as defined by the Centers for Disease Control (CDC). None could work full time: 6 worked part time, and 12 could not work at all. Although 7 patients had mild depression, none had more serious depressive symptoms. The group included 13 women and five men, ages 24 to 49, half of whom had been ill for more than 7.4 years. The syndrome had begun abruptly with an infectious-type illness in 17 of the cases. The investigators required that all participants be medication-free, except for occasional acetaminophen use, for at least two weeks prior to the study. They also had to adhere to a restrictive diet for at least four days prior to blood sampling. The healthy volunteers matched the patients in both sex and age.

The researchers separately compared the CFS patients and the healthy volunteers with another group of ten chronically fatigued patients as well. All suffered from a prolonged, debilitating fatigue following an infectious illness, resembling the onset of CFS. The fatigue patients had no alternative diagnosis, but did not report enough symptoms to conform fully to the CDC definition of CFS. As a group, the immune profiles of these patients mirrored those of the CFS patients, indicating that forms of severe fatigue that do not completely fulfil the CDC criteria can show similar immunologic changes to those seen in CFS.

Like other immunologic studies of CFS, this one represents a snapshot of one group of CFS patients. The NIAID study will continue for several years, however, to allow a more detailed picture of the disease in these patients to emerge. The data collected will be analysed to determine if these or other immune differences found vary with time or correlate with symptom severity or recovery.

Acknowledgment: This article was reprinted from CFS-NEWS, a newsletter edited by Roger Burns and distributed on Internet.

Please note: CD4+ T-cells are commonly known as T4-cells.

Reprinted from Emerge, June 1993.