Journal: In Vivo 2001 Nov-Dec;15(6):461-5
Authors: Krueger GR, Koch B, Hoffmann A, Rojo J, Brandt ME, Wang G, Buja LM.
Affiliation: Department of Pathology & Laboratory Medicine, University of Texas-Houston Medical School, 6431 Fannin St, MSB 2.246, Houston, Texas 77030, USA. mailto:Gerhard.Krueger@uthtmcedu
NLM Citation: PMID: 11887330
The abstract for this study was posted to the Co-Cure list on March 13, 2002 and can be read at http://listserv.nodak.edu/scripts/wa.exe?A2=ind0203b&L=co-cure&F=&S=&P=3587 .
The following is the discussion section from this article.
Similar to Epstein-Barr virus, human herpesvirus-6 persists life-long in infected individuals after primary infection in early childhood and the reactivated virus may be associated with a number of chronic diseases (16). One such disease is CFS.
Although the etiopathogenetic relationship between reactivated herpesviruses and such chronic diseases remains to be elucidated, they can serve as examples of the effects of chronic active herpesvirus infections provided that other immediate causes are excluded. This has been done in-the CFS patients of the present study including detailed searches for other infectious agents (see Methods) and neuropsychiatric workups. HHV-6-positive CFS appears to be an ideal model for chronic active infection with a° syndrome that can mimic various other disorders, preferentially the autoimmune and neuropsychiatric types (16,17).
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Primary autoimmune disorders were excluded in our patients by a newly-developed artificial neural network classifier (17,18). We chose, therefore, CFS with proven active HHV-6 infection to further validate a re-designed computer simulation model as previously described (19). These data supplement data from acute primary HHV-6 infection (11).
Similar to acute primary HHV-6 infection in infectious mononucleosis (11), the exact time of HHV-6 activation cannot be determined. Although subjective complaints began acutely in all 10 CFS patients in this study, it is not certain whether this coincided with reactivation of HHV-6. In addition, all patients came to our attention only after several weeks to months after onset of their disease. The type of infection in our 10 patients must therefore be considered as persistent active infection with unknown initiation.
Follow-up studies showed an obvious variation of all values (HHV-6 DNA copies, apoptosis, cell populations) during the course of CFS in our patients. The marked variability in CD-subtype cell populations was reminiscent of similar early changes in the blood of HIV-infected individuals (20). They appear to reflect the protracted struggle of the immune system with persistent infection indicating a certain failure of defense mechanisms (21,22). The final outcome in persistent HHV-6, however, differs significantly from persistent HIV as immune competence is usually regained in HHV-6 infections and all values return to normal after some duration (possibly many years).
We determined HHV-6 DNA copies in blood as an indicator of intensity of immune stimulation by this infection. Interestingly, copy number were not significantly elevated above values published for reconvalescent patients following acute primary HHV-6 infection (23). Copy numbers fluctuated and only occasionally values were reached like those reported before in acute HHV-6 infection of infectious mononueleosis (11).
More obviously changed – as compared to healthy persons – was the rate of apoptosis in PBL (lymphoid cell window) with transient elevations to 8, 15 or even 25%. This represents a 3-to 5-fold increase, yet repeated spontaneous normalization was observed during the course of CFS in an individual patient. Our data are in accordance with those of Vojdani et al. (24) who reported increased apoptosis in CFS patients accompanied by abnormal cell arrest in the Shase and G2/M boundary of the cell cycle. Interferon-induced protein kinase RNA was elevated in these patients as compared to normal controls.
According to the “three signal model” of lymphocyte stimulation (25), apoptosis occurs when receptor-ligand interactions at these three signal sites of immunocompetent lymphocytes and antigen- presenting cells (i.e., antigen -TCR/CD4, CD80/86 – CD28, CD80/86 – CTLA4 [CD152]) become out of balance. Hassan et al. were able to show that CD28 was significantly reduced in CD8 cells of CFS patients, i.e., one of the necessary receptors for full stimulation of lymphocytes (26). Fluctuation of apoptosis in our CFS patients while persistently stimulated by infectious antigens may well suggest such immunoregulatory imbalance. The incidence of PBL apoptosis in our HHV-6 positive CFS patients also compare with those published in CD4 lymphocytes and in tissue culture cells with HHV-6 infection (27,28).
The effect of persistent active HHV-6 infection on the immune system was monitored in terms of shifts in defined lymphocyte populations in the peripheral blood (aside from apoptosis). In comparison to acute HHV-6 infection in infectious mononucleosis (11) and with respect to our original computer model (19),, cell populations from different compartments – mature and immature – were determined, such as stem cells (CD34+), thymic cortical cells (CD38+), thymic medullary cells (CID4+8+ doublepositives) and mature T cells (CD3) (29-32). In addition, the ClJ4/CD8 helper/suppressor T cell ratio was measured.
T helper/suppressor cell ratio showed fluctuations during the two-year course of CFS from below 1 to above 3, thus indicating T suppressor cell predominance or T helper cells predominance, the first similar to acute viral infection, the latter similar to an extent observed in autoimmune reactions. This variability may again suggest a certain imbalance in the immune system’s reactivity.
Obviously different, however, from what was observed in acute HHV-6 infection (11) were the over-all normal to slightly decreased values in T-cell populations. The cells apparently did not respond in a similar way as in acute infection to viral antigen stimulation. It appears as if persistent low-dose HHV-6 stimulatipn causes non-reactivity in these cell populations rather than their stimulation. Our data concur in part with, those of Hanson et al.(33) and Swanink et al. (34), who reported decreased CD34, CD38, CD8 and CD19 (B lymphocytes) cells. Others did not identify significant differences in cell populations of CFS patients as compared to normal controls (35).
In essence, the data presented from this longitudinal study of selected HHV-6A-positive CFS patients suggest certain imbalances in reactivity of the immune system. They need to be supplemented, however, by respective functional testing. A number of such functional studies have been done with frequently contradictory results (36-40), yet detailed longitudinal testing using standardized methodology still needs to be continued. It is unsatisfactory to only publish such contradictory results without solving the problem of observed discrepancies. The computer model currently being designed by us (19) may assist in the future in more clearly identifying suspected imbalances in the reactivity of the immune system.
Source: Chronic Fatigue Syndrome and Fibromyalgia Information Exchange (Co-Cure)