The Paul-Bunnell Heterophile Antibody Determinant in Epstein-Barr Virus-Associated Disease

Journal: J of Chronic Fatigue Syndrome, Vol. 10 (3/4) 2002, pp. 51-86

Authors: Roberto Patarca-Montero, MD, PhD and Mary Ann Fletcher, PhD

Affiliations: Roberto Patarca-Montero is Co-Director of the E.M. Papper Laboratory of Clinical Immunology and Molecular Biology and Assistant Professor of Microbiology and Immunology. University of Miami School of Medicine.

Mary Ann Fletcher is Director of the E.M. Papper Laboratory of Clinical Immunology and Molecular Biology and Professor of Medicine, Microbiology and Immunology, and Psychology, University of Miami.

Address correspondence to: Mary Ann Fletcher, E.M. Papper Laboratory of Clinical Immunology, Departments of Medicine. and Microbiology and Immunology, University of Miami School of Medicine, P.O. Box 016960 (R-42), Miami, FL 33101.


Reactivation of latent herpes viruses (notably Epstein-Barr virus, human herpesvirus-6) is commonly seen in chronic fatigue syndrome and it is believed to contribute to symptom perpetuation. Epstein-Barr virus (EBV), which was first isolated by Epstein, Barr and Achong (1964) from a cultured Burkitt's lymphoma lymphoblast cell line, is the etiological agent for infectious mononucleosis (IM), polyclonal and oligoclonal lymphomas associated with primary and acquired immunodeficiencies, and the complications of X-linked lymphoproliferative syndrome (XLP) (Cantani and Mastrantoni, 1989; Englund, 1988; Ernberg et al., 1990; Jones and Straus, 1987; Okano et a1., 1988; Purtilo, 1987; Purti1o et a1., 1981; Rowe et al., 1986; Saemundsen et al., 1981) and nasopharyngeal cancer (Pearson et al., 1984). Furthermore, people who have had IM have higher rates of subsequent development of malignant lymphoproliferative disorders (Abo et al., 1982; Snydman et al., 1982) and Hodgkin's disease (Green et al., 1979; Mueller, 1987; Poppema et al., 1985; Weiss et al., 1989), while patients with XLP have a higher incidence of non-Hodgkin's malignant lymphoma (Harrington et al., 1987).

The precise role of EBV in these diseases or in CFS is not well understood. Nonetheless, it is known that EBV infection triggers the formation of heterophile antibodies that, for many decades, have formed the basis for serologic diagnosis of IM.

In this review, we discuss the discovery, species variation, and structure of the erythrocyte membrane-associated Paul-Bunnell (PB) heterophile antibody determinant, its implications to IM diagnosis, and its potential contribution to defective immune surveillance, such as that seen in chronic fatigue syndrome.

KEYWORDS. Epstein-Barr virus, chronic fatigue syndrome, infectious mononucleosis, T-cell proliferation, Hodgkin's disease


Herpesviruses (Epstein-Barr virus, cytomegalovirus, human herpes virus types 6 and 7, herpes simplex virus types 1 and 2) have been associated with chronic fatigue syndrome (CFS). For instance, reactivation/replication of a latent herpesvirus (such as Epstein-Barr virus) could modulate the immune system to induce CFS (Glaser and Kiecolt-Glaser, 1998). In this respect, serologically proven acute infectious illness due to Epstein-Barr virus (EBV) is associated with a range of nonspecific somatic and psychological symptoms, particularly fatigue and malaise rather than anxiety and depression (Bennett et al., 1998). Although improvement in several symptoms occurs rapidly, fatigue commonly remains a prominent complaint at 4 weeks, and resolution of fatigue is associated with improvement in cell-mediated immunity. A prospective cohort study of 250 primary care patients also revealed a higher incidence and longer duration of an acute fatigue syndrome, and a higher prevalence of CFS, after glandular fever as compared to after an ordinary upper respiratory tract infection (White et al., 1998). In another study, anti-EBV titers were higher among CFS patients and were associated with being more symptomatic (Schmaling et al., 1996). However, testing of 548 chronically fatigued, including patients with CFS, for antibodies to 13 viruses (herpes simplex virus 1 and 2, rubella, adenovirus, human herpesvirus 6, Epstein-Barr virus, cytomegalo- virus, and Coxsackie B virus, types 1-6 in patients) found no consistent differences in any of the seroprevalences compared with controls (Buchwald et al., 1996).

Cloned DNA obtained from the culture of an African green monkey simian cytomegalovirus-derived stealth virus contains multipie discrete regions of significant sequence homology to portions of known human cellular genes (Martin, 1998). The stealth virus has also been cultured from several CFS patients and a cytopathic stealth virus was also cultured from the cerebrospinal fluid of a nurse with CFS. The findings lend support to the possibility of replicative RNA forms of certain stealth viruses (Martin, 1997). Review of the clinical histories and brain biopsy findings of 3 patients with severe stealth virus encephalopathy showed that the patients initially developed symptoms consistent with CFS (Martin, 1996a). One patient has remained in a vegetative state for several years, while the other two patients have shown significant, although incomplete, recovery. Histological and electron-microscopic studies revealed vacuolated cells with distorted nuclei and various cytoplasmic inclusio ns suggestive of incomplete viral expression. There was no significant inflammatory response. Viral cultures provided further evidence of stealth viral infections occurring in these patients (Martin, 1996a). Partial sequencing of a stealth virus segments isolated from a CFS patient revealed a fragmented genome and sequence microheterogeneity, which suggest that both the processivity and the fidelity of replication of the viral genome are defective (Martin, 1996b). An unstable viral genome may provide a potential mechanism of recovery from stealth viral illness.

Some studies suggest an association between human herpesvirus-6 (HHV -6) (Roseolovirus genus of the betaherpesvirus subfamily) and CFS (Braun et al., 1997; Cuende et al., 1997; Marsh et al., 1996; Tripathy et al., 1996). One study found that a high proportion (50% by antibody testing and up to 80% by nested-PCR detection of viral DNA but not RNA) of CFS patients were infected with HHV-6 but with low viral load. The latter results do not support HHV-6 reactivation in CFS patients (Cuende et al., 1997). Use of the supernatant fluid from HHV-7 infected cells as antigen in immunoassays yielded high and low HHV-7 antibody in sera from chronic fatigue patients and healthy donors as controls, respectively (Ablashi et al., 1998).

Transfer factors (TF) with specific activity against herpesviruses have been documented in CFS. With some studies suggesting that persistent viral activity may play a role in perpetuation of CFS symptoms, there appears to be a rationale for the use of TF in patients with CFS, and recent reports have suggested that transfer factor may play a beneficial role in this disorder (Ablashi et al., 1996; De Vinci et al., 1996; Hana et al., 1996; Levine, 1996). For instance, specific HHV-6 TF preparation, administered to two CFS patients, inhibited the HHV-6 infection (Ab1ashi et al., 1996). Prior to treatment, both patients exhibited an activated HHV-6 infection. TF treatment significantly improved the clinical manifestations of CFS in one patient who resumed normal duties within weeks, whereas no clinical improvement was observed in the second patient. Of the 20 patients in a placebo-controlled trial of oral TF, improvement was observed in 12 patients, generally within 3-6 weeks of beginn ing treatment (De Vinci et al., 1996). However, in this study herpes virus serology (EBV and HHV-6) seldom correlated with clinical response. Treatment with TF of a group of 222 patients suffering from cellular immunodeficiency (CID), frequently combined with CFS and/or chronic viral infections by EBV and/or CMV, showed that age but not gender substantially influenced the failure rate of CID treatment using TF (Hana et al., 1996). In older people, it is easier to improve the clinical condition than CID: this may be related to the diminished number of lymphocytes; however, a placebo effect cannot be totally excluded.

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