Observations on Childhood Infections with the Epstein-Barr Virus
01 Mar 1970-The Journal of Infectious Diseases (Oxford University Press)-Vol. 121, Iss: 3, pp 303-310
TL;DR: Patients who develop IM were found to lack antibodies to EBV prior to illness and to form high levels of antibody during illness, often in rising titer.
Abstract: The Epstein-Barr virus (EBV), a member of the herpes group and first detected in cultures of Burkitt's lymphoma cells [1], has been identified as the probable cause of infectious mononucleosis (IM) [2-4]. Patients who develop IM were found to lack antibodies to EBV prior to illness and to form high levels of antibody during illness, often in rising titer. A history of typical IM could be elicited only from individuals with antibodies [5, 6], and the disease occurred only among laboratory technicians and students who had no antibodies at an earlier time [2-5, 7]. EBV appears to have a growth-stimulating effect on cultured peripheral leukocytes from antibodynegative, healthy donors [8-11], an observation which might explain the ready and rapid establishment of continuous lines of Mastoid cells from
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623 citations
TL;DR: Results obtained in a recent series of 90 patients with infectious mononucleosis are presented to show that an Epstein-Barr virus specific serodiagnosis can be established in most, if not all, cases, provided the most pertinent tests are performed.
500 citations
TL;DR: Comparative serum titration on acetone and ethanol‐fixed Raji‐EBV cell smears revealed that the transitory anti‐EA response observed in many IM patients was restricted almost exclusively to anti‐D, whereas such sera from NPC or BL patients usually gave positive reactions which in part, however, failed to conform with the R pattern.
Abstract: Examination of numerous sera from patients with infectious mononucleodis (IM), Burkitt's lymphoma (BL) or nasopharyngeal carcinoma (NPC) for antibodieh to Epstein-Barr virus (EBV) induced early antigens (EA) revealed two distinct patterns of immunofluorescence in abortively EBV-infected Raji cells. One showed diguse (D) staining of the nucleus and cytoplasm of invaded cells, the other (R) was restricted to masses in the cytoplasm. Although D- or R-reactive Raji cells became detectable at similar times after exposure to EBV, the percentages of D-positive cells initially exceeded R-positive cells but ultimately both were nearly equal in number. R-positive cells almost invariably contained also D. In EBV-exposed RPM1 64–10 cells, frequently only D was synthesized. D antigen, in contrast to R, resisted fixation by methanol or ethanol, whereas R proved more resistant than D to proteolytic enzymes. Comparative serum titration on acetone, respectively ethanol-fixed Raji-EBV cell smears revealed that the transitory anti-EA response observed in many IM patients was restricted almost exclusively to anti-D. Anti-EA positive sera from NPC patients also showed dominantly anti-D activity whereas, in BL sera, anti-R was usually, but not always, dominant, often being the only antibody to the EA complex present. Preliminary tests with pronase-treated Raji-EBV cell smears indicated that dominantly anti-D reactive sera from IM patients were free of anti-R whereas such sera from NPC or BL patients usually gave positive reactions which in part, however, failed to conform with the R pattern. The possible implications of these results have been discussed.
322 citations
TL;DR: It is evident that the virus must be considered in the diagnosis of various acute neurologic diseases affecting children and young adults, even in the absence of heterophil-antibody response or other signs of infectious mononucleosis.
Abstract: Infectious mononucleosis has been associated with Guillain--Barre syndrome, Bell's palsy, meningoencephalitis and transverse myelitis. Since it is not known that many children with infectious mononucleosis do not develop heterophil antibodies, we looked for evidence of current or recent Epstein-Barr virus infection in young patients with these neurologic diseases by using serodiagnostic procedures for detection and titration of antibodies to various antigens related to Epstein-Barr virus. Seven of 24 cases with Guillain-Barre syndrome and three of 16 with facial palsy were definitely associated with primary infection with Epstein-Barr virus as were two cases each of the other two neurologic diseases. Only one of these patients had obvious clinical infectious mononucleosis, and only a few demonstrated heterophil agglutinins. It is evident that the virus must be considered in the diagnosis of various acute neurologic diseases affecting children and young adults, even in the absence of heterophil-antibody response or other signs of infectious mononucleosis.
249 citations
TL;DR: The persistence of these viral genomes in all malignant cells, yet with the expression of limited latent genes, is consistent with the notion that EBV latent genes are important for malignant cell growth.
Abstract: Latent Epstein–Barr virus (EBV) infection has a substantial role in causing many human disorders. The persistence of these viral genomes in all malignant cells, yet with the expression of limited latent genes, is consistent with the notion that EBV latent genes are important for malignant cell growth. While the EBV-encoded nuclear antigen-1 (EBNA-1) and latent membrane protein-2A (LMP-2A) are critical, the EBNA-leader proteins, EBNA-2, EBNA-3A, EBNA-3C and LMP-1, are individually essential for in vitro transformation of primary B cells to lymphoblastoid cell lines. EBV-encoded RNAs and EBNA-3Bs are dispensable. In this review, the roles of EBV latent genes are summarized.
242 citations
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TL;DR: Indirect immunofluorescence tests led to the brilliant staining of a small proportion of the cells in five different cultures derived from Burkitt's (African) lymphomas, and several observations suggest that the stainable cells might be those which are seen to harbor virus particles under the electron microscope.
Abstract: Henle, Gertrude (Children's Hospital of Philadelphia, Philadelphia, Pa.), and Werner Henle. Immunofluorescence in cells derived from Burkitt's lymphoma. J. Bacteriol. 91:1248-1256. 1966.-Indirect immunofluorescence tests led to the brilliant staining of a small proportion of the cells in five different cultures derived from Burkitt's (African) lymphomas. The reaction was not restricted to the 17 sera from cases of this disease but extended to many sera from American individuals, whether healthy donors or patients suffering from a variety of illnesses. The incidence of positive sera increased with age from about 30% in childhood to > 90% in adults. Fluorescein-isothiocyanate-conjugated human gamma-globulins were suitable for direct staining of the same proportion of cells. The stained cells appeared to be in varying stages of degeneration, but cultural conditions leading to an increase in the cellular death rates failed to result in a rise in fluorescent cells. Several observations suggest that the stainable cells might be those which are seen to harbor virus particles under the electron microscope. Two cell lines derived from leukemic patients in this country also contained a small fraction of stainable cells but two others, and numerous primary human leukocyte cultures, gave consistently negative results. Attempts to relate the staining to known viral antigens have failed to implicate herpes simplex, varicella, cytomegalo, and reo viruses types 1, 2, and 3. The nature of the virus carried by the lymphoma cells as well as of the staining reactions remains to be determined.
1,363 citations
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TL;DR: It is indicated that EBV is related to, and probably the cause of, infectious mononucleosis, and that the agent has a world-wide dissemination.
Abstract: A herpes-type virus has been detected with remarkable frequency in cell lines derived from Burkitt's lymphomas, leukemic tissues, or buffy coats of a variety of patients and healthy donors.'-8 This agent is being named EB virus (EBV), for convenience, after the cell lines in which it was first observed.' M\\ost of the virus particles seen by electron microscopy in a small proportion of the cells are judged noninfectious because they are defective.\" 9. 10 To date, EBV has been transmissible only to cultured human cells of the hematopoietic system.\"'12 Virus-producing cells are readily detectable by indirect immunofluorescence tests with various human sera or by direct staining with fluorescein isothiocyanate-conjugated human y-globulins.'3'-7 Attempts to identify the agent by appropriate virus-specific immunofluorescence tests have failed. Thus EBV appears to be a new member of the herpes group.'3-\"5 From human serum surveys it is evident that infections by EBV, or a close relative of it, are frequent, and that the agent has a world-wide dissemination.\"3 117, 18 The age distribution of antibodies to EBV among American children parallels that of antibodies to other common viruses, such as measles, mumps, or poliomyelitis in the prevaccination era. 18 Except for the fact that all Burkitt's tumor patients studied thus far'3 1' and a high percentage of patients with carcinomas of the postnasal spaces'9 were found to have high titers of antibodies to EBV antigens, no other suggestive relationship of the virus to known disease entities has been recorded. The present report indicates that EBV is related to, and probably the cause of, infectious mononucleosis. Materials and Methods.-The techniques for growth and maintenance of cell lines derived from Burkitt's tumors have been described, as well as the procedures for preparation of cell smears, detection of EB virus antigens, and corresponding antibodies by immunofluorescence.3, 16 Cells of the EB-3 line were routinely used, which had been kept for 4-7 days on arginine-deficient Eagle's basal medium with 25% fetal calf serum (BME25) obtained by preincubation at 370C for 7 days or merely by omission of the amino acid. The arginine deficiency inhibits cellular growth but increases the number of EBV antigen-producing cells by a factor of 5-10 (to be published). Results.-The indirect immunofluorescence test for antibodies to EB virus was used in a search for illnesses that might be caused by this agent. In one series of tests, paired acute stage and convalescent sera from pediatric patients with unidentifiable viral infections were examined with negative results.18 As another approach, serial sera were tested that had been collected from children in prospective studies of viral infections. Such sets of sera were kindly supplied by Dr. John P. Fox from the \"New York Virus Watch,\" and by Dr. John H. Dingle from the Cleveland Family Study. Of the first group, 33 sets were examined that had been collected over periods of from one to four
1,128 citations
"Observations on Childhood Infection..." refers background in this paper
...Thus the diagnostic value of the anti-EBV test is restricted, in that significant 4-fold or greater rises in antibodies are observed only in a limited number of patients [2]....
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...Sera from the prospective study on IM at Yale University were instrumental in relating EBV to IM [2, 3]....
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...It is among these that IM occurs subsequently [2, 3,7]....
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...for antibodies to EBV [2, 5]....
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...This hypothesis appears to be supported by the fact that numerous children from poor environments possess antibodies to EBV at an early age [22], whereas 5096-7096 of college students entering Yale University were found to lack antibodies as yet [2, 3, 7]....
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TL;DR: Cell lines established from hematopoietic cells from two staff members with no known malignant disease contained a herpetic-like virus (leukovirus), produced immunoglobulins, and grew rapidly in various suspension cultures.
Abstract: Rapidly growing and apparently permanent cultures were established from hematopoietic cells from two staff members with no known malignant disease. The cell lines were similar to those derived from leukocytes from the peripheral blood of patients with malignancies of either hematopoietic or nonhematopoietic origin and to the lymphoblastoid cell lines derived from Burkitt's lymphoma. Both cell lines contained a herpetic-like virus (leukovirus), produced immunoglobulins, and grew rapidly in various suspension cultures.
797 citations
"Observations on Childhood Infection..." refers background in this paper
...in cultures of leukocytes from healthy donors or patients with various diseases [15-20]....
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TL;DR: Herpes-type viral antigen and C-group chromosomal marker previously described in cultured Burkitt cells were found in all of the female cell cultures that were obtained.
Abstract: Cultured cells derived from male patients with Burkitt's lymphoma and harboring herpes-type virus particles were lethally irradiated. These irradiated cells induced normal peripheral leukocytes of female infants to grow within 2 to 4 weeks after mixed cultivation. Cells of a line free of this agent failed to stimulate growth. If either type of cell was cultured separately, it did not survive under the experimental conditions. Herpes-type viral antigen and C-group chromosomal marker previously described in cultured Burkitt cells were found in all of the female cell cultures that were obtained.
570 citations
"Observations on Childhood Infection..." refers background in this paper
...EBV appears to have a growth-stimulating effect on cultured peripheral leukocytes from antibodynegative, healthy donors [8-11], an observation which might explain the ready and rapid establishment of continuous lines of Mastoid cells from...
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TL;DR: Observations strongly indicate that EB virus, or a closely related one, is the etiologic agent of IM.
Abstract: In each of 29 patients with infectious mononucleosis (IM) the development of antibodies against a herpes-type virus (EB virus) has been demonstrated by an indirect immunofluorescence test with a virus bearing cell line (EB-3) derived from a Burkitt lymphoma. These antibodies, absent in pre-illness serum specimens, usually appeared early in the disease, rose to peak levels within a few weeks, and remained at relatively high levels during convalescence. They are clearly distinctive from heterophile antibodies and, unlike the latter, they persist for years, probably for life. Tests on sera from 50 randomly selected college freshmen revealed EB virus antibodies in 12, two of whom had positive histories of IM. Of 38 without demonstrable antibodies none had had IM, but the illness developed in three in the next two years. These and other observations strongly indicate that EB virus, or a closely related one, is the etiologic agent of IM.
387 citations
"Observations on Childhood Infection..." refers background in this paper
...Sera from the prospective study on IM at Yale University were instrumental in relating EBV to IM [2, 3]....
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...The data reaffirmed [3, 5] that antibodies to...
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...of the persistence of antibody levels observed here and previously [3], a mislabeling of the one positive serum seems to be the most probable explanation, although the possibility of a transitory cross-reacting antibody response due to infection by another member of the herpes group has not been excluded....
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...It is among these that IM occurs subsequently [2, 3,7]....
[...]
...This hypothesis appears to be supported by the fact that numerous children from poor environments possess antibodies to EBV at an early age [22], whereas 5096-7096 of college students entering Yale University were found to lack antibodies as yet [2, 3, 7]....
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