James F. Jones

T-Cell Lymphomas Containing Epstein–Barr Viral DNA in Patients with Chronic Epstein–Barr Virus Infections

Fatal T-cell lymphomas developed in three patients with a chronic illness manifested by fever, pneumonia, dysgammaglobulinemia, hematologic abnormalities, and extraordinarily high titers of antibody to the Epstein-Barr virus (EBV) capsid antigen (greater than 10,000) and early antigen (greater than 640) but low titers to the EBV nuclear antigen (less than or equal to 40). To understand the pathogenesis of these tumors better, we determined the immunophenotype of the tumor cells and analyzed tumor-cell DNA for EBV genomes and for lymphoid-cell gene rearrangements. More than 80 percent of the cells in tumors had an activated helper T-cell phenotype (T4, T11, la positive). The EBV genome was found by in situ hybridization in tumor tissue from each patient. Southern blot assay of DNA digests from one patient showed the same pattern as that of the EBV-infected marmoset line, B95-8. DNA digests from two patients showed a monoclonal proliferation of T cells determined on the basis of uniform T-cell-receptor gene rearrangements and a single band for the joined termini of the EBV genome. We conclude that EBV may infect T cells and contribute to lymphomas in selected patients with severe EBV infections.

An Anomaly of Neutrophil Morphology with Impaired Function

Abstract Neutrophils from a boy with recurrent bacterial infections since infancy were found to have unique morphologic abnormalities. The nuclei were bilobed, and the cytoplasm appeared nearly dev...

Correlation between allergy and persistent Epstein-Barr virus infections in chronic-active Epstein-Barr virus-infected patients.

Forty-six anti-Epstein Barr nuclear antigen-positive allergic patients, 11 of whom having clinical and laboratory evidence of chronic-active Epstein-Barr virus (CA-EBV) infections, were characterized by EBV serology, percentages of T cells, B cells, and IgE+ cells, serum levels of IgE, and allergen-induced responsiveness of lymphocytes. Results demonstrated patients with CA-EBV have significantly increased responsiveness toward specific allergens, responses toward greater numbers of allergens, numbers of IgE+ T and B cells, and levels of background DNA activity in nonstimulated lymphocytes than do subjects who suffer from allergies in the absence of the CA-EBV syndrome. Further comparison between subjects with laboratory-determined mild and moderate allergy and those with CA-EBV demonstrated a progressive increase in the serum levels of IgE as the degree of allergy increased, no difference in concentrations of T and B cells, and titers of anti-viral capsid antigen and anti-early antigen to be significantly greater in patients with CA-EBV. Statistical analysis demonstrated that patients with CA-EBV could be separated from subjects with allergies by metabolic and immunologic variables. The data suggested that allergen-induced responses may contribute to the CA-EBV syndrome.

Interactions between Human Neutrophils and Vaccinia Virus: Induction of Oxidative Metabolism and Virus Inactivation

Summary: The possible role of human neutrophils (PMN) as direct effector cells against free live virus particles was tested in vitro. Oxygen consumption, production of chemiluminescence and “virus killing” by PMNs was examined during and after incubation of cells and live or dead vaccinia virus with and without specific antibody. Oxygen consumption and chemiluminescence production occurred with unopsonized live but not with inactivated virus and was greatly enhanced with opsonization. Virus titers were determined in PMN-free supernatant and freeze-thawed cell pellet fractions after 15 min incubation. Reduction in titer from virus control was seen in supernatant fractions with and without opsonins, but in the cell fraction only with opsonins; the degree of reduction with opsonins was directly related to the opsonin source. PMNs from a patient with chronic granulomatous disease did not inhibit virus replication. These data suggest an active role for human PMNs in the genesis of and defense against virus infections and indicate areas for further investigation.Speculation: Human neutrophils may play a role in the pathogenesis of and control of virus infections.

The effect of in vivo dexamethasone on lymphocyte subpopulations: differential response of EAhu rosette-forming cells.

The purpose of this study was to compare the differential effect of dexamethasone on “third population” lymphocytes with its effect on B and T lymphocytes. Five human volunteers were given a single oral dose of dexamethasone (6–8 mg). Samples were evaluated prior to the drug, 5 hr after drug ingestion and 24 hr following the poststeroid sample. Surface marker studies included SIg, EAC rosettes, mouse rosettes, EAhu (Ripley) rosettes, total E-rosette-forming lymphocytes, Tμ lymphocytes, and Tγ lymphocytes. Functional studies included mitogen stimulation with phytohemagglutinin, concanavalin A, and pokeweed and antigen stimulation with herpes simplex virus and Candida albicans. At the nadir of the steroid-induced lymphopenia absolute counts for all B-cell markers were decreased. No differential effects were noted in SIg using polyvalent, IgM, IgG, κ, or λ antisera. Total T lymphocytes decreased 55% (P < 0.05). There was a differential effect on Tμ and Tγ subsets and the former were significantly decreased. Unlike other lymphocyte subpopulations, cells with high avidity Fc receptors for IgG molecules, i.e., EAhu (Ripley)-rosette-forming and Tγ lymphocytes, were unresponsive to steroid treatment. EAhu (Ripley)-rosette-forming lymphocytes increased from a baseline value of 15 to 28% after dexamethasone ingestion but absolute cell counts remained essentially unchanged with a mean baseline value of 287/μl compared with a poststeroid count of 250/μl. A rebound phenomenon was noted for B, T, Tμ, and Tγ lymphocytes (P < 0.05). Functional studies of the peripheral blood mixture of lymphocytes at the nadir of the lymphopenia showed significantly suppressed responses to both mitogens and antigens.

Specific allergen-induced Epstein-Barr nuclear antigen-positive B cells from patients with chronic-active Epstein-Barr virus infections

Enriched B cells and peripheral blood lymphocytes from patients with chronic-active Epstein-Barr virus (CA-EBV) infections and subjects with mild and moderate allergies were cultured in vitro with specific allergens known to cause allergic reactions. A significant increase in Epstein-Barr nuclear antigen+ cells occurred only in the B cells obtained from patients with CA-EBV when cells were stimulated with the specific antigen. Results indicate an association between EBV-transformed cells and B cells with idiotypic expressions and may help to explain the association between CA-EBV and allergy in these patients.

Results of a thymic epithelial transplant in a child with Wiskott-Aldrich syndrome and central nervous system lymphoma.

Abstract A 3-year-old boy with Wiskott-Aldrich syndrome who was treated with transfer factor since early infancy developed primary central nervous system lymphoma. After an initial favorable response to radiation therapy, the lymphoma recurred but improved after chemotherapy. A thymic epithelial transplant was performed that resulted in clinical improvement in his eczema, a decrease in serum IgE, and an increase in E-rosette-positive cells in the peripheral blood. The transplant produced no improvement in antibody response to polysaccharide antigen, skin test reactivity, or in the level of thrombocytopenia. The duration of remission of the lymphoma after treatment with chemotherapy plus thymic epithelial transplantation was greater than that achieved with radiation therapy alone.

Serum Interferon in Navajo Children with Severe Combined Immunodeficiency Disease Inhibits Lymphoblastogenesis

Two Navajo Indian children with severe combined immunodeficiency disease (SCID) lost reconstituted immune function after virus infections. A serum factor which inhibited normal lymphocyte response to mitogens was found in one of them and led to the examination of sera from five other Navajos with SCID. Mean inhibition by six Navajo sera was 67%; no inhibitor was found in sera from normal adults and children. The inhibitor activity was nondialyzable and heat stable, yet partially sensitive to pH 2.0, suggesting that interferon(s) was present. Interferon (IFN) activity in patient sera ranged from 10 to 300 U/ml. Normal children had peak serum IFN levels of 100 and 30 U/ml in the acute and convalescent periods, respectively, of virus infections. IFNα, IFNβ, and IFNγ were identified in SCID sera by specific antisera. Both inhibitor and IFN activities in three Navajo sera were 88–95 and 89–100%, respectively, removed with anti-IFN antisera. Similar patterns of inhibition of lymphoblastogenesis were seen with IFN standards. IFN levels in the SCID patients did not correlate with documented infections; elevated levels were present when no infections could be documented. The immunologic imbalances in some forms of SCID may be related to circulating inhibitors, possibly interferon.

Deficiency of UV-induced excision repair in human thymocytes

The capacity of human thymocytes and of differentiated lymphocytes circulating in peripheral blood to perform unscheduled DNA synthesis (a measure of nucleotide excision repair) after UV irradiation was measured by radioautographic analysis. Only 4% of immature T lymphocytes, but 68% of circulating lymphocytes exhibited unscheduled DNA synthesis. When UV sensitivity of peripheral blood lymphocytes and thymocytes from the same donor were compared, the thymocytes, in each case, were significantly more UV sensitive than were the circulating lymphocytes. Peripheral blood lymphocytes from subjects undergoing halothane and morphine anesthesia during surgery showed 56% less excision repair capacity than those from unanesthetized donors. The difference occurred in the number of cells capable of repair rather than in the extent of repair synthesis per cell. Ultraviolet-induced unscheduled DNA synthesis occurred in only 3% of the thymocytes removed from rats killed by cervical dislocation. Therefore, the deficiency of excision repair was observed in rat thymocytes which had not been affected by anesthesia or surgical trauma. Since the thymus contains more than 90% immature T-cells, our results indicate that immature T-cells are deficient in nucleotide excision repair whereas the majority of mature peripheral blood lymphocytes exhibit such repair.

T Cell Lymphomas in Patients with Chronic EBV Infection

EBV is classically associated with infectious mononucleosis, Burkitt’s lympyoma and nasopharyngeal carcinoma (1). More recently, this virus has been associated with development of B-cell lympyhomas in immunocompromised individuals (2). Many clinical illnesses which are not readily recognized as being due to or associated with EBV are missed because of lack of standard laboratory findings that physicians generally associate with infectious mononucleosis. One such group of patients have a severe chronic illness, associated with extraordinarily high anti-VCA (≥10,000) and EA (≥640) antibody titers (3).