Infectious mononucleosis is caused by the Epstein-Barr virus (EBV), an unusual human pathogen because it preferentially infects B lymphocytes and consequently activates them to produce immunoglobulins. When cultures of lymphocytes from patients with infectious mononucleosis were stimulated with polyclonal activators, unseparated cells failed to produce immunoglobulins, whereas purified B cells responded normally. Cocultures demonstrated profound suppressor T-cell activity in blood from patients with infectious mononucleosis. Early in this disease, circulating immunoglobulin-secreting cells were elevated, but during the second week their number was strikingly depressed. These data indicate that during infectious mononucleosis, EBV causes polyclonal activation of B cells, reflected by hypergammaglobulinemia and increased circulating immunoglobulin-secreting cells. Next, suppressor T cells become activated and inhibit further B-cell activation. Thus, activation of suppressor T cells in infectious mononucleosis provides a unique additional mechanism of host defense because these T cells inhibit the activation and proliferation of an important target of the causative virus.

A B S T R A C T The functional maturity of T and B lymphocyte populations from human newborns was evaluated using a reverse hemolytic plaque assay to detect immunoglobulin-secreting cells generated in in vitro cultures stimulated with pokeweed mitogen (PWM), a T cell-dependent polyclonal activator, and the Epstein-Barr virus (EBV), a T cell-independent B cell activator. Cord blood lymphocytes failed to produce immunoglobulin in response to PWM, but did respond with immunoglobulin synthesis to stimulation with EBV. Co-culture experiments demonstrated that cord blood T cells would inhibit immunoglobulin production by adult cells stimulated with PWM, but not with EBV. Cord blood T cells did suppress immunoglobulin production by cord blood B cells when stimulated with a mixture of EBV and PWM, indicating that cord blood, in contrast to adult blood, contains a population of suppressor T cell precursors that are easily activated by PWM. Irradiation of the cord blood T cells with 2,000 rad eliminated the suppressor activity and revealed normal helper function for immunoglobulin (Ig) G, A, and M when these T cells were co-cultured with adult B cells. Cord blood B cells co-cultured with adult T cells or irradiated cord blood T cells did produce immunoglobulin in response to PWM, but the response was significantly lower than that of adult B cells, and only IgM was produced in these cultures. These studies demonstrate that both the T and B cells of the human newborn have significant functional differences compared with the functions of T and B lymphocyte populations in adults. INTRODUCTION The immune status of the human neonate has been the subject of intense investigation for many years.

A B S T R A C T The direct effects of steroid hormones on the production of immunoglobulins and DNA synthesis by human T and B lymphocytes was evaluated in cultures of peripheral blood mononuclear cells. As detected by a reverse hemolytic plaque assay, the addition of 0.1 mM to 10 nM hydrocortisone to lymphocytes in culture in the absence of other stimulants or mitogens, resulted in the dramatic induction of immunoglobulin production with responses comparable to those seen in similar cultures stimulated with pokeweed mitogen. Steroid-stimulated immunoglobulin production was first seen after 48 h and peaked at 8-10 d of culture. The production of IgG, IgA, and IgM was induced following incubation with steroid. Glucocorticoids, but not estrogens or androgens, were capable of mediating this effect, and only compounds with affinity for the glucocorticoid receptor were active. The induction of immunoglobulin production was dependent on both T cells and monocytes; cultures depleted of either cell type did not produce immunoglobulin when stimulated with glucocorticoid hormones. Proliferation of B cells or T cells could not be detected by [3H]thymidine incorporation or total cell recovery from steroid-stimulated cultures, even though such cultures demonstrated marked increases in immunoglobulin production. The mechanism responsible for this functional maturation of B cells to become high rate immunoglobulin producing cells is as yet undefined, although it appears to involve more than merely steroid mediated inactivation of suppressor T cells.

The chicken provides a unique model to study mechanisms of humoral immune responsiveness since agammaglobulinemia can be readily induced in birds by a variety of procedures which result in removal or ablation of the bursa of Fabricius and post bursal peripheral lymphoid cells during embryonic or early extraembryonic life. During the course of experiments utilizing adoptive cell transfer to study the effect of cells from immune agammaglobulinemic chickens on the subsequent immune response of normal birds, it was unexpectedly found that adult normal chickens receiving bone marrow cells from 4-too old agammaglobulinemic donors subsequently developed progressive humoral immunodeficiency and agammaglobulinemia. Materials and MethodsNewly hatched line 6, subline 1 chicks, 1 homozygous at the major histocompatibility locus (BTBT) were surgically bursectomized 1 day after hatching. Normal and bursectomized chicks were then given 550 R whole body X-irradiation. Following this treatment approximately 85% of the bursectomized birds are agammaglobulinemic at 10 wk of age as determined by loss of detectable serum immunoglobulin (less than ¼~0 of the adult normal IgG level). In addition their spleens lack B lymphocytes detectable by either indirect immunofluorescence with rabbit antichicken L chain or antichicken 3,-and t~-chain antisera (1). Irradiated unoperated birds develop normal immunoglobulin levels and have normal numbers of B lymphocytes.Serum immunoglobulin levels were determined by radial diffusion in agarose-containing rabbit antisera specific for chicken ~,-or #-immunoglobulin heavy chains. Results are expressed as a percentage of the value obtained with a standard pool of adult chicken serum. Lower limits of detection are 1% for IgM and 0.1% for IgG. Serum antibody to KLH was determined in microtiter by passive hemagglutination of KLH-coated chicken erythroeytes using chromic chloride (2) as the coupling agent.Bone marrow was obtained from previously heparinized donor birds (500 tt) by flushing the long bones with balanced salt solution. A single cell suspension was prepared by consecutively drawing the bone marrow into syringes fitted with 16, 19, 22, and 25 gauge needles. 1Chickens were obtained from Dr. Howard Stone at the USDA Regional Poultry Research Laboratory, East Lansing, Mich. This strain of chicken was bred in closed families from 1939 until 1962 when strict brother-sister inbreeding procedures were instituted which are now in their 12th generation. When extensively studied in 1969, these birds were homozygous for the B7 allele at the major histocompatibility locus as well as homozygous at RBC alleles A,, E~, Cs, D,, H2, I2, L~, and P4.