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In the preceding paper a population of lymphoid cells was identified which (1) were derived from germinal centres in the appendix, (2) were localized in follicular structures elsewhere, and (3) could perform as antibody-forming cell precursors. The present paper presents evidence (1) that germinal centres in the spleen and lymph nodes perform the same function as germinal centres in the appendix, and (2) that germinal centres are dependent upon a stream of cells derived from the bone marrow. A new hypothesis is put forward regarding the origin and cellular kinetics of the B-cell system in mammals. It is proposed that germinal centres throughout the body function as an essentially antigen-dependent amplification system for the B-cell population of lymphocytes. Implications of this hypothesis are discussed. [ABSTRACT FROM AUTHOR]

Mitogen-transformed human peripheral blood lymphocytes and tonsil blasts were examined by rosette formation to detect the presence of membrane-bound immunoglobulin (Ig) and surface receptors for fixed IgG and fixed C3. In addition, the capacity of these cells to rosette with sheep erythrocytes was evaluated as a reaction characteristic of T lymphocytes. In order for clear morphological recognition of the rosetting transformed lymphocytes and the rosetting tonsil blasts a cytocentrifuge technique was developed and used in conjunction with autoradiography and/or with Romanowsky stains. Using these techniques and the culture methods described in this paper phytohaemagglutinin, pokeweed mitogen, streptococcal filtrates and purified protein derivative stimulated predominantly T cells in the peripheral blood of man. A minority of the transformed cells in these mitogen-stimulated cultures (<24%) did rosette with B lymphocyte markers and presumably represent a B-cell response. No significant differences were found between the T- or B-cell specificity of the mitogens investigated. Lymphoid preparations from tonsils excised from normal donors with recurrent tonsillitis were found to contain 6-15% lymphoblasts and the iarge majority of these cells formed rosettes with the B-cell markers, less than 20% of these lymphoblasts formed spontaneous sheep erythrocyte rosettes. Using a mixed rosetting technique a small proportion (<5%) of PHA-transformed cells and tonsil lymphoblasts were found to have combined sheep Fc or combined sheep C3 receptors. The investigation of B- and T-lymphocyte surface markers on mitogentransformed lymphocytes was extended to neopiastic lymphocyte populations and it was found that the majority of transformed cells (>70%) present in chronic lymphocytic leukaemia cultures stimulated with PHA after 6 days incubation were transformed T lymphocytes. [ABSTRACT FROM AUTHOR]

Bone marrow cells and thymus cells were observed in cell transfer expehments to collaborate in the production of anti-BSA antibodies. The target cells for tolerance induction either with a 'low dose' of antigen (100 µg of deaggregated BSA once a week × 5) or with a 'high dose' (a single injection of 5000 µg) were identified by the same technique. In 'low dose' tolerance, some indication was obtained that thymus-derived cells in peripheral lymphoid systems were the target cells; bone marrow-derived cells appeared not to be so susceptible, and the cells residing in thymus or bone marrow seemed to remain unimpaired, in contrast, the injection of a 'high dose' of tolerogen rendered both types of cells in spleen, thymus cells and bone marrow cells, unresponsive or hyporesponsive in parallel with one another. [ABSTRACT FROM AUTHOR]

Human peripheral lymphocyte preparations were tested with a mixed rosette method for the presence of lymphocytes bearing both the complement receptors characteristic of B lymphocytes, anti the capacity of T lymphocytes to spontaneously bind with sheep red blood cells (SR BC). The large and oval shaped pigeon red blood cells (PRBC) which do not form T-cell rosettes were utilized as indicators for rosette formation with the complement receptor-bearing B cell. In every individual (an average of 2.06%) lymphocytes were observed which formed rosettes with both SRBC' and PRBC indicators. These findings show that independent markers for both T and B cells may be present on the surface of the same lymphocytes. [ABSTRACT FROM AUTHOR]

Mononuclear cell separated from the blood in fourteen cases of infectious mononucleosis at various intervals from the onset were tested for the presence of surface immunoglobulin and for ability to form spontaneous rosettes with washed sheep red blood cells. The mononucleosis during the acute phase of the illness consisted largely of T lymphocytosis. The absolute count of T lymphocytes returned to the normal range approximately 2 months after the onset of the illness. B cells (bearing surface immunoglobulin) were only slightly increased in the acute phase. In four cases appreciable numbers of fluorescent resetting cells were also present, and investigation suggested that these were T cells coated with anti-T-cell autoantibody. During the first 2 weeks of the illness responsiveness to phytohaemagglutinin was severely depressed, but thereafter returned towards normal. It is thought likely that in infectious mononucleosis the vast majority of atypical mononuclear cells are T cells proliferating in response to E-B virus-infected B cells, and cytotoxic towards them. [ABSTRACT FROM AUTHOR]

By using T cell-deprived mice and appropriate controls it has been shown that the adjuvant activity of LPS on the immune response to different doses of SRBC, tends to be oriented more towards B cells than towards T cells. In contrast, lentinan seems to mediate its adjuvant activity largely through a stimulatory effect on helper T cells. [ABSTRACT FROM AUTHOR]

In an investigation of the immunosuppression associated with trypanosomiasis, the thymus-derived lymphocytes (T cells) and the thymus-independent lymphocytes (B cells) in mice with subacute Trypanosoma brucei infections were studied. It was shown that: (a) there was a massive plasma cell response in lymph nodes and spleen which replaced the thymus-dependent areas; (b) a failure of antibody production at the cellular level occurred as shown by the absence of IgM PFC responses to SRBC and lipopolysaccharide; (c) T cells appeared relatively normal as judged by their ability to proliferate following a primary stimulus with oxazolone unless measured during the terminal stages of the disease; (d) immune competence was rapidly restored after treatment with a trypanocidal drug. It appeared that immunosuppression was closely associated with the presence of living trypanosomes, possibly mediated through a B-cell defect. The mechanism whereby this might occur is discussed. [ABSTRACT FROM AUTHOR]

The induction in mice of a humoral immune response to intact sheep erythrocytes, both in vivo and in vitro, requires participation of thymus-derived (T) lymphocytes. In an in vitro system, spleen cells from both neonatally thymectomized and adult thymectomized irradiated bone marrow protected mice were successfully immunized, using washed sonicated sheep erythrocyte membrane fragments as antigen. This obviation of the requirement for T lymphocytes in the immune response, coupled with previous work on macrophage independence, indicates that sonicated membrane fragments were capable of directly immunizing bone marrow-derived (B) lymphocytes in vitro. These results further confirm the signal importance of antigenic structure in determining the cellular requirements for an immunological response; whereas antigens of particulate or monomeric form require the presence of both T cells and macrophages, polymeric antigens of intermediate size such as polymerized flagellin and sonicated sheep erythrocyte membranes require neither of these accessory cells. The results caution against the use of erythrocytes as models of thymus-dependent antigens. The data further suggest that reports of late antibody responses of relatively normal magnitude in thymectomized animals given larger doses of heterologous erythrocytes may have been due to direct immunization of B lymphocytes by degraded erythrocyte antigen. [ABSTRACT FROM AUTHOR]

Surface immunoglobulin can be demonstrated on almost all sheep erythrocyte rosette-forming cells in CBA and AKR mice, either by inhibition of antigen binding by anti-immunoglobulin or by immunofluorescence. When surface immunoglobulin on a rosette-forming cell is `capped' by anti-immunoglobulin, the bound red cells migrate with the immunoglobulin, demonstrating that the receptor-combining site and immunoglobulin antigenic determinants share the same mobile unit in the membrane. These observations strongly support the concept that the antigen receptor is surface immunoglobulin (at least for B cells), and illustrate the usefulness of the `capping' technique for studying the associations between membrane elements. [ABSTRACT FROM AUTHOR]

Normal human lymphoblasioid cell lines, growing in continuous suspension culture, produce inhibitors of in vitro lymphocyte blastogenesis. The inhibitor reduces human lymphocyte blastogenic responses to phytohaemagglutinin, slreptolysin-O and the mixed lymphocyte culture 90-99%, is non-cytotoxic and can inhibit both newly initiated and on-going responses. The inhibitor is heat-stable at 80°C but labile at 100°C, non-dialysable and degraded by pronase but not DNase or RNase. It is species- and tissue-specific and does not inhibit the proliferation of mouse lymphocytes, human melanoma cells or human bone marrow in vitro colony-forming cells. Inhibitor was produced only under very specific conditions of crowding. Thus, maximal inhibitor production occurred at 5 × 106 lymphocytes per cm" culture surface area while only 0-5%, of the maximal amount was produced at 106 or 5 &tiems; 107 lymphoblasts per cm102. This data is relevant to the nature of feedback control of immunological reactions and may guide the development of new classes of immunosuppressants. [ABSTRACT FROM AUTHOR]

Phytohaemagglutinin transformation of normal lymphocytes was significantly inhibited by the plasma and by extracts of lymphocytes in six out of eight cases of untreated chronic lymphatic Ieukaemia compared with similar material from matched control patients. Since the concentration of inhibitor in lymphocytes was much greater than that in plasma and both inhibitors were thermolabile, it is possible that the plasma inhibitor may be produced by the leukaemic cells. These findings indicate modifications of normal T-ceIl function by constituents of neoplastic lymphocytes but the effect may be due to exaggeration of a normal mechanism in which the surface properties of T cells are modified by products of B cells. [ABSTRACT FROM AUTHOR]

The capacity of CBA mouse B lymphocytes to bind polyvalent rabbit anti-mouse immunoglobulin antibody, even when this reagent is present in low concentration, was used as an index of a lymphocyte's B cell status. Various mouse tissues were held for 30 minutes at 0° with 0·2 μg/ml of 125I-labelled anti-Ig, and smear preparations of washed cells were examined, following radioautography, for their content of B cells. The survey covered two areas of B cell differentiation, namely the spontaneous emergence of B cells in the mouse foetus, and the development of B cells in lethally irradiated mice that had received early foetal liver as a source of haematogenous stem cells. The foetal survey suggested a multifocal origin of B cells, commencing 3 days before birth, in all major sites of erythromyelopoiesis, namely liver, spleen and bone marrow. Lymph nodes showed B cells later than did these organs, and thymus contained virtually no B cells at any stage. A rapid influx of B cells into lymph nodes took place shortly after birth. The CBA mouse is born with somewhat over 105 B lymphocytes in toto, of which the majority are in liver, spleen and blood. The irradiation-recovery study showed: (1) that B cells are, statistically, more sensitive to high dose irradiation than T cells; (2) that a B cell-free stem cell source can repopulate the B cell pool; (3) that repopulation is surprisingly slow; and (4) that numerical and functional recovery of B cells parallel each other to a reasonable degree. The significance of the results is discussed from the viewpoints of lymphocyte differentiation and immunological tolerance. [ABSTRACT FROM AUTHOR]

The immunological response to native levan (a fructose homopolymer with molecular weight 2 × 107) has been studied in (DBA/1 × CBA-T6T6)F1 mice by passive hemagglutination and plaque-forming cell (PFC) assays. It resembles type-specific pneumococcal polysaccharide (SSS) in eliciting a prolonged humoral antibody response over a wide dose range (0.0001-100 µg) and in inducing longlasting 'high zone' tolerance with a single injection (1 mg or more). Other similarities include an exclusively IgM response, independence of synergy with thymusderived lymphocytes and absence of immunological memory. On the other hand, parallelism between serum hemagglutinin and PFC levels following all doses of antigen implies that higher immunizing doses of levan, unlike SSS, do not engage in peripheral neutralization of antibody. It was concluded from studying the fate of 14C-labelled levan that this was attributable to more rapid elimination from the circulation and subsequent slow metabolism of this polysaccharide. Levan also differs from SSS in inducing tolerance directly, without a detectable prior immune phase. [ABSTRACT FROM AUTHOR]

Summary, OS chickens were subjected to bursectomy, thymectomy, bursectomyX-irradiation and bursectomy-X-irradiation followed by restoration with autoIogous bursa cells. The influence on the spontaneously occurring tbyroiditis was studied. Less pronounced tbyroiditis and thyroglobulin antibody formation was found in the bursectomized and bursectomized-irradiated but not in the thymectomized chickens. Bursectomized-irradiated chickens which had been reconstituted with autologous bursa cell suspensions showed total restoration of the thyroiditis No restoration of thyroglobulin antibody forming capacity and only partial restoration of immunoglobulin level was observed. The results suggest a dual function of the bursa with regard to thyroid autoimmunity in OS chickens, one humoral and possibly hormonal, which is essential for thyroglobulin antibody formation and one cellular which is necessary for the development of the inflammatory lesions in the thyroid gland. [ABSTRACT FROM AUTHOR]

The histogram of electrophoretic mobilities (EPM) of normal rat lymph node cells indicates a heterogeneous population. It can be resolved into two independent components with Gaussian distribution profiles. These two, Class 'A' cells and Class 'B' cells have different mean EPM. Their response in vivo to an antigenic stimuIation also appears to be different. Neither the mean EPM nor the relative concentration of 'B' cells shows any change. The mean EPM of 'A' cells also remains constant but their relative concentration decreases significantly with a concomitant emergence of a new cell type with a much lower mean EPM. The relative concentration of this new cell type varies with time but its kinetics parallels that of the circulating antibody titre. [ABSTRACT FROM AUTHOR]

Anti-allotypic sera that have no known allotypic determinants other than those also present in the genotype of the lymphocyte donor are as able to induce lymphocyte ‘blast’ transformation in vitro as are anti-allotypic sera that do have allotypic determinants that are not present in the lymphocyte donor. Therefore, anti-allotypic sera do not appear to function in the stimulation of blast transformation by providing access for any of the known allotypic determinants into lymphocytes. [ABSTRACT FROM AUTHOR]

The presence of binding sites for concanavalin A, phytohaemagglutinin and lentil mitogen on the surface of mouse B and I lymphocytes has been investigated in relation to the previously described mitogenic selectivity of these stimulants for T cells. Purified T or B or mixed T/B suspensions of cells have been analysed both for proportions of cells with affinity for phytomitogens and for the relative density of binding sites. In addition, the specificity of mitogens for simple sac-charides has been investigated in relation to binding of the former to T and B cells. Microscopic agglutination and immunofluorescent studies show that virtually 100% of T and B lymphocytes have binding sites for the three phytomitogens. Quantitative absorption experiments have demonstrated that there is virtually no difference in the relative average density of binding sites on T and B cells. Immunofluorescent studies with Con-A suggested that binding sites are uniformly present over the entire cell surface. However, when lymphocytes are metabolically active an interesting altered localization of bound Con-A molecules to one pole of the cell takes place. His suggested that binding sites for the various phytomitogens are qualitatively and topographically distinct on the cell surface but that with respect to any one mitogen T and B cells have qualitatively and quantitatively similar binding sites. The relevance of these observations to lymphocyte activation is considered. [ABSTRACT FROM AUTHOR]

The mitogenic selectivity of four phytomitogens, phytohaemagglutinin (PHA), concanavalin (ConA), lentil mitogen (LM) and pokeweed mitogen .(PWM), and a series of heterologous antilymphocyte sera (ALS) for mouse T and B lymphocytes has been investigated using thymidine uptake as a measure of proliferative activity. The results show that PHA, ConA and LM stimulate T but not B cells whereas PWM activates both T and B cells. Of six mitogenically active ALS, five were T cell specific and one B cell specific. Cortisone resistant (T) cells within the thymus showed a much greater response to all mitogens than unselected thymocytes. However, ConA and LM activated a considerable response in the latter population. Selective activation of T and B cells by aspecific means may be useful both as a clinical tool and as an approach to gaining an understanding of antigen induction of immune responses. [ABSTRACT FROM AUTHOR]

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