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Cell separation techniques and scanning electron microscopy (SEM) were used to characterize the surface morphology of small lymphocytes in mouse bone marrow. Lymphocyte-rich fractions and unfractionated suspensions of bone marrow and spleen cells from 9--10-week-old C3H male mice were glutaraldehyde-fixed, syringed onto gelatin-coated silver membranes, dehydrated in ethanol, infiltrated with amyl acetate, critical point dried, coated with gold-palladium and examined by SEM. High proportions of cells were retained on the membranes. Purified spleen small lymphocytes showed unimodal distribution curves for cell diameter (mode, 3.4 micrometer) and for number of surface microvilli (mode, 55--60). Bone marrow small lymphocytes were identified initially in lymphocyte-rich marrow fractions and in erythroblast-depleted marrow from polycythemic mice as well as in normal whole marrow. The cells resembled spleen small lymphocytes in size distribution and they showed microvilli. However, the number of visible microvilli was lower on small lymphocytes in the bone marrow (mode, 35--40) than in the spleen. While in each small lymphocyte population the total number of microvilli was greater on larger cells than on smaller ones, the density of microvilli per unit area of cell surface tended to decrease with increasing cell size. The results establish that the small lymphocytes in mouse bone marrow, mainly locally-produced immature cells, have villous surfaces, but the number of microvilli per unit cell surface area is less than that on peripheral small lymphocytes, as seen in the spleen. Neither in the bone marrow nor in the spleen are subpopulations of small lymphocytes distinguishable solely by numbers of microvilli. The findings suggest that microvilli on bone marrow small lymphocytes may undergo further development during post-mitotic maturation, surface receptor expression and migration of the cells to peripheral lymphoid tissues.
Lymphocyte proliferation in response to mitogenic lectins is directly dependent upon glutathione (GSH) availability. Thus, proliferation can be enhanced by providing lymphocytes with excess glutathione, and strongly inhibited by limiting the quantity of intracellular GSH available during the mitogenic stimulation. Exogenous GSH, cysteine and 2-mercaptoethanol (2-ME) can all significantly enhance lymphocyte proliferation and augment intracellular GSH levels. Lymphocytes depleted of GSH by buthionine sulfoximine (BSO) fail to undergo a full blast transformation response to mitogenic lectins. In lymphocytes stimulated with mitogen in the presence of BSO, the time profile of intracellular GSH levels shows a rapid decline over the first 24-48 h and a subsequent gradual decline to levels less than 0.5 nmol/10(7) lymphocytes by 72-96 h. Exogenous GSH partially sustains intracellular GSH levels and completely restores lymphocyte proliferation even in the presence of 2000 microM BSO. Other thiols, such as cysteine and 2-ME, do not significantly alter the time profile of intracellular GSH in mitogen-stimulated lymphocytes in the presence of 2000 microM BSO, and their capacity to enhance proliferation is greatly diminished albeit not completely abolished under these conditions. Ongoing GSH synthesis is clearly essential to maintain a normal proliferative response. If intracellular GSH levels are depleted initially and lymphocytes are then stimulated with mitogen in the presence of BSO, there is a diminished capacity of cysteine and 2-ME to restore proliferation relative to exogenous GSH. There is also a diminished capacity of exogenous GSH to restore proliferation with higher concentrations of BSO. This suggests that the restoration of lymphocyte proliferation by exogenous GSH is more closely linked to effects on intracellular rather than extracellular GSH. These studies confirm the importance of intracellular GSH in lymphocyte proliferation. The essential role for intracellular GSH can be demonstrated even in the presence of other exogenous thiols, such as cysteine and 2-ME. The enhancement of lymphocyte proliferation by exogenous cysteine appears to be directly linked to effects on intracellular GSH, whereas the enhancement by 2-ME is probably more complex but clearly linked to effects on intracellular GSH.
Lymphocytes were isolated from the peripheral blood of 21 normal persons and 66 patients with chronic lymphocytic leukemia (CLL), CLL in remission, Hodgkin's disease, Hodgkin's disease in remission, various other tumors, or cardiovascular diseases; The lymphocytes were studied for cap formation and agglutinability by concanavalin A, and for cell attachment to the surface of a petri dish. The frequency of cap formation was lowest in lymphocytes from patients with untreated Hodgkin's disease (2.1 plus or minus 0.8%), next lowest in lymphocytes from patients with CLL who were or were not under treatment (7,0 plus or minus 1;3%), and also low in Hodgkin's disease in remission (10.6 plus or minus 1.2%). The frequencies of cap formation by lymphocytes from patients with various other tumors (19.1 plus or minus 2.5%), with CLL in remission (24.0 plus or minus 0.9%), and with nonmalignant diseases (26.0 plus or minus 2.2%) were more similar to the frequency found in lymphocytes from normal persons (29.4 plus or minus 2.8%). Lymphocytes from all the patients, including those in remission, showed a higher degree of agglutinability by concanavalin A than lymphocytes from normal persons. Cell attachment to a petri dish was highest with CLL, next highest with CLL in remission, and low for normal persons and all the other patients. Lymphocytes from normal persons that consisted predominantly of thymus-derived cells gave similar results to isolated normal bone marrow-derived cells. The results indicate that there were different changes in the surface membrane of lymphocytes from patients with CLL, CLL in remission, Hodgkin's disease, and Hodgkin's disease in remission, and that the patients in clinical remission still showed abnormalities in their lymphocytes.
We have measured clonal survival following gamma-irradiation of unstimulated (G0) T-lymphocytes from 35 donors, of 11 T-lymphocyte cell lines, of six lymphoblastoid cell lines, and of nine primary fibroblast strains for which we have G0 T-lymphocyte material from the same donor. Amongst the G0 lymphocytes we have results from nine normal donors, from eight cord bloods, from seven ataxia-telangiectasia (A-T) patients and from nine A-T heterozygotes. Although there is some variation between samples, G0 T-lymphocytes from normal donors appear to be slightly more radioresistant than T-lymphocyte lines, with a more shouldered survival curve. From our limited sample, lymphoblastoid cell lines appear to be slightly more radiosensitive than T-lymphocytes. The overall radiosensitivity of primary fibroblasts appears to be broadly similar to that of G0 T-lymphocytes. In nine instances, five A-Ts and four A-T heterozygotes, both G0 T-lymphocytes and primary fibroblasts from the same donor were tested. In five cases there was closely similar radiosensitivity in the two cell types, but in four cases there was some discrepancy. Further work, especially with normal donors, will be required in order to establish how reliably radiosensitivity in other cell types can be predicted from that of G0 T-lymphocytes. In all cell types the hypersensitivity of A-T cells was confirmed. Furthermore, the marginally greater sensitivity of A-T heterozygotes, when compared as a group with normals, was confirmed with G0 T-lymphocytes. Our results also suggest a slightly increased radiosensitivity in G0 T-lymphocytes from some, but not all, cord blood samples.
Tissue-specific interactions with specialized high endothelial venules (HEV) direct the homing of lymphocytes from the blood into peripheral lymph nodes, mucosal lymphoid organs, and tissue sites of chronic inflammation. These interactions have been demonstrated in all mammalian species examined and thus appear highly conserved. To assess the degree of evolutionary divergence in lymphocyte-HEV recognition mechanisms, we have studied the ability of lymphocytes to interact with HEV across species barriers. By using an in vitro assay of lymphocyte binding to HEV in frozen sections of lymphoid tissues, we confirm that mouse, guinea pig, and human lymphocytes bind to xenogeneic as well as homologous HEV. In addition, we show that mouse and human lymphoid cell lines that bind selectively to either peripheral lymph node or mucosal vessels (Peyer's patches, appendix) in homologous lymphoid tissues exhibit the same organ specificity in binding to xenogeneic HEV. Furthermore, monoclonal antibodies that recognize lymphocyte "homing receptors" and block homologous lymphocyte binding to peripheral lymph node or to mucosal HEV, also inhibit lymphocyte interactions with xenogeneic HEV in a tissue-specific fashion. Similarly, anti-HEV antibodies against organ-specific mouse high endothelial cell "addressins" involved in lymphocyte homing to peripheral lymph node or mucosal lymphoid organs, not only block the adhesion of mouse lymphocytes but also of human lymphocytes to target mouse HEV. The results illustrate a remarkable degree of functional conservation of elements mediating these cell-cell recognition events involved in organ-specific lymphocyte homing.
AIMS: To examine the course of lymphocytic gastritis and its relation to Helicobacter pylori (H pylori) infection in a 10 year follow up. METHODS: Ninety six patients were originally examined for dyspepsia in 1981. Gastroscopies with stepwise biopsies were performed on all the patients initially and after an interval of 10 years. RESULTS: Nine per cent of the patients (9/96) had features of lymphocytic gastritis in gastric biopsy at the first examination, and 12.5% (12/96) at the second examination; 7/9 patients (78%) had persistent lymphocytic gastritis during the follow up; in two the diagnostic features of lymphocytic gastritis had disappeared, and five had a new diagnosis of lymphocytic gastritis at the second examination. At the second examination 9/12 lymphocytic gastritis patients (75%) were H pylori positive histologically, while all had specific antibodies to H pylori. The lymphocytic gastritis patients had higher grades of gastritis (p = 0.009), neutrophilic and eosinophilic granulocytes, mononuclear inflammatory cells, and foveolar hyperplasia in the corpus mucosa, but smaller numbers of H pylori, than the H pylori positive patients without lymphocytic gastritis. The appearance of lymphocytic gastritis during the 10 year interval was associated with increases in the grades of corpus gastritis and neutrophilic granulocytes (p = 0.043 for both). During the follow up, the patients with lymphocytic gastritis, but not the H pylori positive patients without lymphocytic gastritis, appeared to have a significant increase in the grade of intestinal metaplasia in the corpus mucosa (p = 0.043). CONCLUSIONS: In some patients H pylori may cause a gastritis that predominates in the corpus and is associated with an increase in the intraepithelial lymphocyte count. This form of gastritis may cause progression of intestinal metaplasia.
Interleukin-10 (IL-10) is constitutively produced by peritoneal B1a lymphocytes, and stromal cell-derived factor-1 (SDF-1) by mesothelial cells. Independent studies have shown that both IL-10 and SDF-1 are involved in the persistence of the peritoneal B-lymphocyte compartment. This study shows that IL-10 and SDF-1 act in synergy on peritoneal B lymphocytes. Indeed, autocrine production of IL-10 was absolutely required for all effects of SDF-1 on these cells, including increased proliferation, survival, and chemotaxis. Moreover, adding IL-10 to peritoneal B lymphocytes increased the effects of SDF-1. Neither IL-5, IL-6, nor IL-9 affected the response of peritoneal B lymphocytes to SDF-1. IL-10 was chemokinetic for peritoneal B lymphocytes, increasing their random mobility. It also potentiated the SDF-1-induced reorganization of the cytoskeleton without affecting CXCR4 gene expression by peritoneal B lymphocytes. Despite its chemokinetic properties, IL-10 abolished the migration of peritoneal B lymphocytes in response to B-lymphocyte chemoattractant (BLC), a chemokine targeting B lymphocytes to lymphoid organ follicles. The ability of B1a lymphocytes to produce IL-10 constitutively, combined with the opposite effects of this cytokine on the responses to SDF-1 and BLC, may account for the selective accumulation of B1 lymphocytes in body cavities.
Autotransfusion of 3H-cytidine labeled blood lymphocytes was performed in 4 normal subjects, 3 patients with non-leukemic malignant lymphoma (1 reticulum cell sarcoma, 2 lymphosarcoma), 2 treated, non-leukemic patients with chronic lymphocytic leukemia (CLL) and 11 untreated CLL patients. Immediately after autotransfusion on the average only 41.3% and 47.5% of the infused labeled lymphocytes were recovered in the blood of the normal subjects and of the untreated CLL patients, respectively. During the first hour, in the normal subjects a higher proportion of labeled cells disappeared from the blood that in untreated CLL patients. Thereafter, this initial rapid decrease ceased and levelled off into a plateau with rather constant recovery values. At this time (1-4 hours after autotransfusion), on the average only 6.7% of the normal lymphocytes, but 27.8% of the untreated CLL lymphocytes were recovered in the blood. In the non-leukemic lymphoma of the untreated CLL lymphocytes were recovered in the blood. In the non-leukemic lymphoma patients and treated CLL patients the autotransfused lymphocytes exhibited circulation kinetics similar to those of the normal lymphocytes. The majority of blood lymphocytes from untreated patients with CLL seem to be characterized by a poor exchange rate between intra- and extravascular lymphocyte pools and a prolonged intra-vascular life span. These findings agree with the impaired recirculation kinetics of CLL lymphocytes and their abnormal 0ehaviour in several "in vitro" tests dealing with other lymphocyte functions.
Interleukin 2 (IL2) responsiveness of ovalbumin (OVA)-stimulated lymphocytes from patients with hen-egg allergy was studied. The number of viable cells of 5-day cultured lymphocytes stimulated with OVA was increased by an additional three days incubation with recombinant IL2. This phenomenon was not observed when the lymphocytes of patients allergic to OVA but not to Dermatophagoides farinae extract antigen (Df) were stimulated with Df. Normal lymphocytes stimulated with OVA expressed Tac antigen (low affinity IL2 receptor) but, in contrast to those from the allergic patients, did not absorb nor respond to IL2. The induction of OVA-specific IL2 responsiveness in patient lymphocytes was markedly suppressed on the addition of culture supernatant from OVA-stimulated normal T cells, but Df-specific IL2 responsiveness of the lymphocytes from Df-sensitized patients with bronchial asthma was not suppressed by the same supernatant. The supernatant of lymphocytes from allergic patients did not show such suppressive effect. The patient lymphocytes whose IL2 responsiveness was suppressed with the supernatant from normal lymphocytes still expressed Tac antigen. These observations suggest that the culture supernatant of normal T lymphocytes stimulated with OVA contained an antigen-specific factor suppressing the induction of IL2 responsiveness of OVA-stimulated patient lymphocytes. The production of such a suppressive factor was impaired in the patient, and further, the factor may have inhibited the triggering signal of IL2 receptors having absorbed IL2. The existence of some allogeneic barrier between the factor(s) and patient lymphocytes was suggested, since the supernatant from OVA-stimulated normal T cells did not necessarily suppress the response of all patients tested.
Previous in vitro studies suggest that recognition of phosphomannosyl structures by lymphocytes plays a central role in the binding of lymphocytes to high endothelial venules. However, the physiologic relevance of phosphomannosyl recognition in in vivo lymphocyte migration has not been established. This paper describes experiments that examined this question. It was demonstrated that the phosphomannan monoester core (PPME) from Pichia holstii, a potent inhibitor of peripheral node high endothelial venule interactions in vitro, was a very effective inhibitor of in vivo lymphocyte migration, as little as 39 micrograms/mouse significantly inhibiting popliteal lymph node entry. Furthermore, PPME exhibited a similar hierarchy of inhibition in vivo as previously reported in vitro, most effectively inhibiting entry of lymphocytes into popliteal lymph node, somewhat less effectively inhibiting mesenteric lymph node entry and being a relatively poor inhibitor of Peyer's patch entry. Additionally, PPME inhibited splenic entry of lymphocytes, and inhibition of lymphoid organ entry was accompanied by a substantial leukocytosis. Two additional mannose-containing compounds were found to modify lymphocyte migration, namely a well defined mannose containing pentasaccharide (PENT) with terminal mannose-6-phosphate (M6P) and an unphosphorylated yeast mannan. Both PENT and mannan induced leukocytosis and were particularly effective at inhibiting splenic entry of lymphocytes. In fact, detailed dose-response curves indicated that mannan was a much more potent inhibitor of splenic entry than PPME or PENT, whereas in lymph nodes PPME was the most effective inhibitor. Pretreatment of lymphocytes before injection with either PPME or mannan demonstrated that PPME could act at the lymphocyte level, whereas mannan probably acted at some other site. Collectively, these data suggest that different carbohydrate structures are involved in the entry of lymphocytes into different lymphoid organs, with mannose recognition playing an important role in splenic entry and recognition of M6P-like structures controlling lymph node entry. In contrast, it was found that mannose-and M6P-containing structures, unlike sulfated polysaccharides such as fucoidan, did not affect the subsequent positioning of lymphocytes within lymphoid organs.
The occurrence of cytotoxic lymphocyte subpopulations (i.e., CD 16+, CD 57+ and cytotoxic CD 8+) wa studied in the peripheral blood of 18 B-cell chronic lymphocytic leukemia (B-CLL) patients. The absolute numbers of CD 57+, CD 16+ and cytotoxic CD 8+ lymphocytes were increased in the peripheral blood of untreated patients as compared with healthy donors, suggesting a causal relation with the accumulation of malignant B-cells. For 5 B-CLL patients and 5 hematological normal donors, the lymphocyte subpopulations in peripheral blood, lymph nodes and bone marrow were determined. A significant immune response was observed in the lymph nodes of the patients, as reflected by the CD 3+ lymphocytes, which were 1.7-27 times larger in the patients lymph nodes than in their peripheral blood and bone marrow. In contrast, with peripheral blood this was mainly caused by an increase in CD 4+ lymphocytes. The CD 57 lymphocytes in the lymph nodes of the patients had abnormal orthogonal light-scattering signals and an abnormal density of CD 57+ receptors in comparison with their peripheral blood CD 57+ lymphocytes or the CD 57+ lymphocytes in the peripheral blood, bone marrow and tonsils of the hematological normal donors. This study shows that although a significant increase of cytotoxic lymphocytes in the peripheral blood of B-CLL patients is observed, the actual distributions of the non-malignant lymphocytes can be quite different at the actual tumor sites, i.e., bone marrow and lymph nodes.
Human peripheral lymphocytes were investigated for receptors binding Epstein-Barr virus (EBV) because of the regular association of this virus with infectious mononucleosis and Burkitt's lymphoma. This was done by a cytoadherence technique where virus-producing cells, displaying fresh viral determinants in their cytoplasmatic membrane, were mixed with lymphocytes. Unfractionated lymphocytes were found to adhere to these cells in contrast to column-purified T lymphocytes. The specificity of the binding was confirmed by blocking experiments that showed that sera containing high titers of antibodies directed against the virus could partially inhibit the adherence in contrast to low-titer sera. It is concluded that B lymphocytes, in contrast to T lymphocytes, have receptors for EBV. In a second line of experiments it was found that established human lymphoblastoid lines that carry the EBV genome had receptors characteristic for B lymphocytes and did not form T-lymphocyte rosettes. In contrast, a line of known T-lymphocyte origin that did not carry the EBV genome had receptors characteristic for T lymphocytes. EBV-transformed simian lymphoblastoid lines had surface markers indicating a B-lymphocyte origin in contrast to HVS-transformed simian lines that lacked surface immunoglobulin but carried receptors for sheep red blood cells.
OBJECTIVE: To assess the ability of the CD8 lymphocyte count and immunoglobulin (Ig) A level, measured at the early stage of HIV infection when the CD4 lymphocyte count remains relatively high, to predict the future rate of CD4 lymphocyte loss and hence the risk of AIDS. DESIGN: Cohort of recently infected haemophiliacs with relatively high CD4 lymphocyte counts followed for up to 8.5 years from baseline measurement of CD8 lymphocyte counts and IgA levels. SETTING: A regional haemophilia centre based in a major teaching hospital. PATIENTS: Eighty-four of 111 patients with haemophilia who seroconverted to HIV between 1979 and 1985 in whom CD8 lymphocyte counts and IgA levels were measured soon after seroconversion (mean, 2.7 years; maximum, 5 years) while CD4 lymphocyte counts remained relatively high (median, 600 x 10(6)/l; minimum, 300 x 10(6)/l). OUTCOME MEASURES: Development of severe immunodeficiency defined by a CD4 lymphocyte count falling below 50 x 10(6)/l, and AIDS. RESULTS: Individuals with high CD8 counts (P < 0.008) and high IgA levels (P < 0.003) at baseline experienced a more rapid rate of CD4 lymphocyte loss than those with low baseline levels. A score was derived to combine the predictive ability of CD8 count and IgA level. Estimated proportions with CD4 counts below 50 x 10(6)/l after 8 years of follow-up were 100, 30 and 14% for those with high, intermediate and low baseline scores, respectively. The CD8/IgA score showed similar ability to predict the future occurrence of AIDS (P < 0.0001; log-rank test). CONCLUSION: Immune activation seen in HIV infection, as reflected by raised CD8 counts and IgA levels, appears to be linked to the process of CD4 lymphocyte depletion. Measurement of these markers in the years following infection, when CD4 lymphocyte counts remain high, provides a first indication of a patient's long-term prognosis.
Cytotoxic T lymphocytes were activated in primary one-way mixed lymphocyte cultures of cells matched for serologically defined HLA-A, -B and -C antigens. In 16 out of the 29 combinations mismatched for the HLA-D/DR antigens, cell-mediated lympholysis of the stimulator cells occurred. The specificity of 5 selected cytotoxic T lymphocytes was studied in detail. Three of these cytotoxic T lymphocytes recognize antigenic determinants associated with HLA-Bw35 (Breuning et al. 1984, II). The 2 other cytotoxic T lymphocytes failed to lyse T-target cells enriched by rosetting with sheep red blood cells, whereas target cells from the 'non-T' fraction were strongly lysed, indicating that antigenic determinants associated with Class-II HLA molecules were the targets recognized by these cytotoxic T lymphocytes. This notion was supported by a study of a panel of HLA-typed third-party target cells. One cytotoxic T-lymphocyte population preferentially lysed HLA-DR2-positive target cells. Family studies, including a family with a recombination between HLA-B and -D, showed that the target antigen recognized by the latter cytotoxic T lymphocyte segregated with DR2. The second cytotoxic T-lymphocyte population recognized a determinant associated with DRw8. However, in 13 of the 29 HLA-A-, -B- and -C-identical, D/DR-different combinations, cell-mediated lympholysis of stimulator target cells could not be detected, not even on enriched 'non-T' target cells. Thus, after primary mixed lymphocyte culture of HLA-A-, -B- and C-identical, HLA-D/DR-non-identical cells, cytotoxic T lymphocytes directed against sensitizing Class-II molecules can be detected in some combinations, but not in others.