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Effect of anti-lymphocyte antibody of active systemic lupus erythematosus (SLE) on lymphocyte function was examined. Lymphocytes from normal individuals treated with anti-lymphocyte antibody and complement exhibited marked inhibition of response to concanavalin A (Con A), while the response of lymphocytes to phytohaemagglutinin M (PHA-M) and pokeweed mitogen (PWM) was slightly affected. In mixed lymphocyte culture response, both stimulator and responder cells were insensitive to anti-lymphocyte antibody. Treatment of sensitized lymphocytes with anti-lymphocyte antibody and complement caused a dose-dependent suppression of blastogenic response to purified protein derivatives (PPD). No effect, however, was noted on migration-inhibitory factor (MIF)-producing cells. In PWM-driven Ig synthesis, T lymphocytes lacking the anti-lymphocyte antibody-reactive T-cell subset enhanced PWM-driven Ig synthesis of autologous B lymphocytes. Con-A-induced suppressor function of lymphocytes was abolished by the treatment with anti-lymphocyte antibody and complement. The present study demonstrated that lymphocytes from normal individuals after treatment with anti-lymphocyte antibody and complement showed similar immunological reactivities with lymphocytes from active SLE, indicating that those anti-lymphocyte antibodies could play an important role in defective suppressor cell function.
Our previous work has showed that lymphocytes can synthesize catecholamines (CAs). However, role and mechanism of the endogenous CAs in lymphocytes in modulation of immune function are less known. In the present study, we used alpha-methyl-p-tyrosine (alpha-MT), an inhibitor of tyrosine hydroxylase (TH), and pargyline, an inhibitor of monoamine oxydase, to block the synthesis and degradation of CAs in lymphocytes and then observed changes of lymphocyte proliferation induced by concanavalin A (Con A). Phentolamine and propranolol, antagonists respectively to alpha- and beta-adrenoreceptors, were employed to investigate the receptor mechanism. We found that TH mRNA in the Con A-activated lymphocytes was 2.4 times higher in relative density than that in the resting lymphocytes. Similarly, the intracellular and supernatant CAs, including DA, NE and E, of the Con A-stimulated lymphocytes were significantly raised relative to those of the resting cells. alpha-MT (10(-11), 10(-10) and 10(-9) M) facilitated the Con A-induced lymphocyte proliferation, but pargyline (10(-11), 10(-10) and 10(-9) M) attenuated the cell proliferation. Meanwhile, alpha-MT and pargyline respectively led to decrease and increase in the intracellular and supernatant CAs (DA, NE and E) of the Con A-stimulated lymphocytes. Propranolol completely blocked, but phentolamine partly reversed, the suppressive effect of pargyline on the Con A-induced lymphocyte proliferation. Content of cAMP was remarkably increased in the lymphocytes treated with pargyline alone, but it dropped to control level after these cells were treated with propranolol plus pargyline. These results on the one hand further demonstrate the ability of lymphocytes to synthesize CAs and the enhancive ability of the activated lymphocytes to synthesize CAs, and on the other hand reveal an important role of the endogenous CAs in regulation of function of lymphocytes themselves. Besides, our present findings suggest that CAs synthesized by lymphocytes can secrete out of the lymphocytes via paracrine or autocrine pathway and affect lymphocyte function by beta-adrenoreceptor and cAMP mediating mechanism. Thus, it can be implied that CAs in lymphocytes are also involved in the cross-talk in the neuro-endocrine-immune networks.
This study was undertaken to determine the proportions and in vitro immune capacities of lymphocyte populations in the bone marrows of normal humans. Relatively pure mononuclear cell suspensions were obtained from bone marrow aspirates by linear sucrose gradient centrifugations. Simultaneous peripheral blood and bone marrow specimens from each individual were assayed for lymphocyte surface markers and mitogen responsiveness. Maximal possible contamination of bone marrow aspirates by peripheral blood was determined by performing aspirates on individuals who had received 51chromium-labeled autologous erythrocytes. Rhymus-derived (T) lymphocytes, as determined by the sheep red blood cell (E) rosette assay, comprised 8.6-(plus or minus 1.6)% of the total bone marrow lymphocyte pool. Bone marrow-derived (B) lymphocytes, as determined by the presence of a complement receptor, made up 15.4-(plus or minus 1.9)% of the lymphocyte pool whereas 74.6 (plus or minus 2.4)% of mononuclear cells lacked easily detectable surface markers. These findings could not be explained by contamination with peripheral blood lymphocytes since contamination was corrected for in the calculations. Lymphocyte-enriched suspensions of bone marrow cells responded to stimulation with phytohemagglutinin, concanalin A, and particularly pokeweed mitogen. In vitro incubations of bone marrow and peripheral blood lymphocytes with tritiated thymidine followed by determinations of E and erythrocyte antibody complement (EAC) rosettes were performed. Simultaneous rosetteradioautographs demonstrated that the proliferative potential of bone marrow B lymphocytes was greater than peripheral blood B lymphocytes (P less than 0.01). On the other hand, the proliferative potential of bone marrow T lymphocytes was the same as that of peripheral blood T lymphocytes. These findings demonstrate that in addition to containing B lymphocytes the normal bone marrow contains a small fraction of T lymphocytes similar to the mature T lymphocyte pool found in the peripheral blood. These T cells most probably enter the bone marrow parenchyma as part of the normal recirculating lymphocyte pool.
Previous studies from this laboratory have shown actin to be a major protein of human lymphocytes (Stark, R., Liebes, L. F., Nevrla, D., and Silber, R. Biochem. Med., 27: 200-206, 1982). We now report the purification to homogeneity and characterization of actin from blood lymphocytes of normal subjects and patients with chronic lymphocytic leukemia. The recovery of the purified protein was about 20%. The properties of the lymphocyte actins were compared to each other and to those of rabbit skeletal muscle actin. Lymphocyte actin consisted of beta and gamma forms in a 2:1 ratio. The Mr 42,000 was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Normal and leukemic lymphocyte actin had similar polymerization properties as assessed by viscosity measurements at 25 degrees and 4 degrees, and the ultrastructural appearance of the filaments was the same. Similar patterns were observed between normal and chronic lymphocytic leukemia actin tryptic digests analyzed by high-performance liquid chromatography. The Vmax of the actin-activated myosin Mg2+ ATPase activity was compared using rabbit skeletal muscle heavy meromyosin and subfragment 1 preparations. The values obtained with rabbit skeletal muscle and normal lymphocyte actin were identical. The Vmax observed with chronic lymphocytic leukemia lymphocyte actin was 70% of that obtained with normal lymphocyte actin. The amount of actin needed to produce half-maximal activation (Kapparent) of heavy meromyosin and subfragment 1 were, respectively, 26 and 25 microM for normal lymphocytes and 18 and 24 microM for chronic lymphocytic leukemia lymphocytes. The anomalous ATP activation by actin did not reflect differences in B-:T-cell subpopulations between chronic lymphocytic leukemia and normal lymphocytes. The possible significance of the observed differences between the myosin Mg2+ ATPase activation by chronic lymphocytic leukemia and normal lymphocyte actin is discussed.
The interaction between lymphocytes and cultured high endothelial venule endothelium has been studied using light and electron microscopy. High endothelial cells (HEC) in monolayer culture bound lymphocytes 15-200-fold more efficiently than aortic endothelium, aortic fibroblasts or serum-coated glass. Light microscopy of lymphocytes bound to HEC showed two populations. Type I lymphocytes were phase-light, round and revealed no intracellular detail. Type II lymphocytes were phase-dark and flattened. The nucleus and cytoplasm of type II cells were clearly visible under high power light microscopy. The relative positions of these two populations were determined by electron microscopy. Type I lymphocytes were attached to the surface of HEC and type II lymphocytes were flattened underneath. The transition from type I to type II was accompanied by a loss of surface microvilli and a redistribution of intracellular organelles. This suggested that lymphocytes actively migrated across the HEC layer in this assay. The relationship between migrated lymphocytes and total adherent cells was determined by analysis of surface phenotype. Lymphocytes did not adhere randomly from the cell population plated. After 60 min there was an enrichment for B over T lymphocytes and the adherent T cell population was itself enriched for CD8+ cells over CD4+ cells. Migrated cells were, however, a random subpopulation of lymphocytes which adhered to HEC. This is clear evidence that migration was preceded by specific binding to HEC. Lymphocyte adhesion was independent of viable HEC showing that it was a passive event on the part of the endothelium. Lymphocyte migration was, however, completely dependent on viable high endothelium. We conclude that cultured HEC provide a biologically relevant, 3-dimensional matrix which supports the specific adhesion of lymphocytes and actively promotes lymphocyte migration. These observations suggest to us that cultured high endothelium provides a novel in vitro model for the study of lymphocyte migration into lymph nodes from the blood.
The kinetics of lymphocyte transformation induced by phytohemagglutinin (PHA) and pokeweed mitogen (PWM) were studied daily, with blood lymphocytes from normal individuals and from untreated patients in all stages of Hodgkin's disease (HD). In addition, spleen lymphocytes and lymph node lymphocytes were studied with similar techniques.Peripheral blood lymphocyte transformation stimulated by PHA was found to be depressed in all patients with HD (including those with localized disease and no symptoms) when small numbers of lymphocytes were cultured and studied during a 7-day period. Most patients with HD had an increased number of cells circulating in their blood which were actively synthesizing DNA. HD lymphocytes which demonstrated the highest initial rate of spontaneous DNA synthesis usually did not respond to PHA stimulation. Blood lymphocytes from normal individuals responded equally well to PHA and PWM in our system. HD blood lymphocytes consistently responded better to PWM than to PHA, with the response to PWM frequently within the normal range. Unless the spleen was extensively infiltrated with HD, spleen lymphocytes from patients with HD responded to PHA, even though the blood lymphocyte response was severely reduced. Lymph node lymphocyte response to PHA from patients with HD was variable, but correlated roughly with the blood lymphocyte response. It is hypothesized from the data presented that in HD, circulating thymus-dependent (T-)lymphocytes are stimulated by the presence of active disease. This stimulation of T-lymphocytes leads to a circulating T-cell depletion and to an increase in the number of cells circulating that are active in DNA synthesis. The degree of impairment of cell-mediated immunity would then depend upon the degree of T-lymphocyte depletion.
In male dd-mice given two subcutaneous injections of 0.5 mg of hydrocortisone at 35 and 36 days of age, lymphocytes in the bone marrow were studied qualitatively and quantitatively by electron microscopy. In normal 35-day-old mice, lymphocytes comprise 16.4% of nucleated free cells of the marrow. Marrow lymphocytes were, for the most part, of small type which constituted 15.5% of nucleated marrow cells. Small lymphocytes consisted of two types; dark and light small lymphocytes. At 35 days of age, dark small lymphocytes constituted 94.4% of all the marrow small lymphocytes and light small lymphocytes were the remaining 5.6%. After administration of hydrocortisone, lymphocytes in the marrow decreased markedly. The proportion of lymphocytes failed to 6.1% at 1 day, 4.5% at 5 days and 3.5% at 10 days after injection. Thereafter it slightly increased to 5.0% at 20 days after injection. The percentage of marrow lymphocytes at 20 days after injection was almost the same as that of controls at 60 days of age. Of the two types of marrow small lymphocytes dark small lymphocytes decreased rapidly after administration of hydrocortisone. They found 22.4% of the marrow small lymphocytes at 1 day and 10.7% at 5 days after injection. Thereafter, they increased gradually and occupied 58.0% of marrow small lymphocytes at 20 days. On the other hand, light small lymphocytes appeared more resistant to hydrocortisone than dark small lymphocytes.
BACKGROUND/AIMS: Peripheral blood CD8+ lymphocytes that home to mucosal surfaces express the human mucosal lymphocyte antigen (HML-1). At mucosal surfaces, including the ocular surface, only intraepithelial CD8+ lymphocytes express HML-1. These lymphocytes are retained in the intraepithelial compartment by virtue of the interaction between HML-1 and its natural ligand, E-cadherin, which is expressed on epithelial cells. The purpose of this study was to determine whether ocular surface epithelial cells (ocular mucosa) could induce the expression of human mucosal lymphocyte antigen on peripheral blood lymphocytes. METHODS: Human corneal and conjunctival epithelial cells were co-cultured with peripheral blood lymphocytes. Both non-activated and activated lymphocytes were used in the experiments. After 7 days of incubation, lymphocytes were recovered and analysed for the antigens CD8/HML-1, CD4/HML-1, CD3/CD8, CD3/CD4, CD3/CD25, CD8/CD25, and CD4/CD25 by flowcytometry. RESULTS: Significant statistical differences were observed in the CD8/HML-1 expression when conjunctival epithelial cells were co-cultured with non-activated and activated lymphocytes (p = 0.04 for each) and when corneal epithelial cells were co-cultured with non-activated lymphocytes (p = 0.03). Significant statistical difference in CD4/HML-1 expression was observed only when conjunctival epithelial cells were co-cultured with activated lymphocytes (p = 0.02). CONCLUSION: Ocular surface epithelial cells can induce the expression of human mucosal lymphocyte antigen on CD8+ (and to some extent on CD4+) lymphocytes. This may allow the retention of CD8+ and CD4+ lymphocytes within the epithelial compartment of the conjunctiva and play a part in mucosal homing of lymphocytes.
The effects of corticosteroid given in vivo on human lymphocyte subpopulation function were investigated using an in vitro system of pokeweek mitogen-stimulated immunoglobulin production. Peripheral blood lymphocytes were obtained from normal volunteers before and 4 h after the intravenous administration of methylprednisolone. Unfractioned peripheral blood lymphocytes showed a consistent decrease (mean congruent with 50%) in immunoglobulin and total protein synthesis after steroid administration. Utilizing separated thymus-derived (T) and bone marrow-derived (B) lymphocyte fractions, the pathophysiology of this alteration in immunoglobulin production was elucidated. B lymphocytes obtained after steroid treatment showed a markedly diminished immunoglobulin response (20% of normal) to normal T lymphocytes and to normal T cells that had been irradiated to remove suppressor T lymphocyte function. All major classes of immunoglobulin (IgG, IgM, and IgA) were affected. T lymphocytes procured after steroid administration were capable of providing normal amounts of T cell help for B cells in immunoglobulin production. However, suppressor T lymphocyte activity, observed with normal T lymphocytes at high T to B cell ratios, was absent from the post-steroid T lymphocytes. This loss of suppressor T lymphocyte function was not due to the presence of excess help as irradiated pre- and poststeroid T cells provided equal amounts of helper activity. On recombining the poststeroid treatment B cells, which are hyporesponsive in immunoglobulin synthesis, with the posttreatment T lymphocytes, which lack suppressor activity, diminished amounts of immunoglobulin were produced which correlate well with the effects observed with unseparated cells. Thus, corticosteroids have differential effects on the lymphocyte populations involved in immunoglobulin biosynthesis. B cell responsiveness is diminished, suppressor T lymphocyte activity is removed, and helper T lymphocyte function is unaffected.
BACKGROUND: Steroid therapy profoundly inhibits lymphocyte migration into lymph nodes (LN), thereby disrupting lymphocyte recirculation. This study was undertaken in human subjects to examine two nonmutually exclusive hypotheses proposed to explain this steroid effect: (1) steroids decrease the capacity of LN high endothelial venules (HEV) to support lymphocyte adherence; and/or (2) steroids alter the expression of lymphocyte adhesion molecules specific for entry into LNs. METHODS: Human LNs were obtained from cadaveric organ donors before and after methylprednisolone infusion and examined for their capacity to support lymphocyte adherence using an in vitro lymphocyte-HEV adherence assay. Additionally, six healthy volunteers underwent infusions of saline (placebo) and methylprednisolone (3 mg/kg in saline), and peripheral blood lymphocytes were isolated before, immediately after, and at 1, 2, 4, 8, 24, and 48 hours following infusions. At each timepoint, flow cytometric analysis of lymphocyte L-selectin, CD44, and LFA-1 expression was assessed. Short-term tissue culture studies were also performed to examine the direct effects of steroids on the expression of these lymphocyte proteins. RESULTS: LNs obtained from organ donors before and after steroid infusion displayed no differences in the capacity of HEV to support lymphocyte adherence. In controlled steroid infusion studies, lymphopenia was observed within 1 hour and persisted for 8 hours. Cells isolated during the period of lymphopenia did not adhere to LN HEV, and there was a marked decrease in both the percentage and mean fluorescence intensity level of L-selectin+ lymphocytes; minor changes were observed in the percentage of CD44+ and LFA-1+ cells, while the mean fluorescence intensity level decreased for CD44+ cells and increased for LFA-1+ cells. All such changes in adhesion protein levels among circulating cells reversed with the resolution of lymphopenia. However, in tissue culture experiments, steroids did not alter the expression of lymphocyte adhesion proteins. CONCLUSIONS: The decreased migration of lymphocytes to LN following steroid administration is not due to changes in the capacity of HEV to bind lymphocytes, but results from decreases in the level of L-selectin expressed among circulating cells. Culture studies suggest that steroids do not directly alter lymphocyte adhesion protein expression. The possibility that these agents act indirectly by stimulating the release and/or promoting the activity of relevant biologic mediators affecting lymphocyte adhesion protein expression needs further exploration.
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