Nabih I. Abdou

Suppressor T-cell abnormality in idiopathic systemic lupus erythematosus

Suppressor T cells were evaluated by their capacity to inhibit immunoglobulin (Ig) synthesis and secretion of anti-DNA antibody by B cells when co-cultured in presence of pokeweed mitogen. Ig synthesis was tested by staining the cytoplasm with fluorescent anti-Ig reagent, and antibody secretion was determined by binding of cell supernatants to tritiated native DNA. T cells in the blood of patients with idiopathic systemic lupus erythematosus (SLE), in contrast to T cells from normals, were incapable of suppressing Ig synthesis or antibody secretion when tested against B cells from the patient, from other SLE patients, or from those of normals. T cells from normals were capable of suppressing B cells from each patient tested (P < 0.001). SLE-B cells, when cultured alone, synthesized more Ig than B cells of normals (P < 0.01). There was a significant correlation between disease activity and the degree of suppression of SLE-B cells by the T cells of normals. The emergence of autoreactive clones and hyperfunction of B cells could be secondary to suppressor T-cell deficiency or dysfunction in SLE.

Malakoplakia: Evidence for Monocyte Lysosomal Abnormality Correctable by Cholinergic Agonist in Vitro and in Vivo

We studied monocyte function in a case of malakoplakia in an attempt to characterize the immune defect in this condition. Our patients intracellular cyclic-GMP levels were abnormally low (mean +/- S.D. of 0.17 +/- 0.05 pmol per 10(7) malakoplakia cells, versus 0.79 +/- 0.12 in normals) p less than 0.001). After phagocytosis, his monocytes failed to release beta-glucuronidase. In the bactericidal assay, incubation of the patients monocytes with Escherichia coli allowed growth of 542 +/- 46 colonies, normal monocytes allowed 95 +/- 22 (p less than 0.001). The percentage of monocytes with large lysosomal granules was 23 +/- 4 in the patient and 4 +/- 2 in normal controls. After in vitro incubation of the patients cells or in vivo treatment with bethanechol chloride, the cyclic-GMP levels, bactericidal ability and lysosomal granules of the cells returned to normal levels. Low levels of cyclic-GMP could impair lysosomal function and bacterial killing in this condition. Cholinergic agonists correct the in vitro abnormalities and are beneficial in vivo.

The thymus in myasthenia gravis. Evidence for altered cell populations

Abstract Comparisons of several types of immunologic reactivity were made in thymic cells from six patients with myasthenia gravis and thymic hyperplasia, four patients with myasthenia gravis and thymoma and six age-matched control cardiac-surgery patients. In mixed leukocyte reactions, thymic cells from the subjects with hyperplasia were capable of stimulating autologous peripheral blood lymphocytes. Such reactivity was not seen in thymocyte-blood lymphocyte mixtures from the other two groups. There was an increased number of B cells in the thymic-cell populations from the myasthenic patients as compared to that in the control group, carrying predominantly IgM receptors. The thymic cells from myasthenic patients also responded more vigorously to pokeweed mitogen. These findings suggest altered populations of lymphoid cells in the thymus of myasthenic patients that react with autologous lymphocytes from other cell compartments. The pathogenic implications of these findings remain to be determined. (N Engl...

Suppressor-Cell Antibody in Systemic Lupus Erythematosus: POSSIBLE MECHANISM FOR SUPPRESSOR-CELL DYSFUNCTION

Circulating antibodies that could be responsible for the suppressor thymus-derived (T)-cell dysfunction in active systemic lupus erythematosus (SLE) were investigated. Sera from 14 active and inactive SLE patients were compared with a pool of 22 normal sera. All sera were adsorbed with a pool of normal platelets to exclude antihistocompatibility leukocyte antigen antibodies; with AB erythrocytes to exclude isohemagglutinins; and with a pool of normal bone marrow-derived (B) lymphocytes, monocytes, and neutrophils to deplete anti-B-cell antibodies, Fc-receptor antibodies, and antibodies directed against neutrophils or monocytes. Sera from active SLE patients were capable of inhibiting the activation of normal, blood lymphocytes by concanavalin A to become suppressor cells. The latter were assayed by coculturing the concanavalin A-activated cells with autologous lymphocytes, which were then activated with either phytohemagglutinin for proliferative response or with pokeweed mitogen for B-cell immunoglobulin (Ig) synthesis and secretion. Specific incorporation of cultures with phytohemagglutinin showed a value of 67+/-13 (mean+/-SD) for suppressor cells treated with adsorbed, active SLE sera. This value was significantly different (P < 0.001) from that of cells treated with the inactive SLE sera or with the pool of normal sera. Similar findings were seen with respect to the B-cell target parameters. Cytoplasmic Ig and IgG in supernates of cultures with pokeweed mitogen showed values of 17+/-5% and 717+/-134 ng/culture, respectively, for suppressor cells treated with the adsorbed, active SLE sera. This was significantly different from those treated with the inactive SLE sera or with the pool of normal sera. The antisuppressor-cell factor was shown to be IgG, complement independent, not cytotoxic, active at 37 degrees C and at room temperature, but not at 4 degrees C, and adsorbable with T cells. Suppressor T-cell antibody in sera of active SLE patients could be responsible for the observed suppressor T-cell dysfunction seen in active SLE. The mechanisms responsible for the induction of the antisuppressor-cell antibody are unknown.

Suppressor cell-mediated neutropenia in Felty's syndrome.

The mechanism of neutropenia in Feltys Syndrome (FS) was tested. The suppressor capacity of mononuclear cells from patients with FS on normal bone marrow granulopoiesis was tested by the in vitro colony forming unit in culture assay. Peripheral blood, bone marrow, and spleen cells from FS patients with marked neutropenia (less than 1,000 neutrophils/mm3) suppressed the colony forming unit in culture of normal bone marrow. Cells from rheumatoid arthritis patients without neutropenia, cells from patients with drug-induced neutropenia without rheumatoid arthritis, or plasma from FS patients failed to suppress the colony forming unit in culture. Though suppressor cells were predominantly thymus-derived (T) cells, monocytes were also effective in suppression. The suppressor efficiency of cells from the various compartments were spleen greater than bone marrow greater than peripheral blood. Splenectomy in FS transiently corrected the neutropenia and eliminated suppressor cell activity. Hyperactive suppressor cells may be responsible for the neutropenia in some patients with FS. Correction of neutropenia in these patients should be directed at modulating the suppressor cell subpopulation.

The Monoclonal Nature of Lymphocytes in Multiple Myeloma: Effects of Therapy

Despite the increased amounts of serum immumoglobulins (Ig) in multiple myeloma, the percentage of bone marrow-dependent (B) cells carrying surface Ig in the peripheral blood compartment were decreased, when compared with that in control patients with polyclonal gammopathy or with that in normals (5 plus or minus 2% in patients with multiple myeloma and 19 plus or minus 5% or 22 plus or minus 7% in controls). Most circulating B cells in patients with multiple myeloma were shown to carry individually specific idiotypic Ig. The monoclonal idiotypic nature of the surface Ig was shown by using antiserums raised against the monoclonal Ig. The idiotypic antiserum was capable of actively binding to and stimulating the idiotypic lymphocytes to divide in vitro. Commercial anti-Ig antiserums raised against normal Ig did not bind to the myeloma lymphocytes. After chemotherapy, lymphocytes carrying the idiotypic Ig decreased in numbers, and this correlated with other variables of clinical improvements. Its role in the pathogenesis of myeloma and its importance for diagnosis and follow-up of patients with myeloma are discussed.

Bone Marrow: The Bursa Equivalent in Man?

Human bone marrow lymphoid cells, particularly when enriched with plasma cells, as in multiple myeloma, respond to pokeweed mitogen and to antiserum to immunoglobulin but not to phytohemagglutinin. Cells of patients with X-linked agammaglobulinemia of the bursal deficient type failed to respond to either pokeweed or to the antiserum to immunoglobulin. Leukocytes of the agammaglobulinemia patients however responded in a normal fashion to phytohemagglutinin. Just as the in vitro response to phytohemagglutinin is taken as an index of the thymus-dependent system, the in vitro response to both antiserum to immunoglobulin and pokeweed may be considered an index for the bursaldependent system. Human bone marrow, therefore, contains bursal cells and probably very few or no thymus cells.

Heterogeneity of pathogenetic mechanisms in aplastic anemia. Efficacy of therapy based on in-vitro results.

The mechanisms responsible for the bone marrow failure in 21 aplastic anemia patients were studied by the colony-forming units in culture assay (CFU-C). Twelve patients had no detectable in-vitro defect that could be responsible for the low CFU-C numbers. Three patients had suppressor T cells that inhibited CFU-C (p less than 0.001); one of two patients responded to antithymocyte globulin therapy and the third recovered spontaneously. Three patients had serum inhibitory immunoglobulins directed against their marrow CFU-C; plasmapheresis resulted in recovery of bone marrow function. Three patients had abnormalities at the colony-stimulating factor level: Two had inhibitors of colony-stimulating factor, corrected in vitro and in vivo by indomethacin and cholinergic agonists (p less than 0.01); and the third had colony-stimulating factor generation defect, corrected in vitro and in vivo by lithium. Testing for cellular or humoral suppressor factors directed against precursor cells or for abnormalities at the colony-stimulating factor level gives helpful guidelines to therapy in aplastic anemia.

Histoplasma meningitis with hyperactive suppressor T cells in cerebrospinal fluid

Histoplasma meningitis usually occurs in conjunction with disseminated histoplasmosis. We studied a patient with common variable hypogammaglobulinemia who manifested meningitis without disseminated histoplasmosis. No histoplasma antibody was detected in cerebrospinal fluid (CSF) or blood. Evaluation of lymphocyte function in the blood revealed normal numbers of T cells with increased numbers of B cells. Most blood lymphocytes were identifiable, but most lymphocytes in CSF were null cells. Lymphocyte proliferative response to phytohemagglutinin or pokeweed mitogen was poor. T cells in CSF suppressed proliferative responses to histoplasma antigen by cells from blood or CSF, whereas T cells from blood did not. This difference suggested compartmentalization of T-cell function. The lack of humoral and cellular response to histoplasma in CSF may have allowed meningitis to develop, while the cellular response to histoplasma elsewhere prevented development of disseminated histoplasmosis.

Comparative study of bone marrow and blood B cells in infantile and acquired agammaglobulinemia. Possible role of circulating anti-IgM in pathogenesis.

The status of immunoglobulin (Ig) receptors of the bone marrow dependent (B) cells present in either the bone marrow (BM) or peripheral blood (PB) of three patients with infantile agammaglobulinemia (I-AGG), or seven patients with acquired agammaglobulinemia (A-AGG) is compared with those of 12 controls. Quantitative and qualitative changes of the different classes of Ig receptors on B cells were evaluated by their capacity to bind [(125)I]anti-Ig, to be stained with fluorescinated anti-Ig and their in vitro proliferative capacity upon incubation with the anti-Ig. Patients with I-AGG lacked B cells in both the BM and PB. Whereas BM cells of patients with A-AGG carried receptors similar to control cells, their blood B cells had fewer IgM, IgG, and IgA cells which failed to proliferate in vitro in the presence of the anti-Ig. An anti-IgM of the IgG class was detected in the sera of patients with A-AGG but not in sera of I-AGG. The isolated anti-IgM agglutinated human red cells coated with IgM. The anti-IgM partially blocked the binding of fluorescinated or radiolabeled anti-IgM to IgM peripheral blood lymphocytes of normal controls. The eluted anti-IgM in presence of complement was partially cytotoxic to normal cells. It is concluded that I-AGG-B cell defect is due to failure of B cell development in the bone marrow compartment whereas the peripheral exclusion of IgM cells by an anti-IgM with the subsequent failure of differentiation of both IgG and IgA cells could be an important mechanism in A-AGG-B cell defect.