Ira Green

Nodular Lymphoma — Evidence for Origin from Follicular B Lymphocytes

Abstract To investigate the cellular origin of nodular lymphoma, neoplastic cells from six patients with nodular lymphomas were studied both in cell suspensions and in frozen tissue sections for (1...

Preferential cutaneous infiltration by neoplastic thymus-derived lymphocytes. Morphologic and functional studies.

Abstract The abnormal lymphocytes from three patients with mycosis fungoides and from four patients with lymphocytic leukemia accompanied by exfoliative erythroderma were shown to have membrane pro...

Antibody-Dependent Lymphoid Cell-Mediated Cytotoxicity: No Requirement for Thymus-Derived Lymphocytes

The capacity of lymphoid cells from nonsensitized mice to lyse antibody-coated target erythrocytes in vitro does not require the presence of thymus-derived or thymus-dependent lymphocytes. Thus, spleen cells from thymus-deprived mice and spleen cell populations from which thymus-dependent lymphocytes had been removed were fully competent to mediate destruction of antibody-coated target cells. However, prior treatment of spleen cell populations with antibody to κ chains diminished this function, suggesting a role for bone marrow-derived lymphocytes.

Studies of Immune Functions of Patients with Systemic Lupus Erythematosus: COMPLEMENT-DEPENDENT IMMUNOGLOBULIN M ANTI-THYMUS-DERIVED CELL ANTIBODIES PREFERENTIALLY INACTIVATE SUPPRESSOR CELLS

Patients with systemic lupus erythematosus (SLE) produce excessive amounts of autoantibodies. It has also been demonstrated in several systems that such patients have a relative loss of suppressor thymus-derived (T) cells that inhibit the immune response. This loss of suppressor cells has been suggested as one of the causes of the excessive production of antibodies in patients with SLE. In the present report we have tested the hypothesis that anti-T-cell antibodies found in the plasma of some patients with SLE preferentially kill suppressor cells. T cells from normal individuals can be activated by concanavalin A to develop suppressor cell activity. We therefore cultured normal T cells together with concanavalin A in the presence of plasma or plasma fractions from patients with SLE. We found that plasma from patients with active SLE, in which anti-T-cell antibodies were present, inhibited the development of suppressor activity in such cultures. In contrast, plasma from other active patients and patients with inactive SLE, in which no anti-T-cell antibodies could be detected, failed to block the development of such suppressor activity. Absorption of the plasma that contained anti-T-cell antibodies with T cell, but not non-T cells, could eliminate the suppressor-inhibiting activity of the SLE plasma that contained anti-T-cell antibodies. The immunoglobulin (Ig)M, but not the IgG, fraction of the plasma was shown to possess the inhibiting property and complement was found to be necessary for the effect of such anti-T-cell antibodies. We also demonstrated that exposure of normal T cells to such anti-T-cell antibodies and complement did not affect another population of T cells that could proliferate in response to mitogens.Thus, certain patients with SLE have in their plasma an antibody of the IgM class that can selectively eliminate a population of T cells capable of developing suppressor function. The loss of suppressor T cells in patients with SLE may be the result of the effects of such antibody activity in vivo.

Leukemic reticuloendotheliosis: Presence of a receptor for cytophilic antibody

Abstract Neoplastic cells from the spleens of two patients with leukemic reticuloendotheliosis were studied in cell suspensions and in frozen sections for the antigen-antibody complement (IgMEAC) receptor of B lymphocytes and for the receptor for cytophilic antibody (IgGEA) of monocytes. A high percentage of the neoplastic cells, both in suspension and in sections, bound the IgGEA reagent but failed to bind the IgMEAC reagent. These findings suggest that these cells belong to the monocyte-histiocyte series.

Genetically controlled total deficiency of the fourth component of complement in the guinea pig.

Guinea pigs with a total deficiency of the fourth component of complement (C4) have been discovered. There was no evidence for the presence of a C4 inhibitor in the serum of these animals. Mating studies indicate that C4 deficiency is transmitted as a simple autosomal recessive trait. A colony of these animals is being established at the National Institutes of Health. They will provide an opportunity to more precisely define the role of complement in immune phenomena and the defense against disease.

Structural and functional properties of the "hairy" cells of leukemic reticuloendotheliosis.

Structural and functional studies were performed on „hairy”︁ cells from 7 patients with leukemic reticuloendotheliosis („hairy cell leukemia”︁) (HCL). In all cases tartrate‐resistant acid phosphatase‐containing cells were demonstrated. The abnormal cells displayed complement receptors in 6 cases although there was variation in the number of abnormal cells expressing the receptor. Receptors for IgG were present in all 7 cases on a high number of abnormal cells. In 6 cases the „hairy”︁ cells showed surface immunoglobulins (SIg) when examined immediately after isolation. Procedures to eliminate in vivo bound protein substantially decreased the number of SIg‐bearing cells, indicating that most SIg represented cytophilic protein. In 2 cases, however, SIg restricted to a single light chain type remained on the abnormal cells, suggesting that in these 2 cases the SIg may have been an intrinsic cellular product. Attempts to demonstrate immunoglobulin synthesis were unsuccessful and there was no evidence that the „hairy”︁ cells contained cytoplasmic immunoglobulin. In vitro phagocytosis of latex particles by the abnormal cells was observed in all cases by transmission electron microscopy although the number of phagocytic „hairy”︁ cells varied widely from case to case. In 4 of 5 spleens with HCL, normal macrophages detected by the presence of nonspecific esterase were abundant and markedly enlarged. The electronic size distribution of HCL suspensions demonstrated a characteristic double‐peaked curve and modal volumes seldom seen in other chronic leukemias or lymphomas. Quantitative scanning electron microscopic analysis of HCL populations corroborated that the peculiar „hairy”︁ appearance of the abnormal cells was due to extensive surface ruffles which are not observed in normal or neoplastic lymphocytes. Our findings suggest that the „hairy”︁ cells are structurally and functionally unique elements, different than any other normal or abnormal cell of the lymphoreticular system known at present. Studies of cellular DNA quantitation and thymidine incorporation indicated that the growth rate of the „hairy”︁ cells is exceedingly low.

Receptors for Complement and Immunoglobulin on Human and Animal Lymphoid Cells

The mononuclear cells participating in immune responses are heterogeneous both morphologically and functionally. During the past few years a number of receptors and differentiation antigens have been identified on different immunologically competent cells. The presence or absence of these receptors on mononuclear cells of unknown type may provide information as to their origin. Bone marrow derived (B lymphocytes) can be identified by the presence of easily detectable surface immunoglobulin (Raff 1970); most B lymphocytes also have a receptor for antigen-antibody-complement complexes which is detected by using red cells (E) coated with antibody (A) and complement (C) (Bianco et al. 1970). B lymphocytes can also be identified by the presence of a receptor for he F^ portion of immunogiobulin G (Basten et al. 1972a,b) which can be detected with antigen-antibody complexes, or by using fluorescein-labeled aggregated gamma globulin (Dickler & Kunkel 1972). In the mouse, thymus derived (T lymphocytes) can be identified by the presence of the theta iso-antigen; in man, most T lymphocytes form non-immune rosettes with sheep red blood cells by as yet unknown receptors (Lay et al. 1971, Jondal et al. 1972). It has also been possible to identify human T cells (WilUams et al. 1973) by the use of heterologous anti-thymocyte sera which have been rendered specific for T cells by absorption with a pure population of B cells. Cells of the monocytemacrophage series also bear a receptor for EAC (Huber et al. 1968) and

Plasmodium falciparum malaria. An amelanotic melanoma cell line bears receptors for the knob ligand on infected erythrocytes.

Erythrocytes infected with Plasmodium falciparum trophozoites and schizonts are not seen in the peripheral circulation because they attach to venular endothelium via knoblike structures on the infected erythrocyte membrane. We have recently shown that erythrocytes containing P. falciparum trophozoites and schizonts likewise attach to cultured human venous endothelial cells via knobs. In search of a more practical target cell for large scale binding studies designed to characterize and isolate the knob ligand, we tested various normal cells and continuous cell lines for their ability to bind P. falciparum-infected erythrocytes. Of the 18 cell types tested, binding of infected erythrocytes was observed to a human amelanotic melanoma cell line and amnion epithelial cells as well as to human aortic and umbilical vein endothelial cells. 96-100% of amelanotic melanoma cells bound 17+/-4 (+/-1 SEM) infected erythrocytes per positive cell, whereas fewer endothelial cells (4-59%) and amnion epithelial cells (8-19%) were capable of binding 12+/-5 and 4+/-1 infected erythrocytes per positive cell, respectively. Further studies designed to compare the mechanism of binding to the amelanotic melanoma cell line and endothelial cells showed the following results. First, that adhesion of infected erythrocytes to these two cell types was parasite stage-specific in that only erythrocytes containing late ring forms, trophozoites, and schizonts bound. Erythrocytes containing early ring forms, which do not attach to venular endothelium in vivo, did not bind to either cell type. Second, erythrocytes infected with trophozoites and schizonts of P. vivax or a knobless strain of P. falciparum, both of which continue to circulate in vivo, did not bind to either target cell type. Third, transmission electron microscopy showed that infected erythrocytes attached to the amelanotic melanoma cells via knobs. We conclude that cultured human endothelial cells and an amelanotic melanoma cell line share common determinants on their surface and that the mechanism of binding to these two different cell types is similar. The amelanotic melanoma cell line offers a useful substitute for endothelial cells in binding studies requiring large numbers of target cells.

Studies of immune functions of patients with systemic lupus erythematosus. T-cell subsets and antibodies to T-cell subsets.

Antibodies to T cells present in the plasma of patients with active systemic lupus erythematosus (SLE) plus complement are able to eliminate concanavalin A-induced suppressor function for the proliferative responses of T cells to allogeneic lymphocytes (MLR) and of B cells to pokeweed mitogen (PWM). Such antibodies were found to be effective in eliminating suppressor function only when T cells were treated before activation; there was no effect when treatment was performed after activation. These studies indicate that the antibodies preferentially interact with a T cell necessary for the generation of suppressor cells, rather than with mature, activated suppressor cells. Studies of individual SLE patients indicate that the same defects observed in SLE T cells were induced in normal T cells by plasma from that patient. Such observations suggest that many T-cell defects associated with active SLE may not be intrinsic T-cell abnormalities, but, rather, secondary effects of anti-T-cell antibodies. Studies of the T-cell subpopulations responsible for suppression of the MLR and PWM responses indicate that only T gamma cells (T cells bearing receptors for the Fc portion of immunoglobulin [Ig]G) acted as precursors of suppressor cells for the MLR, whereas both T gamma and T non-gamma cells (T cells not bearing receptors for the Fc portion of IgG) could be activated to suppress the PWM response. Consistent with this observation, SLE anti-T-cell antibodies that preferentially killed T gamma cells preferentially eliminated suppressor cells for the MLR.