Cyclosporin A (CsA) is a potent immunosuppressive agent that inhibits T-cell proliferation and lymphokine production. There is less information on the direct effect of CsA on B-cells. We investigated the proliferative responses of human tonsillar B-lymphocytes to a "T dependent" mitogen, pokeweed mitogen (PWM), and to a "T independent" mitogen, Staphylococcus aureus (SA). Both responses were strongly inhibited by CsA. Nonspecific cytotoxicity was ruled out, and the inhibition was not reversed by adding IL1, IL2, or BCGF individually or in combination. Maximal inhibition of the PWM response occurred when CsA was added early in the culture period. Cyclosporin A added 18 hours after the start of culture was less effective, and adding CsA after 36 hours resulted in only minimal inhibition. However, with SA as mitogen, addition after 36 hours still affected substantial inhibition. These results, on the time of action and resistance to reversal by exogenous growth factors, suggest that CsA can directly inhibit human B-cells by a mechanism similar to its action on T-lymphocytes, blocking an early event critical to entry into cell cycle, but an additional mechanism of inhibition later in the cell cycle may also operate when the proliferative signal is provided by the T-independent mitogen SA.
Summary.-This study examines the link between free immunoglobulin (Ig) lightchain (LC) secretion and the developmental stage of the neoplastic B-cell of origin in B-cell lymphomas. The Kiel developmental scheme for lymphoma classification has been used to define the tumour-cell populations. Twenty-four B-cell lymphomas have been studied. In the small -lymphocytic lymphoma group, secreted Ig consisted of LC exclusively or in excess over heavy-chain (HC). Lymphomas of follicularcentre-cell origin, considered to be from cells further along the normal B-cell differentiation pathway, can be divided into centroblasts or centrocytes according to their histological appearance in tissue sections. Centroblastic lymphomas exhibited strong surface IgM or IgG expression, and the secretion of whole Ig was higher than by cells from the small-lymphocytic lymphomas. Synthesis of HC and LC was balanced in these cultures, both intracellularly and in secreted material. The centrocytic lymphomas comprised a functionally more heterogeneous group, the SIg varied in intensity and was of surface IgM, D or G. Likewise Ig synthesis was variable in quantity and composition, some cases secreting LC exclusively while others, including the cases expressing SIgG, secreted balanced HC and LC. In the Kiel classification centrocytes are considered to be more mature than centroblasts. Our data suggest that centrocytic lymphomas are heterogeneous in origin, some preceding and others following centroblasts in the B-cell maturation sequence. These data are discussed in relation to current concepts of B-cell maturation and lymphoma histology.
Neoplastic cells from 2 cases of CLL synthesized and secreted excess free Ig light chain in culture, confirmed by precipitation with anti-idiotypic antibody. Small and medium sized normal human spleen cell subpopulations, staining predominantly for surface IgM and D, also synthesized and secreted excess free light chain. PWM stimulation induced balanced synthesis of heavy and light chains in CLL and normal spleen subpopulations after 6 days in culture, accompanied in spleen but not CLL by the appearance of mature plasma cells. These data demonstrate that normal cell counterparts of neoplastic lymphoid synthesis patterns can be identified in spleen. Furthermore, the synthesis pattern alteration after PWM stimulation suggests a relationship between free light chain synthesis and B cell immaturity. The failure of CLL cells to develop into detectable plasma cells suggests a restricted maturation response to mitogen compared with normal spleen.
A detailed study is described of a case of hairy cell leukaemia, presenting with a serum paraprotein of an immunoglobulin (Ig) class different from that synthesised by the neoplastic cells. The case was unusual in its association with leukaemic arthropathy but ultrastructurally the hairy cells were typical. By immunofluorenscence and immuno!electron microscopy the neoplastic cells expressed IgAh both on the cell surface and intracellularly in the rough endoplasmic reticulum, perinuclear space and Golgi apparatus. No Ig was observed in the ribosomal-lamellae complexes. These cells also synthesised and secreted Ig of class Ah in culture. However the serum paraprotein was of class IgAx and could not be attributed to an abnormal population of plasma cells in the bone marrow. There was no other evidence for myeloma and the IgAx paraproteinaemia appeared to be benign, apparently unrelated to the neoplastic proliferation of hairy cells.
The ultrastructural localization of immunoglobulin heavy and light chains has been investigated in nine haematopoietic cell lines, using a technique which involves the treatment of lightly prefixed cells with saponin to allow penetration of the antibody‐peroxidase conjugate. The synthesis and secretion of immunoglobulin was also studied in these cell lines. Immunoglobulin was found to be localized in the cisternae and on the membranes of the rough endoplasmic reticulum, perinuclear space and/or Golgi apparatus. In each case staining for heavy chains was weak or absent in the perinuclear space while staining for light chains was usually strong. Additionally in three cell lines immunoperoxidase staining indicated that heavy chains were absent from the Golgi apparatus despite the observed presence of light chains in the Golgi apparatus and the secretion of combined immunoglobulin into the supernatant. The results obtained suggest compartmentalization of the synthesis of light and heavy chains and indicate that the technique of immunoelectron microscopy may significantly contribute to an understanding of the mechanisms involved in immunoglobulin synthesis, intracellular transport and secretion.
The ultrastructural localization of immunoglobulin heavy and light chains has been investigated in nine haematopoietic cell lines, using a technique which involves the treatment of lightly prefixed cells with saponin to allow penetration of the antibody-peroxidase conjugate. The synthesis and secretion of immunoglobulin was also studied in these cell lines. Immunoglobulin was found to be localized in the cisternae and on the membranes of the rough endoplasmic reticulum, perinuclear space and/or Golgi apparatus. In each case staining for heavy chains was weak or absent in the perinuclear space while staining for light chains was usually strong. Additionally in three cell lines immunoperoxidase staining indicated that heavy chains were absent from the Golgi apparatus despite the observed presence of light chains in the Golgi apparatus and the secretion of combined immunoglobulin into the supernatant. The results obtained suggest compartmentalization of the synthesis of light and heavy chains and indicate that the technique of immunoelectron microscopy may significantly contribute to an understanding of the mechanisms involved in immunoglobulin synthesis, intracellular transport and secretion.
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