Idiopathic giant cell granulomatous hypophysitis with hypopituitarism, right abducens nerve paresis and masked diabetes insipidus.

A 38-year-old man presented with headache, fever, and double vision associated with right abducens nerve paresis. He had neither nuchal rigidity nor visual field defect. Laboratory data revealed elevated erythrocyte sedimentation rate (ESR), eosinophilia, and lymphocytic pleocytosis in the cerebrospinal fluid (CSF). Provocation tests of pituitary hormones showed partial hypopituitarism. Magnetic resonance imaging (MRI) revealed swelling of the hypophysis and a mass lesion expanding into the right cavernous sinus. The supplement dose of dexamethasone for hypothalamic hypocortisolism manifested diabetes insipidus. Biopsy, carried out through the transsphenoidal approach, revealed giant cell granuloma. Systemic granulomatous diseases were ruled out, and the lesion was considered to be idiopathic giant cell granulomatous hypophysitis. Right abducens nerve paresis, diabetes insipidus and dysfunction of the anterior lobe were amended by the treatment with prednisolone for 4 months, and findings of the pituitary gland and stalk were normalized. The present case shows that glucocorticoid has an effect on amendment of idiopathic giant cell granulomatous hypophysitis.

Ph-negative non-Hodgkin's lymphoma occurring in chronic phase of Ph-positive chronic myelogenous leukemia is defined as a genetically different neoplasm from extramedullary localized blast crisis: report of two cases and review of the literature.

This report describes two cases of Philadelphia chromosome-negative (Ph(-)) non-Hodgkin's lymphomas (NHLs) recognized in patients with chronic phase Ph-positive (Ph(+)) chronic myelogenous leukemia (CML). Lymph node biopsy of patient 1 was initially diagnosed as diffuse large B cell non-Hodgkin's lymphoma (NHL, T cell rich variant), but at relapse showed immunoblastic features with a marked decrease of admixed lymphocyte components. Patient 2 presented with thickened parietal pleura which revealed a CD30-positive anaplastic large cell lymphoma showing null cell phenotype and genotype with abundant admixed neutrophils and lymphocytes. At the time of lymphoma diagnosis, the patients had CML for 33 and 10 months, respectively. DNA obtained from bone marrow cells at the time of lymphoma diagnosis showed BCR/ABL gene rearrangements by both Southern blot analysis and reverse transcription polymerase chain reaction (RT-PCR), but lacked both immunoglobulin and T cell receptor gene rearrangements. BCR gene rearrangement and BCR/ABL fusion gene were also identified in lymph node and pleural biopsies by Southern blot and RT-PCR analysis, respectively. However, both biopsy specimens also contained reactive lymphocytes and neutrophils, and no fusion signals between BCR and ABL genes were identified in the hyperdiploid lymphoma cells of either case by fluorescence in situ hybridization (FISH). These data suggest the lymphoma cells in both cases were not genetically associated with BCR/ABL. Therefore, these cases were not diagnosed as an extramedullary localized blast crisis in CML, but as Ph(-) NHLs. This represents the first definitive demonstration of peripheral B cell lymphoma occurring by a separate genetic pathway, lacking BCR/ABL, in patients with Ph(+) CML. A review of the literature identified two different subtypes of malignant lymphomas arising in patients with an antecedent or concurrent diagnosis of CML. The most common are T cell lymphomas displaying an immature thymic phenotype, while peripheral B cell lymphomas are more rare. Our study shows, however, that 'Ph(+) NHL' occurring in CML or acute lymphocytic leukemia (ALL) may represent an unrelated neoplasm, even if standard cytogenetic analysis reveals a Ph(+) chromosome, and that FISH is required to confirm whether a localized lymphoid neoplasm is either a true extramedullary localized blast crisis or genetically distinct neoplasm. Leukemia(2000) 14, 169-182.

[The expression of IL-2 receptor subunits on various leukemic cells].

Interleukin-2 receptors are composed of at least two polypeptide chains of alpha (55KD) and beta (75KD). The IL-2R beta chain is an essential component of the functional receptor for signal transduction of IL-2. We previously reported the distribution of IL-2R subunits among peripheral blood mononuclear cells. We here present some data regarding the expression of IL-2R subunits on various hemopoietic malignant cells. Fresh leukemic cells obtained from adult T cell leukemia patients expressed both alpha and beta chains, and leukemic cells derived from some patients with T cell leukemia, B cell leukemia or myeloid leukemia expressed the alpha and/or beta chain of IL-2R. The IL-2R beta chain on these leukemic cells were demonstrated to be functional for cell growth signaling. IL-2R alpha and beta chains should be tumor markers.

Anti-DNA idiotypes deposited in renal glomeruli of patients with lupus nephritis.

Idiotypes (Id) of human anti-DNA antibodies, designated as O-81 Id, were specifically detected on the immune deposits of renal glomeruli in 46% of patients with lupus nephritis. Id-binding to anti-Id antibodies was blocked by free O-81 Id and to some extent by free DNA. DNase or acid buffer treatment failed to reveal new Id determinants on the deposits. O-81 Id and NE-1 Id activity were also detected on the renal eluate-derived IgG, but not IgM from the autopsy cases with lupus nephritis. The incidences of O-81 Id were not associated with histological features in the glomeruli, but the distribution patterns were similar to those of IgG deposits. Our study also showed that 65% to 70% of patients with IgG deposits either in the subendothelium or in the subepithelial area of the glomerular basement membrane (GBM) showed positive tests for O-81 Id. It was also noted that most patients with massive proteinuria had O-81 Id in their glomeruli. It is concluded that O-81 Id deposits are relatively specific for active lupus nephritis and that immunofluorescence studies using anti-Id antibodies may be clinically useful for specifying the renal lesions of systemic lupus erythematosus (SLE).

Selective absorption of anti-DNA antibodies and their idiotype-positive cells in vitro using an anti-idiotypic antibody-affinity column: possible application to plasma exchange.

We examined the possibility of using affinity columns coupled with anti-idiotype (Id) antibodies to selectively remove nephritogenic anti-DNA antibodies in order to determine their possible application to therapeutic plasmapheresis. Monoclonal anti-Id antibodies termed D1E2 or 1F5 were directed to idotypes of human anti-single-stranded and anti-double-stranded DNA antibodies. The mixture of D1E2- and 1F5-coupled Sepharose absorbed 26 to 92% of human anti-DNA antibodies in sera. The affinity columns were also effective in removing anti-DNA idiotype-positive cells from the blood samples of patients, especially those with active lupus nephritis. Thus, an anti-idiotypic antibody-coupled affinity column could, in theory, serve as a tool for selective plasma exchange in the therapy of autoimmune disease.

Impaired accessory cell function of monocytes in systemic lupus erythematosus.

We studied the ability of monocytes from systemic lupus erythematosus (SLE) patients to act as accessory cells in an in vitro antibody response. Depletion of monocytes from peripheral blood mononuclear cells of normal subjects caused markedly diminished immunoglobulin (Ig) production but that of SLE did not. In order to evaluate the accessory cell activity of monocytes in in vitro immunoglobulin (Ig) production, we designed an accessory cell index of monocytes in the antibody responses. The studies revealed that Ig synthesis of isologous lymphocytes, mixed with monocytes from patients with active lupus nephritis, was significantly lower than those mixed with monocytes from healthy subjects. Moreover, the addition of graded numbers of monocytes of the former to unseparated peripheral blood mononuclear cells did not alter in vitro antibody production. These results indicate that monocytes from active SLE patients have an impared accessory cell function in an in vitro antibody response with no stimulating effect on suppressor cell activity.

In vitro manipulation of human anti-DNA antibody production by anti-idiotypic antibodies conjugated with neocarzinostatin.

Anti-DNA Id, 0-81, consist of 5 to 51% of Id in human anti-ssDNA antibodies; NE-1-Id shares 2 to 20% of those in anti-dsDNA antibodies. Thus, both 0-81-Id and NE-1-Id are of the cross-reactive Id that are commonly present among anti-DNA antibodies. In order to manipulate the production of anti-DNA antibodies by human PBL, we used mouse antiidiotypic mAb or those conjugated with a cytotoxic agent, neocarzinostatin. Treatment with the conjugates caused profound suppression of anti-ssDNA and anti-dsDNA antibody synthesis related to 0-81- and NE-1-Id. This was attributed to the specific killing of the clones bearing anti-DNA Id among the lymphocytes, evidenced by the indirect rosette formation tests. The Id-mediated suppression was not solely due to selective elimination of Id-positive B cells, because 50 to 92% of anti-DNA antibodies were suppressed by treatment with the conjugates. This was supported by flow cytometry analysis that showed a decrease of anti-Id-reactive cells when T cells were treated with the conjugates. This method, then, will permit an analysis of the question as to whether T cells reactive to anti-idiotypic antibodies might participate in the regulatory mechanism for anti-DNA production and, in addition, may lead to a new therapy for SLE.

Binding specificity of antiidiotypic autoantibodies to anti-DNA antibodies in humans.

Human antiidiotypic antibodies to anti-DNA antibodies can be separated into at least two categories based on their binding to anti-DNA, antiidiotypic antibodies, and antigens. One type was found mainly in inactive stage of SLE. The antiidiotypic antibodies appear to be directed towards idiotype (Id) determinants in the antigen-binding sites of anti-DNA antibodies. Antibody from patient T.K. acted like a mirror image of anti-single-stranded DNA antibodies, O-81, as determined by a competitive inhibition RIA. Antibodies from patient S.U. also seemed to be Ab 2 beta and Ab 2 gamma to anti-double-stranded(ds) DNA antibodies, NE-1. Most of normal subjects, on the other hand, had antibodies that bound to the human monoclonal anti-ds DNA antibodies, NE-1, NE-13, 7F4, and O-81. The Id-anti-Id interaction was not inhibited by the addition of DNA. Thus, normal subjects had Ab2 alpha activity that recognizes Id determinants in the framework region common among anti-DNA antibodies, whereas antiidiotypic antibodies in most SLE sera appear to show Ab 2 beta and Ab 2 gamma activity. The results provide evidence that the Id network system regulates immunological tolerance to DNA in humans.

Epstein-Barr virus-transformed B cells bearing idiotypes of anti-DNA autoantibodies.

Epstein-Barr virus (EBV)-transformed B cells obtained from healthy subjects had the same idiotypes of anti-DNA autoantibodies on their surface as those obtained from patients suffering from systemic lupus erythematosus. These clones secreted anti-single-stranded or anti-double-stranded DNA antibodies. Among them, some produced anti-DNA idiotype-positive antibodies but failed to bind DNA. This was confirmed by a competitive inhibition radioimmunoassay. It was then considered whether or not the expression of anti-DNA idiotype on B-cell clones related to the anti-DNA antibody activity in vivo. The amounts of anti-DNA antibodies were not associated with the incidence of idiotype-positive B cells in the EBV-transformed cell lines from normals. The results indicate that the clones committed to the synthesis of anti-DNA idiotype-positive antibodies commonly exist at a resting state in the circulation of healthy subjects, probably through the self-tolerance regulatory system.

Heterogeneity of anti-idiotypic antibodies to anti-DNA antibodies in humans.

Serum antibodies in some patients with systemic lupus erythematosus (SLE) were found to have specificity to idiotypes (Id) of 0-81 (human monoclonal anti-single-stranded DNA (ssDNA) antibody) but not to Id of NE-1 (human monoclonal anti-double-stranded DNA (dsDNA) antibody) or pooled human IgM. The interaction of the antibodies and 0-81 was blocked by the co-existence of free ssDNA. Some of SLE sera also showed preferential binding to Id determinants of NE-1, which included the antigen-binding sites of the dsDNA antibody. Some other SLE sera reacted with both Id of 0-81 and NE-13. Thus, there was heterogeneous population among human anti-Id autoantibodies to anti-DNA antibodies. The anti-Id activity was commonly detected in inactive SLE sera, and less frequently in normal controls, suggesting some regulatory role for anti-Id antibodies in the production of autoantibodies.

Antigen inhibition of the interaction between murine monoclonal anti-idiotypic antibodies and human monoclonal anti-DNA antibodies.

Monoclonal anti-idiotypic (Id) antibodies to human monoclonal anti-DNA antibodies were obtained by a somatic cell hybridization. One, termed as D1E2, was directed to Id of anti-single-stranded (ss) DNA antibody (0-81) and the other, 1F5, to anti-double-stranded (ds) DNA antibody (NE-1). Each anti-Id antibody behaved like a mirror image of the corresponding antigens, when determined by competitive inhibition radioimmunoassay. Therefore, D1E2 and 1F5 are regarded as Ab2 beta or Ab2 gamma. These antibodies will make useful reagents to understand and manipulate the autoantibody production in human.

Selective elimination of anti-DNA antibody-producing cells by antiidiotypic antibody conjugated with neocarzinostatin.

A new strategy was shown for the manipulation of autoantibody production in humans. Antiidiotypic antibody to human anti-DNA autoantibody was conjugated with neocarzinostatin (NCS), a cytotoxic agent, by using N-succimidyl 3-(2-pyridyldithio) propionate as a coupling agent. Human B cell clones, which produce anti-DNA autoantibodies, were killed by in vitro treatment with antiidiotype (Id)-NCS conjugates, while clones expressing an Id with irrelevant specificity were unaffected. These results indicate that treatment with anti-Id-NCS conjugates can act as a potent and specific means of generating immunosuppression of autoantibody production. This approach will have a significant advantage in aborting clones that are not effectively suppressed for the autoantibodies by anti-Id antibodies alone, and will result in a potential therapeutic treatment for systemic lupus erythematosus.

Expression of idiotype on the surface of human B cells producing anti-DNA antibody.

We analyzed the idiotype (Id) expression on the surface of human anti-DNA antibody-producing cells. Murine monoclonal anti-Id antibodies with a specificity for determinants associated with the antigen-binding sites of human monoclonal anti-DNA autoantibodies were prepared. One anti-Id antibody reacted only with surface Id on anti-ssDNA-producing cells, but not with those on anti-dsDNA-producing B cell clones. Another anti-Id antibody did bind the surface Id on anti-dsDNA clones, but not those on anti-ssDNA clones. The interaction between anti-Id and surface Id was inhibited by pretreatment of the clones with DNA or appropriate polynucleotide antigens, or by preabsorption of anti-Id antibodies with free anti-DNA antibodies. Surface IgM and IgD expressed the same Id as the antibody secreted from the clones. The treatment of Id-positive clones by anti-Id antibody induced the redistribution of surface Id on the cells, indicating that these cells serve as targets for the regulatory action of anti-Id antibody.

Monoclonal human anti-DNA antibodies from EB virus-transformed lymphocytes of systemic lupus erythematosus (SLE) patients.

Sixteen monoclonal human anti-DNA antibodies were obtained from Epstein-Barr virus-transformed lymphoblastoid cells of patients with systemic lupus erythematosus (SLE) and were studied in terms of antigenic specificity. All of the antibodies showed polyspecificity to polynucleotides. Among them, some antibodies had a specificity to single-stranded (ss) DNA. Especially, O-8 antibodies showed a preference for polynucleotides with pyrimidine bases. The binding specificity of the antibody was also studied using different sizes of dT oligomers in order to assess the size of the epitope. It was revealed that oligonucleotides with a size of more than 25-30 nucleotides are required for inhibition of the antibody to ss-DNA. Other studies also demonstrated that anti-ss-DNA (O-8) antibody and anti-double-stranded (ds) DNA (NE-28) antibody bound to different combining sites in the same polynucleotides, poly(dT). These results suggest that some anti-ss-DNA antibodies are directed to the conformational structure related to the base sequence and that nucleic acids, therefore, might be responsible for the possible immunogenic stimulus causing the anti-DNA immune response. We also indicate that this type of antibody would be popular among serum anti-DNA antibodies in SLE.