Systemic lupus erythematosus induced by therapy with interferon-beta in a patient with multiple sclerosis.
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Biomedical subjects
Publications and source records attributed to E Díaz-Jouanen.
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Urinary bladder histologic changes were found in 16 of 35 necropsies from systemic lupus erythematosus (SLE) patients in whom adequate material was available for study. These included interstitial cystitis (n = 11), hemorrhage (n = 9), congestion (n = 7), vasculitis (n = 5), and perivenular infiltrate (n = 4). Abnormalities were found in only 5 of 30 control necropsies from patients with other diseases and in 4 of them these were hemorrhagic and chiefly due to indwelling catheters. SLE patients with histologic bladder changes were found to have pulmonary hemorrhage more frequently than those without. This suggests a common pathogenetic mechanism between interstitial cystitis and pulmonary hemorrhage in SLE.
Pregnant systemic lupus erythematosus (SLE) patients with inactive disease were found to have normal spontaneously generated suppressor-cell function and slightly higher concanavalin A-induced suppressor function as compared to matched normal pregnant and nonpregnant females. In six SLE patients studied sequentially throughout pregnancy and postpartum, suppressor functions were found to fall sharply within the first week after delivery. One of these patients had been studied before she became pregnant and found to have a decreased suppressor function. Nonpregnant SLE patients had both suppressor functions diminished despite their disease being similarly inactive. This group was also the only one to have decreased responses in autologous mixed-lymphocyte cultures. Both pregnant and nonpregnant SLE patients had decreased absolute numbers of total lymphocytes, T cells, and their subpopulations, but the proportions of these cells were similar in all four groups. Despite this apparent normalcy of immune regulation, pregnant SLE patients had higher levels of Clq-binding immune complexes than did nonpregnant ones. Functional T-cell abnormalities found in SLE patients tend to be corrected by pregnancy. This may explain in part the disease remissions that occur in them during the second half of pregnancy.
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We have completed 59 cytofluorographic studies of DNA/RNA content in acridine orange-stained peripheral blood mononuclear cells from 44 patients with systemic lupus erythematosus, most of whom received no medications. Most such cells were in resting phases of the cell cycle, particularly those from patients with inactive disease. Nine patients with systemic lupus erythematosus had increased percentages of these cells in the synthesis and postsynthesis phases of the cell cycle; the B lymphocyte had a greatest proportions of activated cells. In 11 patients, we found that cells, particularly T lymphocytes, had increased RNA content without a proportional increase in DNA. This DNA block occurred primarily in patients with serum antibodies to DNA and it could be reproduced in normal mitogen-stimulated mononuclear cells incubated in heat-inactivated sera from patients with systemic lupus erythematosus whose own cells showed abnormalities of DNA/RNA content or in purified native DNA antibody. The DNA blocking potential of the DNA antibody was dependent on its Fc portion and on the presence of Fc receptors on T cells. Thus, saturation of Fc receptors by pretreatment with aggregated IgG or incubation with the whole antibody in the cold prevented the DNA block, indicating that it was an active process.
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Human autologous-rosette-forming T cells (Tar cells) have many of the characteristics of post-thymic precursor cells. Thus, they bind to sheep erythrocytes but have neither receptors for the Fc portion of IgG nor for that of IgM. They include a subpopulation that binds peanut agglutinin which suggests that they are immature and, as opposed to T cells with either receptors for the FC portion of IgM (T mu) or of IgG (T gamma), Tar cells adhere to nylon wool, another possible indicator of immaturity, as is their extreme sensitivity to hydrocortisone both in vitro and in vivo. There are more Tar cells in cord blood than in the peripheral blood of young adults and there are more Tar cells in the peripheral blood of young adults than in the peripheral blood of elderly subjects. By co-culturing T mu and B cells, or T mu, or Tar and B cells in the presence of pokeweek mitogen (PWM) we were able to determine that these cells cause feedback inhibition, a function considered characteristic of post-thymic precursors. In co-cultures in which we placed mononuclear cells (MNC) or MNC plus Tar cells, or MNC depleted of Tar cells or MNC depleted of Tar cells plus Tar cells stimulated with PWM, we determined that Tar cells play a role in the generation of suppression thereby confirming that human Tar cells are precursor cells. We also found that Tar cells proliferated and generated T gamma and T mu cells both spontaneously and in greater numbers, under the effect of serum thymic factor.
We have recently described that human autologous rosette-forming (Tar) cells have the characteristics of postthymic precursor cells. Herein we report that we found circulating Tar cells significantly diminished in 32 patients with untreated systemic lupus erythematosus (SLE) as compared to 32 age/sex matched controls. Pretreatment of peripheral blood mononuclear cells (MNC) from SLE patients with serum from young normal adults or wtih serum thymic factors (FTS) increased their percentages of Tar cells significantly but reached near normal values in only 3 patients with inactive disease. Patients and normal subjects had similar percentages of Tar cells binding peanut-agglutinin. Characteristic functions of postthymic precursor cells are feedback inhibition and generation of suppressor cells which we studied in systems where we depleted or added Tar cells to Tmu and B cells, or MNC, respectively, using as indicators the production of immunoglobulins measured in culture supernatants or 3H-thymidine incorporation. We found both functions diminished in SLE patients despite using the presence of a qualitative as well as quantitative defect. In two SLE patients studied both of these functions corrected partially when their Tar cells were pretreated with FTS. In 20 SLE patients we studied Tgamma and Tmu cells as well as Concanavalin-A-induced, spontaneously-expanded suppression and found Concanavalin-A-induced, spontaneously-expanded suppressor function and Tgamma cells diminished. However only the reduction of Tgamma and of spontaneously-expanded suppressor function were found to relate to disease activity. On the other hand, Tmu cells were found to be similar in numbers in SLE patients and normal controls.
The same Fc gamma receptor appears to be shared for two important phenomena: antibody-dependent cellular cytotoxicity (ADCC) and antibody penetration into living cells. ADCC is inhibited through interaction with the Fc gamma receptor during the antibody penetration process, indicating that both mechanisms may modulate each other in vitro.
Cells subjected to nucleoside incorporation studies using radiolabelled materials may suffer radiation damage that can alter the results. We did scintimetric and cytofluorographic analysis to confirm this and to determine the optimal experimental doses of, and exposure times to, [3H]-TdR, in order to prevent or minimize such radiation damage to cells. We found that cultures should be pulsed with 0.125 microCi for 14 hr when stimulated with phytohaemagglutinin 0.125 microCi for 18 hr when stimulated with pokeweed mitogen, 0.5 microCi for 8 hr when stimulated with concanavalin A and 0.5 microCi for 8 hr when subject to allogeneic stimulus, in order to achieve optimal incorporation with minimal disturbance of the cell cycle.
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Autologous rosette-forming cells (Tar cells) have surface and functional characteristics of post-thymic precursors and among these characteristics there are some that have been identified in the responsive cell of the autologous mixed-lymphocyte reaction (AMLR). We therefore did AMLR with circulating mononuclear cells from normal subjects using as responding cells either total T cells, T cells depleted of Tar cells, or purified Tar cells. The response of Tar cells in AMLR was significantly greater than that of total T cells and these responded significantly more than Tar-depleted T cells. Conversely, Tar cells responded less than total T cells or T cells depleted of Tar cells in allogeneic mixed-lymphocyte reactions. Increasing numbers of Tar cells gave significantly greater AMLR responses both alone and when added to diminishing proportions of Tar-depleted T cells to keep the number of T cells constant in the system. Tar cells are the responding cells in AMLR but not in allogeneic mixed-lymphocyte reactions.
Phytohemagglutinin-induced cellular cytotoxicity by normal mononuclear cells (MNC) is inhibited by serum of patients with active untreated systemic lupus erythematosus (SLE) but not by that of patients with untreated inactive SLE or rheumatoid arthritis. Three-hour preincubation of normal MNC with SLE sera suffices to inhibit throughout the assay. Preincubation with phytohemagglutinin (PHA) before addition of sera does not prevent the inhibition. DEAE-cellulose chromatography, Sephadex G-200 fractionation and immunoelectrophoretic analysis have shown the nonimmunoglobulin nature of this factor. It is thermostable and not affected by deoxyribonuclease or ribonuclease treatment. The mitogen-induced cellular cytotoxicity-inhibiting factor seems to be independent of other serum factors capable of blocking PHA-induced blastogenic transformation.
One hundred fifty-eight patients with active, untreated systemic lupus erythematosus (SLE) were studied from the time of diagnosis. Lymphopenia was present in 75%, and another 18% of those patients developed lymphopenia subsequent to disease reactivation. Lymphopenia of less than 1500 cells/microliter occurred more frequently than any of the preliminary criteria for the classification of SLE, and it was the most prevalent initial laboratory abnormality. Lymphocyte counts were significantly lower in lupus than in the other connective tissue diseases except mixed connective tissue disease and polymyositis.
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Six patients are described in whom panniculitis was a major manifestation of systemic lupus erythematosus. These patients were seen in a combined-clinics population of 270 patients with systemic lupus erythematosus for an incidence of approximately 2%. Panniculitis was the first symptom of systemic lupus erythematosus in three of these patients indicating that systemic lupus erythematosus should be considered as an underlying cause in patients with panniculitis or Weber-Christian's disease. Analysis of these six cases and those previously reported suggests that the addition of hydroxychloroquine to the treatment regimen may be beneficial in lupus panniculitis.
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