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Biomedical subjects

J R Klinenberg

Publications and source records attributed to J R Klinenberg.

At least 19 recordsLinked to original sources
PubMed2000

Cyclosporine for lupus membranous nephritis: experience with ten patients and review of the literature.

OBJECTIVES: The treatment of lupus membranous nephritis (LMN), a lupus subset that carries a high morbidity, is unsatisfactory. We report our experience in treating LMN with the immunosuppressive drug cyclosporine (CYS). METHODS: We treated 10 patients with systemic lupus erythematosus fulfilling ACR criteria with CYS for at least 12 months and followed renal function, serologic activity and SLEDAI scores. PATIENT CHARACTERISTICS: 8 females, 2 males, 50% Caucasian, mean age 37.3 y (range 22-48), disease duration 108.7 months (range 16-216), nephritis duration 35.5 months (range 12-59), date of biopsy to date of starting treatment 10.7 months (range 0-90). The patients were started on CYS with a mean dose of 3.8 mg/kg (range 2.2-6) and followed for a mean duration of 24.8 months (range 12-59). A Medline search identified all patients with lupus who were given CYS or had LMN in articles from 1966-1999. RESULTS: Proteinuria improved from a baseline mean of 5,588mg/24h (range 2,712-11,055) to 1,404 mg/24 h (range < 150-2,652). Serum albumin increased from a baseline mean of 2.8 g/100 ml (range 1.31-3.8) to a mean of 3.9 g/100 ml (range 3-4.5) at last follow-up. There was no significant change in lupus activity as measured by SLEDAI. Nephrotoxicity was common as evidenced by an increase in serum creatinine but it returned to baseline with adjustment of the dose of CYS (20% decrease in the dose of CYS for a 20% increase in serum creatinine). More antihypertensive medications were required to control the blood pressure in these ten patients at the end of the study compared to the onset (total number= 13 versus 6). CONCLUSION: Proteinuria and serum albumin improved in all patients on CYS. A literature review is consistent with this. Controlled studies of the use of CYS for membranous lupus nephritis would be useful.

Adult↗
PubMed1999

Exogenous IL-10 and IL-4 down-regulate IL-6 production by SLE-derived PBMC.

The elevated expression of IL-6 and IL-10 may have an important role in SLE pathogenesis. IL-6 production by normal monocytes can be inhibited by IL-10, and it has been suggested that SLE monocytes are refractory to this negative signal. To examine this possibility, the effects of regulatory factors on IL-6 expression by SLE PBMC (N = 51) were compared to effects on control PBMC (N = 21). We found that (1) exogenous rIL-10 and rIL-4 mediated reduction of constitutive and lectin-induced IL-6 in monocytes of SLE patients as effectively as that of controls; (2) IL-6 mRNA decay was significantly delayed in SLE with active disease (P < 0.001); (3) adding rIL-10 or neutralizing endogenous IL-1 beta and TNF-alpha down-regulated IL-6 mainly by destabilizing IL-6 transcripts, whereas exogenous IL-4 and TGF beta 1 down-regulated IL-6 transcriptionally; (4) time kinetics and levels of IL-10 were lower than those of IL-6 and IL-1 beta. Thus, contrary to a previous report, IL-6 production by SLE PBMC responds normally to regulatory signals, and the IL-6 overexpression in SLE may be due, at least in part, to the kinetics and availability of regulatory cytokines.

Adult↗
PubMed1996

A greater variability in the 3' flanking region of the IL-6 gene in patients with systemic lupus erythematosus (SLE).

The causes of the aberrant constitutive expression of cytokines in SLE have not been elucidated yet, but alterations in cytokine gene structure could be a contributing factor. By RFLP (Restriction Fragment Length Polymorphism) analysis of genomic DNA, we found a higher incidence of allelic, higher MW XbaI bands in the IL-6 genes of 9/57 SLE patients vs 1/36 unrelated controls (p = 0.05) HLA DR/DQ typing of the polymorphic patients revealed they were all DQ beta 6. The study of one family indicated that the XbaI polymorphic patient and her polymorphic unaffected offspring had higher than normal levels of constitutive IL-6 mRNA. The SLE-associated IL-6 XbaI restriction alleles had duplications of AT-repeat sequences, approximately 500 bp downstream of the 2nd polyadenylation site, in an AT-rich mini-satellite with similarities to Matrix Associated Regions (MARs), that may be important in DNA replication and in gene expression. These are novel observations that suggest that, in SLE, there is increased variability in the 3' flanking region of the IL-6 gene. This variability may be related to the aberrant IL-6 expression that was reported by us and others in this disease.

Deoxyribonucleases, Type II Site-Specific↗
PubMed1995

Lupus in the 1980s: III. Influence of clinical variables, biopsy, and treatment on the outcome in 150 patients with lupus nephritis seen at a single center.

Of 500 patients with systemic lupus erythematosus observed at our center, 150 fulfilled criteria for lupus nephritis. Of these 150 patients, 91% were female, and 67% were white. The mean age of onset was 26.2 years, and the mean follow-up duration was 11.7 years. Biopsies (n = 142) performed on 107 patients showed the following World Health Organization (WHO) class distribution: class I, n = 1; class II, n = 13; class III, n = 19; class IV, n = 69; class V, n = 17; class VI, n = 8; and class not determinable, n = 15. Ninety-five patients were nephrotic. Therapeutic intervention courses given to all patients (n = 356) included parenteral (IV) cyclophosphamide (n = 58), high-dose oral steroids (n = 126), pulse steroids (n = 49), apheresis (n = 39), azathioprine (n = 43), oral cyclophosphamide (n = 5), nitrogen mustard (n = 27), and chlorambucil (n = 6). In addition to examining the course of disease for various subsets, various predictors for fatality and end-stage renal disease (ESRD) were analyzed. Descriptive data for the short-term response to five therapies are provided for the complete patient sample, proliferative disease, and nephrotic syndrome. Twenty patients died, primarily from cardiovascular complications and sepsis, with 97% and 92% 5- and 10-year survival rates, respectively. Twenty-nine were dialyzed, and 11 were transplanted. Risk of ESRD by WHO class at 5 years was as follows: class III, 0%; IV, 9%; V, 16% (P = .04 for class V v other patterns).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Elevated in vivo and in vitro secretion of CD8-alpha molecules in patients with systemic lupus erythematosus.

Endogenously activated CD8+ cells contribute to the aberrant immune regulation that characterizes SLE. Because stimulation of CD8+ cells with lectin/Ag triggers release of CD8-alpha molecules (sCD8), we measured, in patients with SLE, serum sCD8 content, its correlation with disease activity, and the in vitro release of sCD8 by SLE PBMCs. sCD8 levels, measured by ELISA in sera of 50 SLE patients, were higher than normal in 16 out of 21 mildly active and 15 out of 15 active SLE patients. sCD8 correlated positively with the clinical index for disease activity (r = 0.57, p = 0.001) and with sIL-2R levels (r = 0.52, p < 0.0001), and negatively with serum C3 levels (r = -0.5, p < 0.04). Freshly isolated SLE PBMCs had higher than normal CD8-alpha mRNA levels and secreted high levels of sCD8 in vitro (p < 0.05 vs control PBMC). sCD8 in vitro release by SLE PBMCs may be modulated by non-CD8+ cells. Thus, anti-CD2 mAb inhibited sCD8 release, whereas anti-HLA mAb increased it in unseparated PBMCs, but not in CD8+ enriched cultures. Moreover, sCD8 release increased significantly in PBMC cultures enriched for CD8+ DR+ cells by negative selection. Added-back monocytes decreased sCD8 to original levels, but not after glutaraldehyde fixation, nor in the presence of anti-HLA mAb. Further, lectin-induced IgG production and proliferation were reduced in the presence of sCD8, suggesting that the soluble CD8 molecules may be immunoregulatory. Because the high sCD8 levels in sera of active SLE likely reflect pathogenic cell activation, serum CD8 content may be an additional serologic activity marker, and its study could provide insights into mechanisms of disease.

CD8 Antigens↗
PubMed1992

Cutaneous lupus erythematosus without systemic lupus erythematosus: clinical and laboratory features.

Sixty-seven patients with cutaneous lupus erythematosus (CLE) were followed up as part of a series of 570 lupus erythematosus patients seen in a private practice between 1980 and 1989. Clinical and laboratory features, treatment, and natural course were observed. Findings of interest included (1) a ratio of at least one CLE case for every seven cases of systemic lupus erythematosus (SLE); (2) occurrence of CLE in fewer women and apparently associated with an older age at diagnosis than SLE; (3) similar frequency of cutaneous lupus subsets in CLE and SLE; (4) strong family history for SLE but not CLE in CLE patients; (5) other cutaneous and musculoskeletal features in a majority of CLE patients and constitutional symptoms in 10%; (6) positive ANA titers, high sedimentation rates, and leukopenia common in CLE; (7) anticardiolipin antibody in 31% of CLE patients but not associated with systemic complications; (8) antimalarials required by 75% of patients and systemic steroids by 33%; and (9) an excellent prognosis associated with CLE, organ-threatening disease being rare.

Adult↗
PubMed1991

Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis.

Elevated spontaneous IgG production is characteristic of SLE. To identify the factors that support it, IL-6, a cytokine with an important role in the differentiation of IgG-secreting cells, was studied in SLE patients. Higher than normal levels of IL-6 were found, by a B9 assay, in sera of 63 of 70 patients (p less than 0.05). IL-6 was detected in 36 of 37 active SLE sera in higher titers (p = 0.009) than those for inactive SLE (n = 33), which were higher (p less than 0.05) than healthy controls (n = 15). IL-6 mRNA was detected in freshly isolated PBMC of 11 of 11 patients but not in normal PBMC, whereas IL-1 mRNA was detected only in patients with active disease. IL-6 activity was recovered from PBMC of four SLE patients, but not from four normal donors. By immunoperoxidase, IL-6 was detected in the cytoplasm of SLE monocytes and lymphocytes. When SLE PBMC were grown in short term cultures with no deliberate stimulation, expression of the IL-6 gene declined rapidly. Accordingly, the spontaneous production of IgG by SLE PBMC could be enhanced by exogenous IL-6. Spontaneous IgG production was diminished by 20 to 65% in the presence of neutralizing antibodies to IL-6, TNF-alpha, or IL-1. In contrast, neutralization of endogenous IL-4 increased production by approximately 40%. Anti-TNF-alpha treatment decreased IL-6 content of PBMC cultures, whereas anti-IL-4 augmented it, and exogenous IL-6 reversed anti-TNF-alpha effects on IgG production. Therefore, it is possible that the neutralization of TNF-alpha and IL-4 affected IgG production by modulating the synthesis/activity of IL-6. These results support the concept that SLE B cell hyperactivity is promoted by dysregulation of endogenous cytokines and suggest that IL-6, in particular, has an important pathogenic role.

Blotting, Northern↗
PubMed1991

Lupus erythematosus in the 1980s: a survey of 570 patients.

Five hundred seventy lupus erythematosus patients observed in a private practice between 1980 and 1989 were surveyed. Fifty-five percent were diagnosed after 1980. Five hundred three fulfilled criteria for systemic lupus erythematosus ( [SLE]; 464 idiopathic, 23 overlap, 16 drug-induced) and 67 had biopsy-documented cutaneous (discoid) lupus. In the idiopathic SLE group, symptoms began at a mean age of 31 years and patients were observed for a mean of 6 years. Findings in idiopathic SLE patients were (1) 27% have a family history of autoimmune disease; (2) nephritis patients without nephrotic syndrome rarely develop renal failure (4%); (3) nephrotic syndrome patients are relatively cyclophosphamide-resistant; (4) organ-threatening disease is present in 54%; and (5) 13% of women who become pregnant are recurrent aborters and 26% never conceive. In an analysis of cohort data, 5- and 10-year survivals were 97% +/- 2% and 93% +/- 3%, respectively. Additionally, men and patients with renal disease or thrombocytopenia had a poorer prognosis. Blacks had similar clinical findings and survival to whites. Approximately 50% of deaths were from active disease and 50% from complications of therapy. Prolonged survival has resulted from new diagnostic procedures and serologic tests, and improved antibiotics and antihypertensive agents, as well as more efficacious treatment modalities.

Adolescent↗
PubMed1991

Inhibition of protein-kinase C in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: effect on spontaneous immunoglobulin production.

Systemic Lupus Erythematosus (SLE) is a multisystem disease characterized by an increase in the spontaneous secretion of immunoglobulin (Ig) molecules, many of which are autoreactive. We have previously shown (Biochem & Biophys. Res. Comm. (1989) 161: 1319-1326) that normal human peripheral blood mononuclear cells (PBMCs) can be stimulated to secrete large quantities of Ig upon incubation with the protein kinase-C activator 1 oleoyl-2-acetyglycerol (OAG). Specific blockage of protein kinase C with the isoquinoline sulfonyl piperazine compound (H-7) inhibited the OAG-induced Ig production. In experiments reported here, PBMC of 5 patients with active SLE produced high levels of IgG spontaneously in culture. PBMC of 6 inactive SLE patients and 7 normal control subjects produced comparable low levels of IgG spontaneously. Pokeweed mitogen (PWM) stimulation of PBMC in inactive SLE and control groups, but not active SLE patients produced markedly enhanced IgG production. The lack of response to PWM stimulation in active SLE patients is likely due to inherent maximal stimulation of active SLE B-cells. In addition, we examined the ability of H-7 to inhibit both mitogen-stimulated (normal and inactive SLE) and spontaneous (active SLE) Ig production. In other experiments, we also examined the ability of the isoquinoline sulfonamide (HA-1004), a potent inhibitor of cAMP-dependent protein kinase to regulate mitogen stimulated and spontaneous Ig production in the patient groups indicated above. H-7 significantly inhibited PWM stimulated Ig production in normal (P less than 0.0001) and inactive SLE patients, (P less than 0.040) suppressing PWM stimulated levels to spontaneous levels.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

1,25 dihydroxyvitamin-D3 regulation of immunoglobulin production in peripheral blood mononuclear cells of patients with systemic lupus erythematosus.

Systemic Lupus Erythematosus (SLE) is a multisystem disease characterized by an increase in the secretion of autoantibodies. The mechanisms of autoantibody-induced disease have not been clarified. 1,25-Dihydroxy-vitamin D3 (1,25-D3) is known to be important in the regulation of normal human lymphocyte functions. Among its regulatory functions is the ability to inhibit mitogen-stimulated production of immunoglobulin. The experiments reported here explored the regulation of IgG production by peripheral blood mononuclear cells (PBMCs) of patients with inactive and active SLE. 1,25-Dihydroxyvitamin D3 inhibited mitogen-stimulated IgG production in cells from normal individuals and inactive SLE patients, but not spontaneous IgG production by PBMCs from active SLE patients. Addition of exogenous IL-2 (5-50 U/ml) to 1,25-D3-treated cells from all patient groups did not affect IgG production significantly under any conditions tested. The addition of IL-2 to PMBCs had no effect on IgG production in normal individuals or inactive SLE patients, but stimulated IgG production in PBMCs of active SLE patients. We conclude that the regulation of mitogen-stimulated IgG production in inactive SLE patients by 1,25-D3 and IL-2 is similar to normal individuals, but IgG production by active SLE PBMCs is unresponsive to 1,25-D3 regulation and is increased with the addition of IL-2.

Adult↗
PubMed1989

Quantitative computerized joint scanning in rheumatoid arthritis: an accurate reproducible method of quantitating synovitis--preliminary report.

Clinical trials in rheumatoid arthritis have been hampered by the highly subjective nature of disease assessment measures and lack of a consistently reliable laboratory test to follow. The authors devised a method of quantitating synovitis by computerized joint scanning and compared it with six conventional parameters in 18 patients entered into two treatment protocols and a control group. The results indicate that quantitative joint scanning probably is at least as reliable as the conventional measures and has the advantage of having no placebo or subjective component.

Adult↗
PubMed1988

Predictive value of clinical, laboratory, pathologic, and treatment variables in steroid/immunosuppressive resistant lupus nephritis.

Twenty-seven patients with lupus nephritis and nephrotic syndrome had persistent disease activity despite an adequate trial of corticosteroids and immunosuppressive drugs; 30% were Asians, compared with 7% of our overall SLE population. Two years later, seven had a very good outcome and seven a poor outcome. Thirty clinical, pathological, laboratory, and treatment variables were analyzed in a good versus poor responder subset comparison in an effort to determine which factors were associated with favorable outcome. Administration of pulse steroids (P = .069) and a low biopsy chronicity index (P = .048) were associated with the good responder subset. Serum creatinine, biopsy class, blood pressure, complement, and anti-DNA values at entry as well as the choice of immunosuppressive drug were not helpful in predicting outcome. All seven good responders were plasmapheresed (P = .026). Patients with refractory lupus nephritis who have a low biopsy chronicity index may benefit from the use of pulse steroids or plasmapheresis, and controlled studies are suggested.

Adult↗
PubMed1988

Studies of IgG, IgM and IgA antiphospholipid antibody isotypes in systemic lupus erythematosus.

We evaluated the clinical relevance of 6 antiphospholipid antibodies including cardiolipin and their IgG, IgM and IgA isotypes in 92 patients with systemic lupus erythematosus (SLE). Antiphospholipid antibodies generally had significant associations with thrombocytopenia and a history of false-positive syphilis serologies. In 4 of 6 antiphospholipid antibodies, an inverse association with renal disease was observed. Antiphospholipid antibodies may moderate or protect against renal disease, or this may reflect the high doses of corticosteroids and cytotoxic drugs received by this group. Further studies are needed to determine how many antibody families cause these activities and to elucidate whether certain SLE subgroups possess differing specificities for each of the phospholipids.

Adolescent↗