Abnormal interferon modulation of natural cytotoxicity in systemic lupus erythematosus relation to suppressive serum factors

In the present study we examined one aspect of the derangement in natural cytotoxicity (natural killer, NK) activity observed in some patients with systemic lupus erythematosus (SLE), i.e., the lack of enhancement of NK activity usually seen with interferon (IFN). NK activity of SLE patients as a group was 23.0 ± 3.9 lytic units (LU)/10⁷ cells (mean ± SE). This contrasted with the NK activity found in normal controls (45.0 ± 3.8 LU/10⁷ cells) (P < 0.05). The enhancement seen with IFN was an increase of 15.4 ± 4.0 LU/10⁷ cells in SLE patients compared with 104.6 ± 192 LU/10⁷ cells in control subjects (P < 0.05). SLE sera and aggregated IgG (Agg-IgG) also inhibited the increase in NK activity of normal peripheral blood mononuclear cells after IFN priming. The results reported here support the hypothesis that the impaired baseline NK activity and poor response to IFN noted in SLE are secondary, in part, to the presence of inhibitory serum factors and preactivation by IFN.     

Alopecia in systemic lupus erythematosus. Relation to disease manifestations

Alopecia was observed in 40/74 (54%) patients with systemic lupus erythematosus (SLE). Patients with alopecia had a significantly higher rating for cutaneous manifestations, Raynaud's phenomenon and muscle tenderness, and most of these signs correlated with the magnitude of alopecia. There was no difference between patients with or without alopecia for arthritis, nephritis or central nervous system manifestations. Alopecia correlated with disease activity index but did not correlate with various specific measurements of disease exacerbation.     

Antibody-dependent and phytohaemagglutinin-induced lymphocyte cytotoxicity in systemic lupus erythematosus.

An investigation of cell-mediated cytotoxicity in 22 patients with systemic lupus erythematosus (SLE), using both whole blood and purified peripheral blood mononuclear cells (PBM) to measure antibody-dependent (ADCC) and phytohaemagglutinin (PHA)-induced lymphocyte cytotoxicity for Chang liver cells, has revealed 2 distinct abnormalities in patients with active disease. PHA-induced cytotoxicity was found to be selectively reduced in whole blood assays only (P less than 0.05), whereas ADCC was impaired in both whole blood (P = 0.02) and PBM (P less than 0.05) assays, when comparison was made with 52 normal controls. The addition of patients' sera to corresponding assays utilizing control PBM confirmed that the impaired PHA-induced cytotoxicity resulted from circulating inhibitory serum factors. Surprisingly little effect, however, was exerted on ADCC assays. These findings suggest that there is a reduction in numbers and/or functional capacity of Fc-receptor cells in active SLE, which may have pathogenetic implications.     

Peripheral blood lymphocytes in systemic lupus erythematosus. Relation to activity.

Peripheral blood lymphocytes from 20 patients with systemic lupus erythematosus (SLE), 3 patients with drug-induced lupus and 20 normal controls were studied. The absolute number of E-rosette-forming cells (ERFC) and surface immunoglobulin-bearing cells were determined during active and inactive stages of the disease. An attempt was made to establish the relationship between the number of ERFC and the clinical stages of the disease on one hand and treatment on the other. A decrease in ERFC was observed in all SLE patients, but it was most prominent in patients with active disease. No correlation was found between treatment and the decreased numbers of ERFC.     

Natural cell mediated cytotoxicity in systemic lupus erythematosus

The significantly reduced natural killer (NK) cell activity was demonstrated in the peripheral blood lymphocytes (PBL) from 20 female patients with systemic lupus erythematosus (SLE) when compared with NK activity in the age and sex-matched controls. The reduced NK activity did not correlate with clinical parameters including daily prednisolone doses, serum CH50, antinuclear antibody titers, antiDNA activities, circulating immune complex levels, and cytotoxic activities of antilymphocyte antibodies (ALA). The effects of prednisolone and aggregated human IgG on NK activity were only slightly suppressive in the in vitro studies. When normal PBL were pretreated with rabbit complement and SLE sera containing ALA, the NK activity of the surviving cells was markedly decreased. The decrease was specific and did not seem to be due to the physical hindrance of the dead cells. Other heterologous ALA of rabbit origin did not exert a suppressive effect on NK activity. These results suggest that the suppressed NK activity in SLE can be ascribed to an antiNK cell specific antibody in lupus sera, although the participation of circulating immune complexes was not completely excluded.     

Relation of antivimentin antibodies to anticardiolipin antibodies in systemic lupus erythematosus.

Tests for antivimentin antibodies (AVA) were performed on 50 systemic lupus erythematosus (SLE) and 63 control sera by indirect immunofluorescence and enzyme linked immunosorbent assay (ELISA). The prevalence was significantly raised in SLE (38% and 50% of sera positive for IgM-AVA and IgG-AVA, respectively, by immunofluorescence; 36% and 64% of sera positive for IgM-AVA and IgG-AVA, respectively, by ELISA) in comparison with the control sera. A significant correlation existed between IgM-AVA, on the one hand, and anticardiolipin antibodies (ACA) and anti-single-stranded DNA (ssDNA), on the other. A stepwise principal component analysis demonstrated that IgM-AVA and IgG-AVA accounted for 71% of the total variance in SLE (50 patients x 5 parameters = total variance). Twenty ACA positive serum samples from patients with syphilis were therefore tested for the presence of AVA, but hardly any were found to be positive. IgM-AVA from patients with SLE were inhibited by cardiolipin and absorbed with ssDNA. An association between AVA positivity and arthralgia was also shown in SLE.     

Prognostic factors in systemic lupus erythematosus

Summary In the past 40 years an impressive improvement in the prognosis of SLE patients has occurred. Factors which might be responsible for this improvement are discussed. Two of the factors most frequently cited are the advances in disease recognition and treatment. However, as already noted by Albert (1979) this is questionable, as average disease duration and survival have increased in a linear fashion related to the number of publications devoted to this subject from 1950 on. Further evaluation of the literature shows that the most prominent factors which have an impact on the survival rate are specific disease manifestations (lupus nephritis) and the overall disease course (number of exacerbations). This effect of morbidity on the survival rate is greater than that of factors such as sex and race. Socio-economic factors or age at onset have no effect on the outcome.     

Inhibition of natural killer cell activity by serum from patients with systemic lupus erythematosus: roles of disease activity and serum interferon.

Among their immunological alterations patients with systemic lupus erythematosus (SLE) have been shown to have diminished natural killer (NK) cell activity. This abnormality is at least in part related to humoral factors, as sera from patients with SLE can inhibit the NK activity of peripheral blood mononuclear cells from normal individuals. The present study extends these findings to demonstrate that the inhibitory ability of sera from patients with SLE varies with disease activity. Furthermore, sera from patients with active SLE containing interferon (IFN), a potent stimulator of NK activity, were equally or more inhibitory than sera which did not contain IFN. Thus the factors in SLE sera which can inhibit NK function vary with disease activity and cannot be overcome by IFN present in these sera.     

Serum alpha interferon and lymphocyte inclusions in systemic lupus erythematosus.

The relationship between serum acid-labile alpha interferon and tubuloreticular inclusions within the cytoplasm of circulating lymphocytes was studied in 46 patients with systemic lupus erythematosus. Elevated levels of interferon (greater than or equal to 8 IU/ml) were found in 17 patients and lymphocyte inclusions in 35. The mean serum interferon concentration in patients with lymphocyte inclusions was significantly higher than in patients without inclusions (17.2 versus 2.4 IU/ml, p less than 0.01). Inclusions were found in 16 of 17 patients with elevated interferon and also in 19 of 29 patients without interferon (p = 0.026). In lupus, serum interferon appears to be a sufficient though not an essential marker for the presence of lymphocyte inclusions.     

Thrombosis in systemic lupus erythematosus. Relation to the presence of circulating anticoagulants

In an earlier report on the kidney in systemic lupus erythematosus (SLE), we described a subset of patients with circulating anticoagulants; many had glomerular and arteriolar thrombosis in the absence of necrosis and subendothelial deposits. The present study extends these observations to a larger group of patients with SLE and a circulating anticoagulant, and compares its findings with those in patients with SLE without evidence of an anticoagulant. It demonstrates (1) a higher prevalence of clinically recognizable thrombotic events in the venous and arterial circulations in patients with SLE and a detectable anticoagulant; (2) a probable shortening in life span; (3) a higher prevalence of glomerular thrombi; (4) elevated levels of factor VIII antigen and von Willebrand factor; and (5) significantly lower platelet counts and decreased in vitro platelet aggregation in response to adenosine diphosphate, epinephrine, and collagen. Since prednisone treatment often results in improvement or disappearance of a prolonged partial thromboplastin time, the test most commonly used for screening of a circulating anticoagulant, we suggest that the prevalence of this abnormality may be underestimated in patients with SLE.     

Serum interferon levels in patients with systemic lupus erythematosus

Levels of interferon (IFN) were measured in 81 serum samples from 23 patients with systemic lupus erythematosus (SLE) by a plaque-reduction method and correlated retrospectively with clinical records of disease activity, anti-DNA binding, and serum complement measurements. IFN titers were found to correlate with both clinical disease activity and anti-DNA binding, but no relation was found to serum complement. Most (76.6%, 31 of 41) serum samples obtained during periods of active disease contained measureable amounts of IFN, but only 9.1% (2 of 22) of results of tests on samples obtained during periods of disease quiescence were positive (P less than 0.005). Of samples with clearly elevated anti-DNA binding (greater than 40%), 69.7% (23 of 33) had positive results for IFN, but 57.1% (8 of 14) had negative results when the anti-DNA binding was normal (less than 20%) (P less than 0.005). Measurement of serum IFN titers in patients with SLE, therefore, provides another serologic marker of disease activity. Contrary to the findings of previous studies, the IFN found in the present study was characterized as IFN-alpha, or Type I IFN, on the basis of acid stability and neutralization by antibody to IFN-alpha. Of interest are the questions raised about the origin of IFN in the sera of patients with SLE and what role IFN might have in the pathogenesis of the autoimmune disease in view of the many documented immunomodulating effects of IFN.     

Environmental factors predicting nephritis in systemic lupus erythematosus.

OBJECTIVES--To evaluate social class, ethnic origin, and various endocrine variables as potential risk factors in the development of nephritis in patients with systemic lupus erythematosus (SLE). METHODS--A cross-sectional survey was carried out of all outpatients with SLE attending the lupus Clinic of St Thomas's Hospital from March to October 1992 using retrospective survival data. The main outcome measure was the duration of SLE before the onset of nephritis. RESULTS--Two hundred and ninety six women and 11 men were studied; the male patients were excluded from the analysis. Univariate analysis showed an increased risk of nephritis in patients with SLE of West Indian origin with 54 v 19% with nephritis at five years, in patients of lower social class, in patients who did not drink alcohol, and in those with a history of fetal loss after the onset of lupus. No significant effect of the age of onset of SLE, use of oral contraceptives, normal pregnancy, or smoking was seen. Multivariate analysis showed that ethnic origin did not influence the risk of nephritis independently of social class. CONCLUSIONS--Factors associated with socioeconomic deprivation may increase disease severity in patients with SLE.     

Immunoglobulin from systemic lupus erythematosus serum induces interferon release by normal mononuclear cells

Ig fractions from patients with systemic lupus erythematosus (SLE) were tested with cultured normal peripheral blood mononuclear cells for induction of interferon release. Lymphocyte eluates, euglobulins containing IgG and IgM, and IgG or IgM from DEAE or sucrose gradients all induced interferon production. Lymphocytotoxic antibody in SLE sera showed a high correlation with capacity of isolated Ig fractions to induce interferon. Most interferon produced was of the gamma type. Monoclonal SLE IgM antilymphocyte antibody induced interferon synthesis.     

Resistin in systemic lupus erythematosus: Relation to lupus nephritis and premature atherosclerosis

BackgroundLupus nephritis (LN) is one of the most severe complications of SLE. SLE patients have a greater risk of developing premature atherosclerosis. Resistin is an adipocyte-secreted peptide. It has pro-inflammatory and atherogenic effects.Aim of the workTo assess the serum levels of resistin in SLE patients and to evaluate it as a marker of nephritis and premature atherosclerosis.Patients and methodsThis study included 50 SLE nonpregnant female adult (mean age 23.1 ± 6.9 years) patients as well as 40 healthy volunteers matched in age and sex as a control group. Serum levels of resistin were assayed using enzyme-linked immunosorbent assay (ELISA). All patients and controls underwent laboratory investigations and carotid duplex. Disease activity was assessed using SLE Disease Activity Index (SLEDAI). Renal biopsy was performed for SLE patients with LN.ResultsThere was a highly statistically significant increase in mean serum resistin levels (14.1 ± 3.88 ng/ml) in patients versus the control group (6.44 ± 1.34 ng/ml) being more obvious in those with LN. Resistin had a significant positive correlation with markers of inflammation, SLEDAI and carotid intima media thickness (CIMT).ConclusionSerum level of resistin may serve as a marker of LN and atherosclerosis in SLE patients. A more aggressive control of the underlying inflammatory process along with the control of traditional risk factors (hypertension and cholesterol) may be beneficial in reducing the risk factors of renal and atherosclerotic involvement in SLE. Therapeutic approaches with drugs that target resistin might be useful in the treatment of SLE.