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)/10(7) cells (mean +/- SE). This contrasted with the NK activity found in normal controls (45.0 +/- 3.8 LU/10(7) cells) (P less than 0.05). The enhancement seen with IFN was an increase of 15.4 +/- 4.0 LU/10(7) cells in SLE patients compared with 104.6 +/- 192 LU/10(7) cells in control subjects (P less than 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.     

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.     

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.     

Decreased serum erythropoietin and its relation to anti-erythropoietin antibodies in anaemia of systemic lupus erythematosus

OBJECTIVE: This study was performed to assess erythropoietin levels and anti-erythropoietin antibodies in patients with systemic lupus erythematosus (SLE). METHODS: The sera of 100 patients with SLE were investigated for serum erythropoietin levels and the presence of anti-erythropoietin antibodies by ELISA. Routine laboratory parameters such as peripheral blood count, relevant parameters of blood chemistry, and immunological parameters of SLE were recorded. RESULTS: Erythropoietin levels were significantly decreased in SLE patients when related to individual haemoglobin and haematocrit values (P<0.001), suggesting an inadequate erythropoietin response in SLE. Anti-erythropoietin antibodies were found in 46% of SLE patients, and erythropoietin levels (but not haemoglobin or haematocrit values) were significantly decreased in these patients compared with patients without anti-erythropoietin antibodies. Serum erythropoietin concentration as determined by ELISA was reduced in the presence of anti-erythropoietin antibodies. Furthermore, anti-erythropoietin antibodies also correlated with younger age, decreased serum levels of complement factors C3 and C4 and elevated anti-double-stranded DNA antibodies. CONCLUSIONS: We conclude that the anaemia of SLE is characterized by an inadequate erythropoietin response. Anti-erythropoietin antibodies are frequently present in SLE and interfere with the measurement of serum erythropoietin level. However, these antibodies are not associated with increased severity of SLE-associated anaemia.     

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.     

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.     

Atherosclerosis risk factors in systemic lupus erythematosus

Cardiovascular disease (CVD) has emerged as a leading cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Growing evidence suggests that inflammation plays a key role in the pathogenesis of atherosclerosis from initial endothelial dysfunction to rupture of atheromatous plaques. The increased frequency of atherosclerosis in SLE is likely due to a complex interplay among traditional risk factors, disease-related factors such as medications and disease activity, and inflammatory and immunogenic factors. Identification of these novel risk factors will lead to a better understanding of CVD pathogenesis and may also provide targets for potential treatment strategies. When caring for SLE patients, clinicians should be aware of the increased CVD risk and treat the known modifiable risk factors in addition to controlling disease activity and inflammation.     

系统性红斑狼疮患者血清中可溶性人类白细胞抗原-G表达水平的研究

目的 探讨血清可溶性人类白细胞抗原(HLA)-G(sHLA-G)在系统性红斑狼疮(SLE)患者中表达水平及与疾病活动度相关性.方法 采用酶联免疫吸附试验(ELISA)方法检测58例SLE患者与60名健康人血清sHLA-G水平.结果 SLE患者血清sHLA-G水平(120±92)ng/ml显著高于健康对照组(35±33)ng/ml(P＜0.01);SLE活动期组血清sHLA-G水平(170±70)ns/mJ显著高于SLE缓解期组血清sHLA-G水平(95±88)ng/ml(P＜0.01);血清sHLA-G水平与SLEDAI呈正相关(r=0.30,P=0.01);与抗双链DNA(dsDNA)、C3、C4及抗核抗体滴度无显著相关性(P＞0.05).结论 SLE患者血清中sHLA-G表达增高,且与疾病活动度呈正相关,sHLA-G在SLE疾病发生、发展中可能发挥了一定的作用.     

Abnormal differentiation of memory T cells in systemic lupus erythematosus

OBJECTIVE: The chemokine receptor CCR7 and the tumor necrosis factor receptor family member CD27 define 3 distinct, progressively more differentiated maturational stages of CD4 memory subpopulations in healthy individuals: the CCR7+, CD27+, the CCR7-, CD27+, and the CCR7-, CD27- populations. The goal of this study was to examine maturational disturbances in CD4 T cell differentiation in systemic lupus erythematosus (SLE), using these phenotypic markers. METHODS: Phenotypic analysis by flow cytometry, in vitro stimulation experiments, telomere length measurement, and determination of inducible telomerase were carried out. RESULTS. In SLE patients, significant increases of CCR7-, CD27- and CCR7-, CD27+ and a reduction of CCR7+, CD27+ CD4 memory T cells were found. In vitro stimulation of SLE T cells showed a stepwise differentiation from naive to CCR7+, CD27+ to CCR7-, CD27+ to CCR7-, CD27-; telomere length and inducible telomerase decreased in these subsets in the same progressive sequence. The in vitro proliferative response of these populations progressively declined as their susceptibility to apoptosis increased. Interestingly, a significant reduction in inducible telomerase was noted in SLE naive and CCR7+, CD27+ CD4+ memory T cells. Additionally, SLE CCR7-, CD27+ and CCR7-, CD27- CD4 memory T cells proliferated poorly in response to in vitro stimulation and underwent significantly more apoptosis than their normal counterparts. Finally, expression of CXCR4 was significantly reduced in all SLE subsets compared with normal. CONCLUSION: Together these data indicate an increased degree of in vivo T cell stimulation in SLE, resulting in the accumulation of terminally differentiated memory T cells with a decreased proliferative capacity and an increased tendency to undergo apoptosis upon stimulation.     

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.     

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.