Impaired natural killer cell function in systemic lupus erythematosus

Immune regulation requires clonal expansion of regulatory T cells which is dependent on the presence of interleukin-2 (IL-2). Previously, both natural killer (NK) cell function and IL-2 production were found to be depressed in systemic lupus erythematosus (SLE). This study was designed to determine the relationship between IL-2 production and NK cell activity in SLE. NK activity as determined by a standard 4-hour ⁵¹Cr-release assay was impaired in SLE (11.0 ± 5.1 lytic units/10⁷ cells) compared with controls (25.1 ± 7.1 lytic units/10⁷ cells) (P < 0.05). IL-2 production was induced with concanavalin A and phorbol ester and quantitated using the IL-2 dependent cell line HT-2. IL-2 production was impaired in only 1 SLE patient, despite concomitant abnormalities in NK function in the SLE group as a whole. Moreover, in patients with impaired NK activity, incubation of lymphocytes with exogenous IL-2 did not restore NK activity to normal levels. These findings demonstrate that impaired NK activity in SLE is independent of IL-2 production and that defects in IL-2 production in SLE may not be as common as previously reported.     

Effects of ultraviolet irradiation on natural killer cell function in systemic lupus erythematosus.

In vitro irradiation with long wavelength ultraviolet light (UV-A), in clinically relevant dosages, of a natural killer cell line containing cell preparations from 17 control subjects reduced natural killer cell cytotoxicity with the cell line K562 as target. The spontaneous function of natural killer cells from 12 patients with systemic lupus erythematosus (SLE) correlated inversely with the one hour erythrocyte sedimentation rate, but not with glucocorticoid doses. After UV-A exposure, natural killer cells from patients with SLE exert either increased or decreased cytotoxicity, and the direction of change is inversely correlated with the spontaneous natural killer cell function.     

Impaired release of a soluble natural killer cytotoxic factor in systemic lupus erythematosus

Disease states characterized by abnormalities in immune regulation often demonstrate concomitant abnormalities in cytotoxicity mediated by natural killer (NK) cells. For example, some patients with systemic lupus erythematosus (SLE) have depressed NK activity despite the presence of normal numbers of effector cell:target cell conjugates. This study was designed to determine if defects in NK cell function were directly related to impaired release of a soluble cytotoxic factor. NK activity of peripheral blood mononuclear cells and large granular lymphocytes was measured using 51Cr-labeled K562 target cells in 4-hour release assays. The SLE patients had significantly decreased NK activity relative to normal controls. However, the number of effector cell:target cell conjugates was not different in SLE patients versus control subjects. The release of a soluble natural killer cytotoxic factor (NKCF) by peripheral blood mononuclear cells was measured by cytotoxicity induced in K562 cells. NKCF was released preferentially by suspensions enriched in NK cells (large granular lymphocytes). At a 1:1 dilution, NKCF release was significantly lower in SLE patients than in controls. The release of NKCF correlated well with NK activity. Thus, this study shows that the defect in NK cell activity in SLE patients may be related to an impairment in release of a soluble cytotoxic factor with specificity for NK cell-sensitive targets.     

Impaired endothelial function in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) patients suffer from excess cardiac deaths due to accelerated atherosclerosis. Endothelial dysfunction is a marker of early atherosclerosis. We tested the hypothesis that SLE patients have impaired endothelial function and assessed the relationship between endothelial function and clinical outcome over the subsequent five years. Thirty-six female SLE patients were compared with 22 healthy age and sex matched controls. Endothelial dependent vasodilatation (EDD) was assessed at the brachial artery in response to shear stress. Endothelium-independent dilatation induced by glyceryl trinitrate was also measured. Patients were followed for up to five years and the development of damage in the cardiovascular and other systems recorded. SLE patients showed significantly impaired endothelial function (median EDD 5.6%, IQR 3.1-7.2%) compared with healthy controls (median EDD 8.0%, IQR 6.3-9.3%; P = 0.001). Endothelium independent dilatation did not differ between the two groups. Endothelial function was significantly worse in postmenopausal compared with premenopausal women (median EDD 6.6%, IQR 3.9-7.8% versus 3.1%, IQR 2.6-5.1%; P = 0.016). Total cholesterol was inversely correlated with endothelial function in SLE patients (Spearman correlation r = -0.422, P = 0.025). There was no relationship between endothelial function and the development of damage in any organ system, including the cardiovascular system during patient follow-up. Patients with SLE have impaired endothelial Lupus (2007) 16, 84-88.     

Natural killer function in systemic lupus erythematosus

Peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE) demonstrated significantly less cytotoxicity against two different lymphoblastoid cell lines and one myeloid cell line than peripheral blood lymphocytes from normal individuals. Short-term culture and other attempts to remove interfering immune complexes failed to restore low natural killer (NK) function. Six day culture in fetal calf serum resulted in increased cytotoxicity by mononuclear cells from normal individuals and some SLE patients, but this effect was shown to be dependent on Fc⁻, not Fc⁺, effector cells. Suppressor cells were not demonstrable as a cause for decreased NK activity.     

Relationship between circulating interferon and anti-interferon antibodies and impaired natural killer cell activity in systemic lupus erythematosus

Interferon (IFN) production and response are impaired in a high percentage of systemic lupus erythematosus (SLE) patients. In addition, elevated serum levels of alpha-IFN or anti-alpha-IFN antibodies are present in some SLE patients. This study examined the relationship of circulating IFN and anti-IFN antibodies to the impairment of natural killer (NK) cell function in SLE. All 15 SLE patients studied had measurable circulating alpha-IFN, while the normal controls had minimal serum IFN. Neither patient nor control sera contained any detectable anti-alpha-IFN activity. However, most of the SLE patients demonstrated defects in NK cell function. Because these defects in NK cell function appeared to be associated with circulating IFN, but not anti-IFN, antibodies, the effect of prolonged in vitro IFN exposure on NK cell function of peripheral blood mononuclear cells was determined. It was found that prolonged exposure to IFN induced both an apparent defect in IFN response and a definite impairment of baseline NK cell function. These results suggest that prolonged elevation of circulating alpha-IFN levels could be responsible, in part, for the defects in natural cytotoxicity present in SLE.     

Natural killer cell activity in untreated systemic lupus erythematosus

With strictly selected controls natural killer cell activity was evaluated in 10 untreated patients with systemic lupus erythematosus. Natural killer levels of the patients were significantly lower than those of the age- and sex-matched normal controls. Natural killer levels, however, did not correlate with disease activity.     

Soluble interleukin-2 receptors in systemic lupus erythematosus

We studied levels of soluble interleukin-2 receptors (IL-2R), which are released by activated lymphocytes, in 139 serum samples from 12 patients with systemic lupus erythematosus (SLE). Concentrations of soluble IL-2R were significantly increased in SLE patients compared with controls (P less than 0.001), and they were significantly higher in patients during active SLE defined by low C3 levels (P less than 0.001), low C4 levels (P less than 0.001), or proteinuria (P less than 0.05) than during inactive SLE. Elevated levels of soluble IL-2R correlated with hypocomplementemia in longitudinal studies (P less than 0.001). Measurement of serum concentrations of soluble IL-2R may provide a sensitive and specific method for monitoring disease activity and immune activation in patients with SLE.     

Decreased natural killer T-like cells correlated to disease activity in systemic lupus erythematosus

Clinical Rheumatology - To evaluate the absolute numbers and frequencies of natural killer T-like (NKT-like) cells in systemic lupus erythematosus (SLE) and to characterize the possible role of the...     

Impaired response to pneumococcal vaccine in systemic lupus erythematosus

An immunization proram with pneumococcal vaccine was carried out in 38 patients with systemic lupus erythematosus (SLE). Mean antibody levels at 1 month and 1 year were significantly lower than in normal controls. This decreased response did not correlate with drug therapy at the time of immunization. Other parameters such as anergy state, renal function, and serum immunoglobulin levels also did not correlate with antibody response. There were no adverse effects noted in the vaccinated group in comparison to matched non-vaccinated SLE patients.     

系统性红斑狼疮患者杀伤细胞免疫球蛋白样受体基因型分析

目的探讨杀伤细胞免疫球蛋白样受体（KIR）基因型在系统性红斑狼疮（SEE）患者中的分布规律。方法采用序列特异性引物聚合酶链反应（PCR—SSP）法，分析93例SEE患者和123例无血缘关系的健康对照组KIR基因型。结果SEE组中3DL3＋，2DS2^-，2DL2^＋，2DL3^＋，KIRZ^＋，2DL1^＋，2DL4＋．3DL1^＋,3DS1^-，2DL5^-，2DS3^-，2DS5^-，2DS1^＋，2DS4^＋，3DL24^＋因型阳性率最高，占16．13％（与对照组比较P〈0．01），对照组中3DL3^＋，2DS2^-，2DL2^-，2DL3^＋，KIRZ^＋，2DL1^＋，2DL4^＋，3DL1^＋，3DS1^-，2DL5^-，2DS3^-，2DS5^-．2DS1^-，2DS4^＋，3DL2^＋因型阳性率最高，占19．51％（P=0．004），差异均有统计学意义。结论SLE与正常对照组中KIR基因型分布差异可能参与SLE发病。     

B cell differentiation factor production in systemic lupus erythematosus

Spontaneous and mitogen stimulated B cell differentiation factor (BCDF) production by peripheral blood lymphocytes (PBL) from patients with systemic lupus erythematosus (SLE) was compared with that of normal control subjects. BCDF production was measured by a cellular interleukin assay in which a BCDF responsive cell line was cocultured with increasing numbers of PBL from the donor populations. It was found that no significant differences occurred in BCDF production by SLE and normal PBL under the conditions used. Indeed there was a trend toward decreased BCDF release from SLE PBL. This would support the hypothesis that human SLE is the result of enhanced B cell responsiveness to helper cell factors rather than due to increased release of such factors.     

Hemocytopenia in systemic lupus erythematosus. Relationship to antiphospholipid antibodies

We studied 500 consecutive patients with systemic lupus erythematosus (SLE) for antibodies to phospholipids (APLA) by an ELISA method using cardiolipin as antigen and antiimmunoglobulins G, M and A to determine their isotype. Once entered into this prospective study the patients were followed for up to 16 months (mean 7.7 +/- 4.72 SD) with periodic determinations of APLA. Of the 500 patients with SLE, 88 had had thrombocytopenia, 25 had had hemolytic anemia, 25 had had both, and 362 had no history of these hemocytopenias. If we considered the odds ratio of these 362 patients for having high titer APLA as 1, patients with a history of thrombocytopenia, hemolytic anemia or both had significantly higher odds ratios of having APLA than did those without hemocytopenia. Patients with thrombocytopenia had significantly higher levels of IgG APLA, those with hemolytic anemia had significantly higher titers of IgM APLA and patients with both had significantly higher titers of both of these APLA isotypes, than did patients without hemocytopenias. A correlation between positive direct Coombs' tests and IgM APLA was also found. We conclude that APLA is associated with these hemocytopenias in SLE. This might be due to their interaction with negatively charged phospholipids in the cell walls of the respective cells.     

Further characterization of interleukin-2 production by lymphocytes of patients with systemic lupus erythematosus

To further characterize the mechanisms responsible for defective interleukin-2 (IL-2) production in patients with systemic lupus erythematosus (SLE), we studied the effect of irradiation on the capacity of lymphocytes to produce this lymphokine when stimulated with phytohemagglutinin (PHA), or with a combination of PHA and a phorbol myristic acid ester (PMA). Irradiation increased PHA induced IL-2 production in patients with SLE and normal controls, and reached normal levels in 10 of 16 patients with SLE. This effect was due to inactivation of CD8+ suppressor cells. When PMA was used as a costimulant, maximal enhancement of IL-2 production was observed in both groups, but values in SLE remained significantly lower than in normals. These differences were not overcome by irradiation, raising the possibility that SLE suppressor cells act upon a site proximal to protein kinase C. Our studies have confirmed that active endogenous suppression may be responsible for most of the defective PHA induced IL-2 production in SLE and that this suppression is radiosensitive.     

Dysregulation of interleukin-10 production in relatives of patients with systemic lupus erythematosus

Objective. To evaluate interleukin-10 (IL-10) production in relatives of patients with systemic lupus erythematosus (SLE). Methods. Production of IL-10 was evaluated in 13 families in which several members had SLE. The constitutive IL-10 production in SLE patients (n = 16) was compared with that in healthy members of these multiplex families (n = 70), in 30 SLE patients who had no relatives with SLE, and in 46 healthy unrelated controls. Results. The level of IL-10 production did not differ between SLE patients who were members and those who were not members of multiplex families (mean ± SEM 4,384 ± 908 pg/ml and 4,709 ± 560 pg/ml, respectively), but was higher in both groups than in healthy unrelated controls (515 ± 88 pg/ml). The healthy members of the multiplex families constitutively produced large amounts of IL-10 (3,080 ± 311 pg/ml; P < 0.001 compared with healthy unrelated controls). This high IL-10 production was independent of age and sex, and was similar in first- and second-degree relatives of SLE patients. The IL-10 was produced both by monocytes and by a subpopulation of B lymphocytes in SLE patients and in their relatives. Conclusion. The dysregulation of IL-10 production previously identified in SLE patients is also present in healthy members of families with several cases of SLE, and it may contribute to the immunologic abnormalities affecting relatives of SLE patients.