Tubulointerstitial nephritis is a less frequently recognized but important complication of systemic lupus erythematosus. We have investigated the cytokine β2-microglobulin (β2M) and Tamm-Horsfall glycoprotein (THG) excretions in the urine of systemic lupus erythematosus patients to identify indices for evaluation of tubulointerstitial inflammation in lupus nephritis (LN). Daily urine was collected from 15 patients with active LN, from 12 patients with inactive LN, and from 17 normal subjects. The amounts of soluble interleukin (IL) 2 receptor, IL-6, IL-8, β2M, and THG in urine were measured. β2M and THG were regarded as indicators of proximal and distal renal tubule function, respectively. The urinary excretions of IL-6 and IL-8 were significantly higher in patients with active LN than in those with inactive LN and in normal individuals. The excretion of soluble IL-2 receptor in all three groups of subjects was not significantly different. On the other hand, the excretion of β2M in patients with LN was significantly higher than that in normal individuals. The excretion of β2M in patients with active or inactive LN was not significantly different. The THG excretion was lower in patients with active LN and tubulointerstitial inflammation as compared with patients with inactive LN or normal individuals. Six patients underwent pulse cyclophosphamide therapy during the course of experiments. Five of them showed a decrease in IL-8 and IL-6 excretions in urine after the treatment. The excretions of β2M and THG in urine, in addition to IL-6 and IL-8, can reflect the renal inflammatory activity in patients with lupus tubulointerstitial nephritis as well as in those having lupus glomerulonephritis.
SUMMARYDecreased number and impaired functions of polymorphonuclear neutrophils (PMN) due to the presence of anti-PMN autoantibodies in the serum render patients with systemic lupus erythematosus (SLE) susceptible to bacterial infections. However, the cognate antigens and pathological mechanisms of anti-PMN autoantibodies in SLE are rarely reported in the literature. In this study, we found approximately 20% of SLE sera contained anti-PMN autoantibodies detected by human PMN-coated cellular ELISA. A membrane protein with molecular weight of 50 kDa was identified as the cognate antigen of anti-PMN in Western blot after membrane-biotinylation and streptavidin column elution. The 50 kDa molecule was proved to be SSB/La after immunoscreening, molecular cloning and nucleotide sequencing of the gene from the human leucocyte cDNA library. Human anti-SSB/La autoantibodies purified from active SLE sera passing through the recombinant SSB/La conjugated Sepharose 4B affinity column could bind and penetrate into normal human PMN. Functional analysis revealed that the anti-SSB/ La autoantibodies exerted a number of potent effects on human PMN, including suppressed phagocytosis, accelerated apoptosis and enhanced IL-8 production. These in vitro results suggest that anti-SSB/ La is one of the anti-PMN autoantibodies capable of penetrating into PMN and responsible for neutropenia and functional impairment of PMN in patients with SLE.
Interleukin-1 receptor antagonist (IL-1ra) binds competitively to IL-1 receptors but does not transduce the signal which blocks the biological activities induced by IL-1. In this study, polymorphonuclear neutrophils (PMN) and mononuclear cells (MNC) from the patients with active systemic lupus erythematosus (SLE) (n = 11), inactive SLE (n = 13) and normal individuals (n = 13) were compared for the IL-1ra producing capacity of these cells. PMN and MNC at a concentration of 1 x 10(6) cells/ml were incubated with medium alone (spontaneous) or stimulated with lipopolysaccharide (LPS, 100 ng/ml) for 24 h. The IL-1ra concentration in the supernatants was quantified by ELISA method. Both spontaneous and LPS-stimulated production of IL-1ra by PMN, but not by MNC, of active SLE were significantly lower than that of inactive SLE or normal groups. Prednisolone (1 and 5 micrograms/ml) did not change the production of IL-1ra by normal PMN either spontaneously or LPS-stimulation in in vitro study. Moreover, the IL-1ra producing capacity of PMN in seven active SLE on admission and after intensive immunosuppressive treatment was measured. These results suggest that the defective IL-1ra production by SLE-PMN is relevant to disease activity and may be regarded as a new indicator of disease activity in patients with active SLE.
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