Utility of osteopontin in cerebrospinal fluid as a diagnostic marker for neuropsychiatric systemic lupus erythematosus.

The whole protein of osteopontin (OPN full) and its cleaved form (OPN N-half) are involved in the immune response and the migration of immune cells to an inflammatory lesion. We have reported that serum OPN full and urine OPN N-half are elevated in lupus nephritis (LN). Neuropsychiatric systemic lupus erythematosus (NPSLE) is a refractory complication of SLE. To investigate whether OPN full and OPN N-half could serve as diagnostic markers for NPSLE, and to elucidate their role in NPSLE pathogenesis, the concentrations of OPN full and OPN N-half in cerebrospinal fluid (CSF) were measured in NPSLE and non-NPSLE patients. We found that the concentration of OPN full in the CSF was significantly higher in NPSLE than in non-NPSLE, and it decreased after treatment. When the cutoff value of OPN full in CSF was set to 963.4 ng/ml, the sensitivity and specificity for the diagnosis of NPSLE were 70% and 100%, respectively. The correlation analysis of OPN full, OPN N-half and various cytokines/chemokines suggested that the cytokines/chemokines could be divided into two clusters: cluster A, which contains OPN full and cluster B, which contains interleukin-6. OPN full in CSF could be a novel diagnostic marker for NPSLE.

Serum milk fat globule epidermal growth factor 8 elevation may subdivide systemic lupus erythematosus into two pathophysiologically distinct subsets.

OBJECTIVE: Impaired clearance of apoptotic cells is a potential trigger of systemic lupus erythematosus (SLE). Milk fat globule epidermal growth factor 8 (MFG-E8) plays an important role in the clearance of dying cells. Previously, we reported serum MFG-E8 was elevated in some SLE patients. Here we further investigated the prevalence of MFG-E8 in active SLE and other autoimmune diseases and also tried to clarify the characteristics of MFG-E8-positive and -negative SLE. METHODS: Serum MFG-E8 was measured in 40 active non-treated SLE patients, 104 disease controls and 104 healthy controls by ELISA. Clinical characteristics and serum cytokine profiles were compared between MFG-E8-positive and MFG-E8-negative SLE patients. RESULTS: Prevalence of MFG-E8 was significantly higher in SLE patients (40%) than in various controls (p < 0.05). MFG-E8 level became negative after treatment, and increased again upon relapse. When compared, MFG-E8-positive SLE patients showed higher immune complex (p = 0.021) and lower complement (p = 0.004 for CH50). In contrast, MFG-E8-negative SLE patients tended to show higher CRP (p = 0.094). There was a positive correlation between MFG-E8 level and immune complex level (r s = 0.49, p = 0.049). TNF-α (p = 0.019), IFN-γ (p = 0.031) and IL-10 (p = 0.013) were significantly higher in MFG-E8-positive SLE. CONCLUSION: MFG-E8-positive SLE and -negative SLE may have different clinical features, the one with stronger immunological response and the other with stronger inflammatory response, and those two groups may be two distinct subtypes of SLE driven by different mechanisms. Further, MFG-E8 could be used as a biomarker for diagnosis and monitoring of disease activity in certain SLE patients.

Association between anti-U1 ribonucleoprotein antibodies and inflammatory mediators in cerebrospinal fluid of patients with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: We investigated possible associations between neurotoxic inflammatory mediators (IMs) and anti-U1RNP antibodies (Abs) in cerebrospinal fluid (CSF) of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Serum and CSF anti-U1RNP Abs were detected using an RNA-immunoprecipitation assay and CSF anti-U1RNP Ab levels were measured by ELISA. IFN-α, MCP-1 and IL-8 levels in CSF were determined by quantitative multiplex cytokine analysis. IM levels were compared among anti-U1RNP-positive and anti-U1RNP-negative NPSLE as well as other rheumatic disease controls (controls). RESULTS: Anti-U1RNP Abs were detected in serum (58%) and in CSF (18%) of 82 NPSLE patients. CSF MCP-1 levels were higher in NPSLE than in controls. CSF IFN-α level was higher in CSF anti-U1RNP Ab-positive than in -negative patients or controls. When limited to serum anti-U1RNP Ab-positive patients, however, levels of all three IMs in CSF were higher in CSF anti-U1RNP Ab-positive than in -negative patients. Anti-U1RNP Ab levels in CSF correlated with CSF MCP-1, but not IFN-α and IL-8 levels. CONCLUSIONS: CSF anti-U1RNP Ab positivity is associated with increased level of CSF IFN-α. MCP-1 levels correlated with CSF anti-U1RNP Ab levels, whereas the increased CSF MCP-1 was not specific to CSF anti-U1RNP Ab-positive NPSLE.

Type I interferon induces CX3CL1 (fractalkine) and CCL5 (RANTES) production in human pulmonary vascular endothelial cells.

Type I interferon (IFN) medications cause various adverse reactions, including vascular diseases. Although an association between chemokines and vascular diseases has also been reported, the relationship between type I IFN and chemokines in vascular endothelial cells (VEC) remains unclear. To provide clues to pathogenesis of the diseases, we analysed the effects of type I IFN on chemokine production in human VEC. Type I IFN induced higher CX3CL1 (fractalkine) mRNA expression and protein secretion in pulmonary arterial VEC than in umbilical vein VEC. Type I IFN also induced CCL5 [regulated upon activation normal T cell expressed and secreted (RANTES)] production in VEC, especially in lung micro-VEC. IFN-ß induced much higher chemokine production than IFN-α, and Janus protein tyrosine kinase (JAK) inhibitor I prevented type I IFN-induced chemokine secretion. Type I IFN-induced chemokines may be involved in the pathophysiology of pulmonary vascular diseases, and the JAK inhibitor may serve as a therapeutic option for these diseases.

Zoonotic potential of infection with Fasciola spp. by consumption of freshly prepared raw liver containing immature flukes.

Mice were successfully infected with metacercariae of the Japanese Fasciola sp., resulting in the recovery of a mean number of 110 live immature flukes per mouse 4-5 days after inoculation. Twenty-four mice were then inoculated orally, each with a mean number of 68 freshly recovered immature flukes. The livers of 7 of the 24 recipient mice showed migratory lesions of capsular and subcapsular granulomatous infiltration and 2 of those mice also had haemorrhagic lesions. The lesions were typical of those caused by active migration of early immature flukes. However, no flukes were found in the livers of the recipient mice at necropsy when the flukes were aged 14 weeks. In another experiment, 10 piglets were given fresh livers of mice harbouring approximately 2000 live immature flukes aged 3-7 days. Two additional piglets were inoculated with 2000 metacercariae of Fasciola. All pigs were killed when the flukes were 14 days old. Granulomatous lesions were present in all pigs, except in those that were given livers containing flukes aged 7 days. The lesions were localized, forming well-defined foci, different from the typical migratory lesions normally observed in mouse or sheep liver at the early stage of fluke migration. From the 10 pigs given livers, 65 live flukes were recovered at necropsy, 0.29% of the estimated number of immature flukes given. From the 2 pigs which received 2000 metacercariae each, a total of 198 flukes were recovered (5%). The results of the experiments suggest that humans consuming raw liver dishes prepared from fresh livers infected with immature Fasciola spp. could become infected with liver fluke.