Simultaneous changes in serum HMGB1 and IFN-α levels and in LAIR-1 expression on plasmatoid dendritic cells of patients with juvenile SLE.. New therapeutic options?

Abstract

We investigated the simultaneous changes in serum levels of HMGB1 and IFN-α as well as in LAIR-1 expression on plasmatoid dendritic cells (pDCs) of juvenile systemic lupus erythematosus (jSLE) patients in order to explore their involvement in the disease pathogenesis and their correlation with disease activity and other characteristics. In total, 62 blood samples were studied from 26 jSLE patients (18 girls), aged 8-16 years. Twenty healthy subjects (16 girls) of comparable age were included as healthy controls (HCs). Concentrations of serum HMGB1 and IFN-α were assessed by ELISA and LAIR-1 expression on pDCs by five-color flow cytometry. The disease activity index was assessed by SLEDAI and ECLAM scores. It was found that mean serum levels both of HMGB1 and IFN-α were significantly increased in jSLE patients compared to HCs and in jSLE patients with active disease with or without active nephritis compared to those with inactive disease. Mean serum levels of HMGB1 were positively correlated with levels of IFN-α and both were positively correlated with the SLEDAI and ECLAM scores. The expression of LAIR -1 on pDCs of jSLE patients was significantly lower than that of HCs. In conclusion, our findings indicate that serum HMGB1 not only represents a potential marker of disease activity but together with the lack of LAIR-1 inhibitory function may contribute to the sustained inflammatory action of IFN-α in jSLE. In this regard, blocking the action of HMGB1 and its receptors or enhancing the expression/inhibitory function of LAIR-1 on pDCs should be included in future immune interventions for controlling jSLE.

Evidence for C1q-mediated crosslinking of CD33/LAIR-1 inhibitory immunoreceptors and biological control of CD33/LAIR-1 expression

“…Aside from reduced expression of CD33 and LAIR-1, C1q-mediated LAIR-1/CD33 inhibitory activity may be compromised by auto-antibodies directed either to gC1q and/or CLR, both of which have been described in SLE 46–48 . Because LAIR-1 is also abnormally distributed on B cells and plasmacytoid DCs in SLE 49–51 , abnormal C1q function in SLE may be linked to impaired LAIR-1 expression on these cell lineages, independent of CD33.…”

Beyond apoptosis in lupus

“…Strikingly, the single genetic ablation of SCARF1 was shown to lead to impaired apoptotic cell uptake and accumulation, immune cell activation, and a lupus-like disorder in mice, characterized by antinuclear autoantibodies and nephritis[62*]. LAIR-1 is expressed on both myeloid and lymphoid cells, but a reduction in expression on SLE B cells [64] and pDCs [65] has been reported. C1q binding to LAIR-1 delivers an ITIM-mediated inhibitory signal, resulting in the blockade of dendritic cell differentiation from monocytes, and inhibition of IFNa production by pDC [63*].…”

Recent Developments in the Role of High-Mobility Group Box 1 in Systemic Lupus Erythematosus

“…As mentioned before, ELISA is not suitable for measuring HMGB1 in active SLE patients, but from these data, it is suggested that active SLE patients will have much higher amounts of HMGB1 in their serum. Recently increased HMGB1 levels were reported in juvenile SLE patients (70).…”