Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE.

Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE.

Organ damage in high-risk patients with systemic and incomplete lupus syndromes.

The objective of this study was to characterize organ damage in lupus patients enrolled in Dallas Regional Autoimmune Disease Registry (DRADR). Retrospective chart review was carried out on 99 patients with four or more diagnostic criteria for systemic lupus erythematosus (SLE) and 15 with less than four of these criteria, who were designated as having incomplete lupus erythematosus (ILE). The majority of patients (84 %) were African American or Hispanic/Latino; mean disease duration was 9.5 years. The mean damage score was 1.57 (range 0-8), and a damage score greater than 0 was present in 64 % of the patients. The ILE group had lower mean damage scores (0.67) than the SLE group (1.67; P = 0.04), explained in part by the shorter disease duration in the ILE patients (4.33 vs. 10.24 years; P = 0.003). The most prevalent damage category was renal, present in 24 % of patients. Malignancies occurred in individuals who were significantly older than those who had renal or peripheral vascular damage (P = 0.0007). The findings confirm clinical impressions that DRADR includes a high-risk lupus population. The ILE patients have less damage but also shorter disease duration, suggesting that this might represent an earlier disease stage. These results are consistent with the hypothesis that ILE patients include a subset that is likely to experience progressive organ damage. Longitudinal study of these patients has significant likelihood of tracking the changes that are correlated with disease progression to SLE.

Autoantibody profiling to follow evolution of lupus syndromes.

INTRODUCTION: Identification of patients who are in early stages of lupus is currently done through clinical evaluation and is not greatly facilitated by available diagnostic tests. Profiling for patient characteristics and antibody specificities that predict disease would enhance the ability of physicians to identify and treat early cases prior to onset of organ damaging illness. METHODS: A group of 22 patients with 4 or fewer diagnostic criteria for lupus were studied for changes in clinical and autoantibody profiles after a mean follow up period of 2.4 years. An array with more than 80 autoantigens was used to profile immunoglobulin G (IgG) and immunoglobulin M (IgM) autoantibodies. Correlations with clinical disease progression were examined. RESULTS: 3 of the 22 patients (14%) added sufficient criteria during follow up to satisfy a diagnosis of systemic lupus erythematosus (SLE) or to acquire a diagnosis of SLE renal disease. Patients who progressed were all females and were younger than those who did not progress (P=0.00054). IgG but not IgM autoreactivity showed greater increases in the progressor group than in the non-progressor group (P=0.047). IgG specificities that were higher at baseline in progressors included proliferating cell nuclear antigen (PCNA), beta 2 microglobulin, C1q and hemocyanin (P<0.019). Progressors had significant increases in La/SSB and liver cytosol type 1 (LC1) IgG autoantibodies over the period of evaluation (P≤0.0072). A quantitative risk profile generated from baseline demographic and autoantibody variables yielded highly different scores for the progressor and non-progressor groups (P=1.38 × 10⁻7) CONCLUSIONS: In addition to demographic features, autoantibody profiles using an expanded array of specificities were correlated with the risk of progressive disease in patients with lupus. These findings suggest the feasibility of developing a simple diagnostic that could be applied by nonspecialists to screen for lupus and permit effective triage for specialty care.