Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.

Juvenile systemic sclerosis (jSSc) is an orphan disease. Currently the majority of jSSc cohort studies are retrospective in design without standardised assessment. This study was conducted prospectively to investigate the difference in manifestations of limited cutaneous (lcjSSc) and diffuse cutaneous (dcjSSc) subtypes. An additional aim was to compare these data to other historic jSSc cohorts and a large established adult onset SSc cohort. Methods: Patients fulfilling the PRES jSSc-classification criteria were included. Clinical characteristics and patient related outcomes were assessed. Results: Eighty patients were enrolled, 72.5% with dcjSSc with a mean modified Rodnan Skin Score (mRSS) of 18(SD), and 27.5% lcjSSc with mean mRSS of 9(SD). Mean disease duration at enrolment was 3.7 and 3.0 years in dcjSSc and lcjSSc patients, respectively. The mean age at onset of Raynaud's and first non-Raynaud's symptoms was similar in both groups, approximately 9 and 10.5 years old, respectively. Active digital tip ulcerations were present in 29% dcjSSc and none in the lcjSSc subjects(p=0.005). Of those with cardiopulmonary testing, 3% of dcjSSc and 32% of lcjSSc group had cardiac involvement (p=0.024), and 41% dcjSSc and 22% of the lcjSSc group had pulmonary involvement (p=0.009). Physician global disease damage assessment was higher in the dcjSSc compared to the lcjSSc group, 35 and 15 respectively (p=0.021).

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against intracellular components, the formation of immune complexes, and inflammation in various organs, typically the skin and kidney glomeruli. The etiology of the disease is not well understood but is most likely the result of the interaction between genetic and environmental factors. In order to identify susceptibility loci for SLE, we have performed genome scans with microsatellite markers covering the whole genome in families from Argentina, Italy, and Europe. The results reveal a heterogeneous disease with different susceptibility loci in different family sets. We have found significant linkage to chromosome 17p12-q11 in the Argentine set of families. The maximum LOD score was given by marker D17S1294 in combination with D17S1293, when assuming a dominant inheritance model (Z = 3.88). We also analyzed a repeat in the promoter region of the NOS2A gene, a strong candidate gene in the region, but no association was found. The locus on chromosome 17 has previously been identified in genetic studies of multiple sclerosis families. Several other interesting regions were found at 1p35, 1q31, 3q26, 5p15, 11q23 and 19q13, confirming previously identified loci for SLE or other autoimmune diseases.

Significance and Innovations:1. Juvenile systemic sclerosis (jSSc) patients demonstrate significant differences between dcjSSc and lcjSSc subtype regarding frequency of skin, vascular, pulmonary and cardiac involvement.2. Physician global assessment of disease activity and damage is higher in the dcjSSc group.3. jSSc patients with overlap features are not 'protected' from major internal organ involvement and have a higher frequency of lung disease compared to those without overlap features.

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