Rheumatoid arthritis (RA) is characterized by synovial joint inflammation and by development of pathogenic humoral and cellular autoimmunity to citrullinated proteins. Neutrophil extracellular traps (NETs) are a source of citrullinated autoantigens and activate RA synovial fibroblasts (FLS), cells crucial in joint damage. We investigated the molecular mechanisms by which NETs promote proinflammatory phenotypes in FLS, and whether these interactions generate pathogenic anti-citrulline adaptive immune responses. NETs containing citrullinated peptides are internalized by FLS through a RAGE-TLR9 pathway promoting FLS inflammatory phenotype and their upregulation of MHC class II. Once internalized, arthritogenic NET-peptides are loaded into FLS MHC class II and presented to Ag-specific T cells. HLADRB1*0401 transgenic mice immunized with mouse FLS loaded with NETs develop antibodies specific to citrullinated forms of relevant RA autoantigens implicated in RA pathogenesis as well as cartilage damage. These results implicate FLS as mediators in RA pathogenesis, through the internalization and presentation of NET citrullinated peptides to the adaptive immune system leading to pathogenic autoimmunity and cartilage damage.

The frequency of hypercalciuria was determined in the families of nine hypercalciuric patients with idiopathic hypercaliuria who formed recurrent calcium oxalate renal stones. Idiopathic hypercalciuria occurred in 26 of 73 relatives, in three consecutive generations of two families and in two successive generations of four other families. Multiple siblings or children of the probands were affected in three families. Nineteen of 44 first-degree relatives (43 per cent) had idiopathic hypercalciuria, as compared to seven of 29 (29 per cent) other relatives; there was no relation to age or sex. Renal stones were formed by 19 of the 44 first-degree relatives but by none of the others; nine of the 19 were women. We conclude that there is a familial form of hypercalciuria, which appears to be transmitted as an autosomal dominant trait. Stone disease is frequent in first-degree relatives, and affects both sexes equally.

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