Rheumatoid arthritis (RA) is the most common, crippling human autoimmune disease. Using Western blotting and tandem mass spectroscopy, we have identified the endoplasmic reticulum chaperone BiP, a 78-kDa glucose-regulated protein, as a possible autoantigen. It preferentially stimulated increased proliferation of synovial T cells from patients with RA but not from patients with other arthritides. Mice with established collagen- or pristane-induced arthritis developed IgG Abs to BiP. Although BiP injected in CFA failed to induce arthritis in several strains of rats and mice, including HLA-DR4+/−- and HLA-DR1+/+-transgenic animals, it completely inhibited the development of arthritis when given i.v. 1 wk before the injection of type II collagen arthritis. Preimmunization with BiP suppressed the development of adjuvant arthritis in Lewis rats in a similar manner. This is the first report of a mammalian chaperone that is an autoantigen in human RA and in experimental arthritis and that can also prevent the induction of experimental arthritis. These findings may stimulate the development of new immunotherapies for the treatment of RA.

Genes that are expressed during leaf senescence in Brassica napus were identified by the isolation of representative cDNA clones. DNA sequence and deduced protein sequence from two senescence-related cDNAs, LSC94 and LSC222, representing genes that are expressed early in leaf senescence before any yellowing of the leaves is visible, showed similarities to genes for pathogenesis-related (PR) proteins: a PR-1a-like protein and a class IV chitinase, respectively. The LSC94 and LSC222 genes showed differential regulation with respect to each other; an increase in expression was detected at different times during development of healthy leaves. Expression of both genes was induced by salicylic acid treatment. These findings suggest that some PR genes, as well as being induced by pathogen infection, may have alternative functions during plant development, for example in the process of leaf senescence.

Objective. Levels of interleukin-6 (IL-6) have been shown to correlate with the fever and disease activity of systemic juvenile idiopathic arthritis (JIA). In a previous case-control study, a significant association between the IL-6 ؊174 nucleotide variant and systemic JIA was noted, and HeLa cell transfection assays show functional differences in levels of transcription of the IL-6 ؊174 alleles. The present study was undertaken to confirm the previous findings and to assess possible association with variations of the A n T n tract in the promoter.Methods. We studied a cohort of JIA families from 3 countries, using transmission disequilibrium testing. Genotyping of the ؊174 nucleotide variant was done by restriction fragment length polymorphism, heteroduplex analysis, or allelic discrimination. The A n T n tract at ؊392 to ؊373 was typed using DNA sequencing. Statistical analysis was performed using the programs Transmit and EHplus.Results. There was a significant excess transmission of the ؊174G allele in the systemic JIA families (P ‫؍‬ 0.041). The excess transmission was only to systemic JIA patients with age at onset >5 years (P ‫؍‬ 0.007). No significant association with the other subtypes was found. No A n T n alleles or ؊174/A n T n haplotypes were significantly associated with systemic JIA.Conclusion. This study confirms that the IL-6 -174 nucleotide variant is significantly associated with systemic JIA. The significant excess transmission to patients with age at onset >5 years but not to those with age at onset <5 years suggests that there may be genetic heterogeneity between the 2 groups.

Interleukin-6 (IL-6) is a pleiotropic cytokine crucial in both adaptive and innate immunity. Numerous genetic studies have shown association with variants of this gene in a multitude of diseases and phenotypes. Most tests of association have focused on a limited set of promoter polymorphisms, in particular, the À174G4C; however, there are many inconsistencies within and between these studies. We propose that there is a more complex regulatory haplotype extending further upstream of the previously characterised promoter region which will provide a more detailed view of the effect of variation on lL-6 regulation. We have exploited two additional single nucleotide polymorphisms (SNPs) in IL-6 that, when examined as a haplotype with existing markers, show an increased level of association with systemic onset juvenile arthritis in a family-based study. This suggests that the haplotype effect may be more functionally relevant to the disease.