Homozygosity for DNASE2 single nucleotide polymorphisms in the 5'-regulatory region is associated with rheumatoid arthritis.

OBJECTIVES: To analyse the distribution of single nucleotide polymorphisms (SNPs) in the 5'-regulatory region of the DNASE2 gene, in patients with rheumatoid arthritis (RA) and healthy controls. METHODS: A total of 906 patients with RA and 878 healthy controls were genotyped. All subjects were of German Caucasian origin. Genotyping was performed by real-time polymerase chain reaction technology, using a TaqMan 5'-allele discrimination assay. RESULTS: In the initial analysis of unrelated case-control samples, three DNASE2 SNP alleles in the 5'-regulatory region were significantly more frequent in patients with RA than in healthy controls. The strongest association was found for the -1066G allele (33.5% vs 27.2%, p = 0.007, odds ratio (OR) = 1.34). Homozygosity for this allele (genotype GG) resulted in an additional increase in disease susceptibility (12.5% vs 6.2%, OR = 2.17). The association was replicated in a second case-control series of 483 patients with RA from two German multicentre studies and 474 controls. The association of DNASE2 -1066 GG homozygosity with RA was limited to rheumatoid factor-positive disease, but was not influenced by the presence of anti-cyclic citrullinated peptide or antinuclear antibodies. Similarly, the presence or absence of the HLA-DRB1 shared epitope or the RA-associated PTPN22 allele had no influence on this association. CONCLUSIONS: The association of SNPs in the 5'-regulatory region of the DNA degrading enzyme DNASE2 with RA implies a role for this enzyme in the pathogenesis of this autoimmune disease.

[T cell-dependent monocyte activation, TNFalpha and apolipoprotein A-I in autoimmunity and inflammation]. / T-Zell-abhängige Monozytenaktivierung, TNFalpha und Apolipoprotein A-I in Autoimmunität und Inflammation.

Rheumatoid arthritis is characterized by a massive overproduction of monokines like TNFalpha, IL-6 and IL-1beta, which are predominantly produced by monocytes and macrophages. To date, the exact mechanisms of monocyte/macrophage activation have not been fully elucidated. One possible mechanism is their cell contact-dependent activation by activated T cells. The direct cell contact of monocytes/macrophages and T cells leads to an increased production of pro-inflammatory cytokines such as TNFalpha and IL-1beta. Stringent control of this mechanism by inhibitory factors appears mandatory under physiological conditions in order to avoid systemic cytokine release syndromes. The presence of inhibitory factors in the serum could represent such a mechanism. In healthy donors, apolipoprotein A-I was identified as such an inhibitory serum protein. In patients with rheumatoid arthritis, apolipoprotein A-I is found in decreased concentrations, possibly due to its role as a negative acute phase protein. The role of this and other inhibitory serum molecules are discussed.

Hazards in the theater.

The authors offer a survey of the myriad and unique safety and health hazards faced past and present by performers and theatrical workers, from preproduction work, through the show, and during the strike (dismantling). Special emphasis is given to health hazards posed by the many new plastic resin systems and adhesives used in set, prop, and costume construction; the hazards of special-effect fogs, smokes, haze, dusts, and pyrotechnic emissions; and theatrical makeup.

Diverse regulation of microfilament assembly, production of TNF-alpha, and reactive oxygen intermediates by actin modulating substances and inhibitors of ADP-ribosylation in human monocytes stimulated with LPS.

Lipopolysaccharide (LPS), a potent activator of human monocytes, induced F-actin polymerization in a concentration- and time-dependent manner. To test whether cytoskeletal events participate in the control of the LPS-induced ROI and TNF-alpha production, three natural occurring actin-modulating substances, cytochalasin D (Cyt D), latrunculin B (Lat B), and jasplakinolide (JK), were used. Here we show that treatment of monocytes with Cyt D, Lat B, or JK led to a rearrangement of the actin cytoskeleton, which upon addition of LPS was further modified. Cyt D and Lat B induced generation of ROI in the absence of LPS and enhanced the LPS-triggered respiratory burst. JK also proved to be a potent activator of ROI-production but only in the presence of LPS. TNF-alpha production was hardly affected by the three substances. There was no correlation between a specific state of Cyt D-, Lat B-, or JK-modified actin polymerization and ROI-production. Inhibitors of ADP-ribosylation proved to be activators of F-actin polymerization. They were shown to prevent ROI- and TNF-alpha production and to reduce the capability of LPS to mediate maximal F-actin assembly. At concentrations at which inhibition was greatest, maximal blockage of ROI and TNF-alpha production was observed. These findings may argue for a role of ADP-ribosylation in the transduction pathways mediating the biological responses, with involvement in the assembly of actin-containing cytoskeletal microfilaments.