Staphylococcal peptidoglycans induce arthritis.

Staphylococcus aureus is one of the most important pathogens in septic arthritis. To analyse the arthritogenic properties of staphylococcal peptidoglycan (PGN), highly purified PGN from S. aureus was intra-articularly injected into murine joints. The results demonstrate that PGN will trigger arthritis in a dose-dependent manner. A single injection of this compound leads to massive infiltration of predominantly macrophages and polymorphonuclear cells with occasional signs of cartilage and/or bone destruction, lasting for at least 14 days. Further studies showed that this condition is mediated by the combined impact of acquired and innate immune systems. Our results indicate that PGN exerts a central role in joint inflammation triggered by S. aureus.

Intracisternally localized bacterial DNA containing CpG motifs induces meningitis.

Unmethylated CpG motifs are frequently found in bacterial DNA, and have recently been shown to exert immunostimulatory effects on leukocytes. Since bacterial infections in the CNS will lead to local release of prokaryotic DNA, we wanted to investigate whether such an event might trigger meningitis. To that end, we have intracisternally injected mice and rats with bacterial DNA and oligonucleotides containing CpG motifs. Histopathological signs of meningitis were evident within 12 h and lasted for at least 14 days, and were characterized by an influx of monocytic, Mac-3(+) cells and by a lack of T lymphocytes. To study the mechanisms whereby unmethylated CpG DNA gives rise to meningitis, we deleted the monocyte/macrophage population leading to abrogation of brain inflammation. Also, interaction with NF-kappaB using antisense technology led to down-regulation of proinflammatory cytokine production and frequency of meningitis. Furthermore, specific interactions with vascular selectin expression and inhibition of NO synthase led to a significant amelioration of meningitis, altogether indicating that this condition is dependent on macrophages and their products. In contrast, neutrophils, NK cells, T/B lymphocytes, IL-12, and complement system were not instrumental in meningitis triggered by bacterial DNA containing CpG motifs. This study proves that bacterial DNA containing unmethylated CpG motifs induces meningitis, and indicates that this condition is mediated in vivo by activated macrophages.

Synovial cytokine mRNA expression during arthritis triggered by CpG motifs of bacterial DNA.

Our results show that cytokines derived from macrophages play an important role in pathogenesis of arthritis triggered by CpG oligodinucleotide (CpG ODN). IL-12 is in this respect an important immunomodulator during the development of joint inflammation.

The major role of macrophages and their product tumor necrosis factor alpha in the induction of arthritis triggered by bacterial DNA containing CpG motifs.

OBJECTIVE: To understand the mechanisms of arthritis triggered by CpG-containing oligonucleotides (ODN). METHODS: Following the induction of CpG ODN-triggered arthritis in mice, we analyzed the impact of depletion of immune cells, including neutrophils, natural killer (NK) cells, and monocyte/macrophages, on the arthritis, as well as the impact in SCID mice lacking T and B cells. In addition, tumor necrosis factor alpha (TNFalpha) knockout mice were studied, and intraarticular administration of p65 antisense to nuclear factor kappaB (NF-kappaB) was used to examine effects in CpG ODN-triggered arthritis. Cytokine messenger RNA expression in synovial tissue was evaluated by in situ hybridization. RESULTS: The presence of macrophages was mandatory for the mediation of arthritis triggered by CpG ODN, whereas the absence of neutrophils, NK cells, T cells, and B cells was of minor importance in this regard. The proinflammatory cytokines TNFalpha, interleukin-1beta, and interleukin-12, which originate from macrophages, were frequently found in the inflamed joints, and TNFalpha was confirmed to be an important mediator in the development of arthritis, since the incidence and severity of joint inflammation were markedly reduced in TNFalpha knockout mice. NF-kappaB exerted an important regulatory role in the development of CpG ODN-mediated arthritis, since local administration of antisense to the p65 subunit of NF-kappaB diminished the incidence of inflammation by 50%. CONCLUSION: Macrophages and their products play an important role in the development of arthritis triggered by bacterial DNA containing CpG motifs.

The role of bacterial DNA in septic arthritis.

Unmethylated CpG motifs are frequently found in bacterial DNA and have recently been shown to exert immunostimulatory effects on leukocytes. Bacteria produce severe septic arthritis; bacterial DNA may be involved in this process. We injected intraarticularly bacterial DNA and oligonucleotides containing unmethylated CpG motifs into knee joints of mice. Arthritis was seen by histopathology within 2 h and lasted for at least 14 days, and was characterized by an influx of monocytic, Mac-1+ cells and by a lack of T lymphocytes. Macrophages and their products such as tumor necrosis factor (TNF) alpha are essential for development of arthritis triggered by bacterial DNA containing CpG motifs. In contrast, neurophils, NK cells, and T/B cells were not instrumental in this condition. This review demonstrates that bacterial DNA containing unmethylated CpG motifs induces arthritis and indicates an important pathogenic role for bacterial DNA in septic arthritis.

The features of arthritis induced by CpG motifs in bacterial DNA.

OBJECTIVE: To investigate the features of arthritis induced by bacterial DNA that contain CpG motifs. METHODS: Bacterial DNA originating from Escherichia coli and Staphylococcus aureus or synthetic oligonucleotides containing CpG motifs were injected directly into knee joints of mice. Histopathologic joint damage, antibody levels, cytokine levels, and synovial messenger RNA (mRNA) expression of cytokines and chemokines were assessed. RESULTS: Histopathologic signs of arthritis were evident within 2 hours and lasted for at least 3 weeks. Nonmethylated CpG motifs were responsible for the induction of arthritis since oligonucleotides containing these motifs triggered arthritis, whereas methylation of these nucleotides abrogated the inflammatory response. Arthritis was characterized by an influx of monocytic, Mac-1+ cells and by a scarcity of T lymphocytes. The disease was characterized locally by mRNA expression of macrophage-derived cytokines (tumor necrosis factor alpha, interleukin-12 [IL-12], IL-1beta) and chemokines (monocyte chemoattractant protein 1, RANTES) in arthritic joints. Systemically, the arthritis was characterized by increased levels of circulating IL-6 and immunoglobulins. CONCLUSION: These findings demonstrate that bacterial DNA that contain nonmethylated CpG motifs induces arthritis, suggesting an important pathogenic role for bacterial DNA in septic arthritis.

Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis.

Unmethylated CpG motifs are often found in bacterial DNA, and exert immunostimulatory effects on hematopoietic cells. Bacteria produce severe joint inflammation in septic and reactive arthritides; bacterial DNA may be involved in this process. We injected bacterial DNA originating from Escherichia coli and Staphylococcus aureus and oligonucleotides containing CpG directly into the knee joints of mice of different strains. Arthritis was seen by histopathology within 2 hours and lasted for at least 14 days. Unmethylated CpG motifs were responsible for this induction of arthritis, as oligonucleotides containing these motifs produced the arthritis. The arthritis was characterized by an influx of monocytic, Mac-1+ cells and by a lack of T lymphocytes. Depletion of monocytes resulted in abrogation of the synovial inflammation. Tumor necrosis factor (TNF)-alpha, a cytokine produced by cells of the monocyte/macrophage lineage, is an important mediator of this disease, as expression of mRNA for TNF-alpha was evident in the inflamed joints, and the CpG-mediated inflammation was abrogated in mice genetically unable to produce this cytokine. These findings demonstrate that bacterial DNA containing unmethylated CpG motifs induces arthritis, and indicate an important pathogenic role for bacterial DNA in septic arthritis.

An improved mathematical model of hormone secretion in the hypothalamo-pituitary-gonadal axis in man.

We propose an improved mathematical model for the secretion in the hypothalamo-pituitary-gonadal axis. We think this model is more reasonable than any previous one and can interpret a large number of experimental facts.