An Antibody Against Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) Dampens Proinflammatory Cytokine Secretion by Lamina Propria Cells from Patients with IBD.

Background: Triggering receptor expressed on myeloid cells 1 (TREM-1) is a potent amplifier of inflammation. Recently, the antimicrobial peptide PGLYRP-1 was shown to be the ligand of TREM-1. Here, the ability of an anti-TREM-1 antibody to dampen the release of proinflammatory cytokines by colon lamina propria cells (LPCs) from patients with IBD was investigated and correlated with PGLYRP-1 levels.

Endogenous activation of adaptive immunity: tenascin-C drives interleukin-17 synthesis in murine arthritic joint disease.

Objective: Rheumatoid arthritis is characterized by persistent synovial inflammation and progressive joint destruction, which are mediated by innate and adaptive immune responses. Cytokine blockade successfully treats some patient subsets; however, ∼50% do not respond to this approach. Targeting of pathogenic T lymphocytes is emerging as an effective alternative/complementary therapeutic strategy, yet the factors that control T cell activation in joint disease are not well understood.

ENU-based phenotype-driven screening.

Deciphering the contribution of individual genes and in turn pathways to cellular processes can be complicated and is often based on prior knowledge or assumptions of gene function. Phenotype-driven mutagenesis screens based around n-ethyl-n-nitrosurea (ENU) have been successful in a wide range of physiological systems in identifying novel genes that contribute to a given phenotype. Here, we describe methodologies we have employed in analysing cellular phenotypes in pipelines of mutagenised mice.

Detection of a secreted metalloprotease within the nuclei of liver cells.

ADAMTS13 is a secreted zinc metalloprotease expressed by various cell types. Here, we investigate its cellular pathway in endogenously expressing liver cell lines and after transient transfection with ADAMTS13. Besides compartmentalizations of the cellular secretory system, we detected an appreciable level of endogenous ADAMTS13 within the nucleus.

Cell signalling in macrophages, the principal innate immune effector cells of rheumatoid arthritis.

Rheumatoid arthritis is a multisystemic auto-inflammatory disease affecting up to 1% of the population and leading to the destruction of the joints. Evidence exists for the involvement of the innate as well as the adaptive immune systems in the pathology of the disease. The success of anti-tumour necrosis factor-alpha indicates the importance of pro-inflammatory mediators produced by innate immune cells in rheumatoid arthritis progression.

The centromeric region of chromosome 7 from MRL mice (Lmb3) is an epistatic modifier of Fas for autoimmune disease expression.

Lupus is a prototypic systemic autoimmune disease that has a significant genetic component in its etiology. Several genome-wide screens have identified multiple loci that contribute to disease susceptibility in lupus-prone mice, including the Fas-deficient MRL/Fas(lpr) strain, with each locus contributing in a threshold liability manner. The centromeric region of chromosome 7 was identified as a lupus susceptibility locus in MRL/Fas(lpr) mice as Lmb3.

Oxazolone and diclofenac-induced popliteal lymph node assay reactions are attenuated in mice orally pretreated with the respective compound: potential role for the induction of regulatory mechanisms following enteric administration.

The murine popliteal lymph node assay (PLNA) was examined as a preclinical assay with the potential to identify low-molecular-weight compounds (LMWCs) that are likely to be associated with immune-mediated drug hypersensitivity reactions (IDHRs) in humans. We hypothesized that the contact sensitizer oxazolone (OX) would cause a strong PLN reaction in naive mice and that the PLN reaction would be attenuated in mice orally pretreated with OX due to the induction of oral tolerance. In naive mice, OX induced a strong PLN reaction and caused dose-dependent increases in PLN size, weight, cellularity, percentage of CD4(+) PLN T cells, and percentage of PLN B cells, with a concomitant decrease in the percentage of CD8(+) PLN T cells.

Intrinsic T cell defects in systemic autoimmunity.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of T cell tolerance to nuclear antigens. Studies in mice and humans have demonstrated that T cells from individuals with lupus are abnormal. Here, we review the known T cell defects in lupus and their possible biochemical nature, genetic causes, and significance for lupus pathogenesis.