Precocious osteoarthritis in a family with recurrent COL2A1 mutation.

Objective: To examine the genotypic and phenotypic characteristics of a Micronesian kindred with autosomal dominant precocious osteoarthritis (OA).

Methods: We reviewed records and radiographs of 3 index patients and their parents, administered questionnaires to 16 additional kindred members, performed whole-genome scans of 24 family members, and sequenced relevant genes from 16 family members.

Results: The kindred displayed early onset OA, enlarged epiphyses, platyspondyly, and brachydactyly with dysplastic findings consistent with mild spondyloepiphyseal dysplasia.

The host type I interferon response to viral and bacterial infections.

Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNs are produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN production were largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infections by recognizing various viral components.

Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF kappa B kinase-binding kinase 1.

Type I IFNs are well established antiviral cytokines that have also been shown to be induced by bacteria. However, the signaling mechanisms regulating the activation of these cytokines during bacterial infections remain poorly defined. We show that although Gram-negative bacteria can activate the type I IFN pathway through TLR4, the intracellular Gram-positive bacterium Listeria monocytogenes (LM) can do so independently of TLR4 and TLR2.

Type I interferon production enhances susceptibility to Listeria monocytogenes infection.

Numerous bacterial products such as lipopolysaccharide potently induce type I interferons (IFNs); however, the contribution of this innate response to host defense against bacterial infection remains unclear. Although mice deficient in either IFN regulatory factor (IRF)3 or the type I IFN receptor (IFNAR)1 are highly susceptible to viral infection, we show that these mice exhibit a profound resistance to infection caused by the Gram-positive intracellular bacterium Listeria monocytogenes compared with wild-type controls. Furthermore, this enhanced bacterial clearance is accompanied by a block in L.

Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection.

TANK-binding kinase-1 (TBK1) and the inducible IkappaB kinase (IKK-i) have been shown recently to activate interferon (IFN) regulatory factor-3 (IRF3), the primary transcription factor regulating induction of type I IFNs. Here, we have compared the role and specificity of TBK1 in the type I IFN response to lipopolysaccharide (LPS), polyI:C, and viral challenge by examining IRF3 nuclear translocation, signal transducer and activator of transcription 1 phosphorylation, and induction of IFN-regulated genes. The LPS and polyI:C-induced IFN responses were abolished and delayed, respectively, in macrophages from mice with a targeted disruption of the TBK1 gene.