Self Protection from Anti-Viral Responses – Ro52 Promotes Degradation of the Transcription Factor IRF7 Downstream of the Viral Toll-Like Receptors

Ro52 is a member of the TRIM family of single-protein E3 ligases and is also a target for autoantibody production in systemic lupus erythematosus and Sjögren's syndrome. We previously demonstrated a novel function of Ro52 in the ubiquitination and proteasomal degradation of IRF3 following TLR3/4 stimulation. We now present evidence that Ro52 has a similar role in regulating the stability and activity of IRF7. Endogenous immunoprecipitation of Ro52-bound proteins revealed that IRF7 associates with Ro52, an effect which increases following TLR7 and TLR9 stimulation, suggesting that Ro52 interacts with IRF7 post-pathogen recognition. Furthermore, we show that Ro52 ubiquitinates IRF7 in a dose-dependent manner, resulting in a decrease in total IRF7 expression and a subsequent decrease in IFN-α production. IRF7 stability was increased in bone marrow-derived macrophages from Ro52-deficient mice stimulated with imiquimod or CpG-B, consistent with a role for Ro52 in the negative regulation of IRF7 signalling. Taken together, these results suggest that Ro52-mediated ubiquitination promotes the degradation of IRF7 following TLR7 and TLR9 stimulation. As Ro52 is known to be IFN-inducible, this system constitutes a negative-feedback loop that acts to protect the host from the prolonged activation of the immune response

A qualitative grounded theory study of the conceptions of clinical practice in osteopathy – A continuum from technical rationality to professional artistry

How practitioners conceive clinical practice influences many aspects of their clinical work including how they view knowledge, clinical decision-making, and their actions. Osteopaths have relied upon the philosophical and theoretical foundations upon which the profession was built to guide clinical practice. However, it is currently unknown how osteopaths conceive clinical practice, and how these conceptions develop and influence their clinical work. This paper reports the conceptions of practice of experienced osteopaths in the UK. A constructivist grounded theory approach was taken in this study. The constant comparative method of analysis was used to code and analyse data. Purposive sampling was employed to initially select participants. Subsequent theoretical sampling, informed by data analysis, allowed specific participants to be sampled. Data collection methods involved semi-structured interviews and non-participant observation of practitioners during a patient appointment, which was video-recorded and followed by a video-prompted reflective interview. Participants' conception of practice lay on a continuum, from technical rationality to professional artistry and the development of which was influenced by their educational experience, view of health and disease, epistemology of practice knowledge, theory-practice relationship and their perceived therapeutic role. The findings from this study provide the first theoretical insight of osteopaths' conceptions of clinical practice and the factors which influence such conceptions

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

The concept that viral sensing systems, via their ability to drive pro-inflammatory cytokine and interferon production, contribute to the development of autoimmune and autoinflammatory disease is supported by a wide range of clinical and experimental observations. Recently, the tripartite motif-containing proteins (TRIMs) have emerged as having key roles in antiviral immunity — either as viral restriction factors or as regulators of pathways downstream of viral RNA and DNA sensors, and the inflammasome. Given their involvement in these pathways, we propose that TRIM proteins contribute to the development and pathology of autoimmune and autoinflammatory conditions, thus making them potential novel targets for therapeutic manipulation