Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

Walking cadence affects rate of plantar foot temperature change but not final temperature in younger and older adults.

This study examined the relationship between (1) foot temperature in healthy individuals and walking cadence, (2) temperature change at different locations of the foot, and (3) temperature change and its relationship with vertical pressures exerted on the foot. Eighteen healthy adult volunteers (10 between 30 and 40 years - Age: 33.4±2.4years; 8 above 40 years - Age: 54.1±7.7years) were recruited. A custom-made insole with temperature sensors was placed directly onto the plantar surface of the foot and held in position using a sock. The foot was placed on a pressure sensor and the whole system placed in a canvas shoe. Participants visited the lab on three separate occasions when foot temperature and pressure data were recorded during walking on a treadmill at one of three cadences (80, 100, 120steps/min). The plantar foot temperature increased during walking in both age groups 30-40 years: 4.62±2.00°C, >40years: 5.49±2.30°C, with the rise inversely proportional to initial foot temperature (30-40 years: R(2)=-0.669, >40years: R(2)=-0.816). Foot temperature changes were not different between the two age groups or the different foot locations and did not depend on vertical pressures. Walking cadence affected the rate of change of plantar foot temperature but not the final measured value and no association between temperature change and vertical pressure was found. These results provide baseline values for comparing foot temperature changes in pathological conditions which could inform understanding of pathophysiology and support development of evidence based healthcare guidelines for managing conditions such as diabetic foot ulceration (DFU)

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist