The expression and regulation of pregnancy-specific glycoproteins in the mouse

Pregnancy-Specific Glycoproteins (PSG) are the most abundant fetally expressed proteins in the maternal bloodstream at term. This multigene family are immunoglobulin superfamily members and are predominantly expressed in the syncytiotrophoblast of human placenta and in giant cells and spongiotrophoblast of rodent placenta. PSGs are encoded by seventeen genes in the mouse and ten genes in the human. Little is known about the function of this gene family, although they have been implicated in immune modulation and angiogenesis through the induction of cytokines such as IL-10 and TGFβ1 in monocytes, and more recently, have been shown to inhibit the platelet-fibrinogen interaction. I provide new information concerning the evolution of the murine Psg genomic locus structure and organisation, through the discovery of a recent gene inversion event of Psg22 within the major murine Psg cluster. In addition to this, I have performed an examination of the expression patterns of individual Psg genes in placental and non-placental tissues. This study centres on Psg22, which is the most abundant murine Psg transcript detected in the first half of pregnancy. A novel alternative splice variant transcript of Psg22 lacking the protein N1-domain was discovered, and similar to the full length isoform induces TGFβ1 in macrophage and monocytic cell lines. The identification of a bidirectional antisense long non-coding RNA transcript directly adjacent to Psg22 and its associated active local chromatin conformation, suggests an interesting epigenetic gene-specific regulatory mechanism that may be responsible for the high level of Psg22 expression relative to the other Psg family members upon trophoblast giant cell differentiation

Preclinical atherosclerosis in rheumatoid arthritis

Introduction: There is accumulating evidence of an increased risk of cardiovascular morbidity and mortality in rheumatoid arthritis patients. A combination of both traditional cardiovascular risks and rheumatoid specific factors appear to be responsible for driving this phenomenon. Rheumatoid arthritis has been an orphan of cardiologists in the past and rheumatologists themselves are not good at CVD screening. Identifying the extent of preclinical atherosclerosis in RA patients will help us to appreciate the magnitude of this serious problem in an Irish population. Methods: We undertook a cross-sectional study of 63 RA patients and 48 OA controls and compared the 2 groups with respect to 1) traditional CV risks factors, 2) serum biomarkers of inflammation, including CRP, TNFα, IL6 and PAI-1, 3) carotid intima-media thickness (cIMT), carotid plaque and ankle-brachial index (ABI) as markers of pre-clinical atherosclerosis, 4) biochemical and ultrasonic measures of endothelial dysfunction and 5) serum and echocardiographic measures of diastolic dysfunction. Within the RA group, we also investigated for associations between markers of inflammation, subclinical atherosclerosis and diastolic dysfunction. Results: Prevalence of traditional CV risks was similar in the RA and OA groups. A number of biomarkers of inflammation were significantly higher in the RA group: CRP, fibrinogen, IL- 2, -4, -6, TNFα. PAI-1, a marker of thrombosis, correlated with disease activity and subclinical atherosclerosis in RA patients. With regard to subclinical atherosclerosis measures, RA patients had a significantly lower ABI than OA patients. Carotid plaque and cIMT readings were similar in RA and OA patients. Assessment of endothelial function revealed that RA patients had significantly higher concentrations of adhesion molecules, in particular sero-positive RA patients and RA smokers. Adhesion molecule concentrations were associated with markers of diastolic dysfunction in RA. Urine PCR, another marker of endothelial dysfunction also correlated with diastolic dysfunction in RA. Assessment of endothelial function with flow mediated dilatation (FMD) found no difference between the RA and OA groups. Disease activity scores in RA patients were associated with endothelial dysfunction, as assessed by FMD. Conclusions: We did not find significant differences in measures of subclinical atherosclerosis, flow mediated dilatation or diastolic function between RA and OA patients. This is most likely in part due to the fact that there is increasing evidence that OA has an inflammatory component to its pathogenesis and is associated with metabolic syndrome and increased CV risk. We reported a significant association between urinary PCR and measures of diastolic dysfunction. Urinary PCR may be a useful screening tool for diastolic dysfunction in RA. The association between RA disease activity and measures of vascular function supports the theory that the excess cardiovascular burden in RA is linked to uncontrolled inflammation.