The role of Human Endogenous Retrovirus K10 (HERV-K10) in the pathogenesis of rheumatoid arthritis via molecular mimicry

Rheumatoid arthritis (RA) is a chronic joint disease of unknown aetiology. The autoimmune nature of RA is underlined by abundant generation of rheumatoid factor (RF) autoantibodies to IgG1 Fc, and anti-citrullinated protein antibodies (ACPA) to citrullinated autoantigens such as fibrinogen. Although RA pathogenesis has not been elucidated, genetic predisposition, environmental insults and viral pathogens are considered contributory factors. Human endogenous retrovirus K10 (HERV-K10) is one such virus as it retained the capacity to produce viral particles in RA synovium. This study set out to explore how HERV-K10 Gag matrix region could contribute to RA pathogenesis and perpetuation, with particular emphasis on its ability to mimic host autoantigens. We showed that Gag region exhibits high levels of sequence and structural homology to IgG1 Fc and it could provide a key epitope important for auto-reactivity in RA. Analysis of how HERV-K10 may evoke immune responses in RA was broadened by investigation of serological cross-reactivity of novel anti-K10 polyclonal antibody (PAbMAG) with IgG1 Fc. We showed that PAbMAG cross-reacted with linear and conformational epitopes on IgG1 Fc. In a further development, we showed a significantly elevated mean IgG response to HERV-K10 epitopes in serum samples from RA patients when compared to other arthritides. These data suggest that molecular mimicry between viral and host proteins has the potential to lead to antigen-driven high-affinity RF IgG immunological reactivity in RA. Finally, we broadened our study of mimicry in RA by the investigation of citrullinated autoantigens. Structural studies demonstrated high levels of homology between citrullinated fibrinogen, IgG1 Fc and HERV. We further explored how protein citrullination affects the cross-reactivity of autoantibody responses in RA. These experiments revealed that generation of neoepitopes through citrullination of HERV-K10 and autoantigens IgG1 Fc and fibrinogen enhanced the reactivity of RA sera to these targets. Moreover, we showed that RF autoantibodies could mediate responses to a classical ACPA target fibrinogen, only when it is citrullinated, in the absence of ACPAs. These data provide a new insight into the initiation and propagation of immunological responses in RA and how viral/host molecular mimics and citrullination could modulate serum cross-reactivity profiles in RA.South Staffordshire Medical Foundation, Rotha Abraham Bequest, The Royal Wolverhampton Hospital Charity, New Cross Kidney Patients Association, James Beattie Charitable Trust.A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosoph

Pendekatan Ekologis Dan Tektonika Bahan Pada Perancangan Galeri Seni Ketukangan

Arsitektur di nusantara saat ini lebih mengedepankan ‘tren\u27 modern dan kurang mempertimbangkan seni ketukangan dengan aspek lokal dalam berkarya sehingga identitas arsitektur nusantara semakin terkikis dan budaya/kearifan lokal bukan lagi menjadi pertimbangan utama para penggiat arsitektur dalam merancang. Perancangan objek ini berusaha untuk meningkatkan kemampuan para tukang agar terus berinovasi dalam mencipta serta mengenalkan potensi ketukangan lokal kepada masyarakat umum. Dengan mengeksplorasi potensi alam dan ketukangan menggunakan pendekatan arsitektur ekologis kedalam objek rancang Galeri Seni Ketukangan diharapkan dapat melestarikan identitas kelokalan arsitektur nusantara serta para tukang di masa depan dapat terus berinovasi dalam berkarya dan dapat menarik antusias masyarakat terutama para penggiat arsitektur untuk kembali menerapkan aspek budaya lokal nusantara dalam mencipta karya. Objek rancang mewadahi kegiatan eksplorasi ketukangan untuk melestarikan identitas serta potensi material arsitektur di nusantara. Metoda desain yang akan digunakan adalah metoda desain William M. Pena & Steven A. Pharsall dengan pendekatan ekologis guna meminimalisir dampak objek rancang terhadap lahan dan lingkungan

Interleukin 21 inhibits cancer-mediated FOXP3 induction in naïve human CD4 T cells

IL-21 is known to promote anti-tumour immunity due to its ability to promote T cell responses and counteract Treg-mediated suppression. It has also been shown to limit Treg frequencies during tumour-antigen stimulations. However, whether this represents inhibition of FOXP3 induction in naïve CD4 T cells or curtailed expansion of natural Treg remains unclear. Moreover, whether this effect is maintained in an environment of tumour-derived immunosuppressive factors is not known. Here, we show that in the context of a number of cancers, naïve CD45RA+ CD4 T cells are induced to express high levels of FOXP3, and that FOXP3 expression correlates with inhibition of T cell proliferation. FOXP3 expression was most potently induced by tumours secreting higher levels of total and active TGFβ1 and this induction could be potently counteracted with IL-21, restoring T cell proliferation. We conclude that Treg induction in naïve T cells is a common phenomenon amongst a number of different cancers and that the ability of IL-21 to counteract this effect is further evidence of its promise in cancer therapy

Exercise-induces changes during symptom-limited exercise on a bicycle ergometer in 32 asymptomatic aortic valve stenosis patients (AS) and 32 well-matched Controls (C) in Interleukin- 10 (IL-10).

<p>Exercise-induces changes during symptom-limited exercise on a bicycle ergometer in 32 asymptomatic aortic valve stenosis patients (AS) and 32 well-matched Controls (C) in Interleukin- 10 (IL-10).</p

Exercise-induces changes during symptom-limited exercise on a bicycle ergometer in 32 asymptomatic aortic valve stenosis patients (AS) and 32 well-matched Controls (C) in HGF (hepatocyte growth factor).

<p>Exercise-induces changes during symptom-limited exercise on a bicycle ergometer in 32 asymptomatic aortic valve stenosis patients (AS) and 32 well-matched Controls (C) in HGF (hepatocyte growth factor).</p

Clinical, exercise and echocardiographic data.

<p>Clinical, exercise and echocardiographic data.</p

Exercise-induces changes during symptom-limited exercise on a bicycle ergometer in 32 asymptomatic aortic valve stenosis patients (AS) and 32 well-matched Controls (C) in VEGF (vascular endothelial growth factor).

<p>Exercise-induces changes during symptom-limited exercise on a bicycle ergometer in 32 asymptomatic aortic valve stenosis patients (AS) and 32 well-matched Controls (C) in VEGF (vascular endothelial growth factor).</p

Exercise-induces changes during symptom-limited exercise on a bicycle ergometer in 32 asymptomatic aortic valve stenosis patients (AS) and 32 well-matched Controls (C) in TGF-β (transforming growth factor).

<p>Exercise-induces changes during symptom-limited exercise on a bicycle ergometer in 32 asymptomatic aortic valve stenosis patients (AS) and 32 well-matched Controls (C) in TGF-β (transforming growth factor).</p