Pegylated Arginine Deiminase Downregulates Colitis in Murine Models

Arginine deiminase (ADI), an arginine-metabolizing enzyme involved in cell signaling, is dysregulated in multiple inflammatory diseases and cancers. We hypothesized that pegylated ADI (ADI-PEG) provide protection against colitis. Methods. Dextran sodium sulfate colitis was induced in IL-10-deficient and BALB/c (WT) mice. ADI-PEG was administered i.p., and inflammatory mediators and pathology were evaluated. Results. Acute colitis in mice was manifested by increases in inflammatory biomarkers, such as serum amyloid A (SAA, P < 0.001), IL-12 p40, and disease index (3-Fold). In contrast, ADI-PEG significantly decreased clinical disease index, SAA levels, and inflammatory cytokines in blood as well as in colonic explants. Animals developed moderate (2.2 ± 0.3 WT) to severe (3.6 ± 0.5 IL-10 deficient) colonic pathology; and ADI-PEG treatment significantly improved the severity of colitis (P < 0.05). Marked infiltration of CD68+ macrophages and iNOS expression were detected in colonic submucosa in colitic animals but not detected in ADI-PEG-treated animals. Conclusion. ADI-PEG attenuated inflammatory responses by suppression of macrophage infiltration and iNOS expression in colitic animals. ADI-PEG can serve as a potential therapeutic value in IBD

Autoimmune Enteropathy with a CD8\u3csup\u3e+\u3c/sup\u3e CD7\u3csup\u3e-\u3c/sup\u3e T-cell Small Bowel Intraepithelial Lymphocytosis: Case Report and Literature Review

Background Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, are uncertain. We present a unique case of AIE associated with a CD8+CD7- lymphocytosis and review the literature to characterize the histologic and immunologic abnormalities, and the autoantibodies and autoimmune conditions associated with AIE. Case Presentation We present a case of immune mediated enteropathy distinguished by the CD8+CD7- intra-epithelial and lamina propria lymphocytosis. Twenty-nine cases of AIE have been reported. The majority of patients had auto-antibodies (typically anti-enterocyte), preferential small bowel involvement, and predominately CD3+ CD4+ infiltrates. Common therapies included steroids or immuno-suppressive agents and clinical response with associated with histologic improvement. Conclusions AIE is most often characterized (1) IgG subclass anti-epithelial cell antibodies, (2) preferential small bowel involvement, and (3) CD3+ alphabeta TCR+ infiltrates; there is insufficient evidence to conclude CD4+ T-cells are solely responsible in all cases of AIE

Serum amyloid A and inflammasome activation : a link to breast cancer progression?

CITATION: Fourie, C. et al. 2021.Serum amyloid A and inflammasome activation: A link to breast cancer progression? Cytokine & Growth Factor Reviews, 59:62-70. doi:10.1016/j.cytogfr.2020.10.006The original publication is available at https://www.sciencedirect.com/journal/cytokine-and-growth-factor-reviewsBreast cancer is the most frequently diagnosed cancer in women globally. Although there have been many significant advances made in the diagnosis and treatment of breast cancer, numerous unresolved challenges remain, which include prevention, early diagnosis, metastasis and recurrence. The role of inflammation in cancer development is well established and is believed to be one of the leading hallmarks of cancer progression. Recently, the role of the inflammasome, a cytosolic multiprotein complex, has received attention in different cancers. By contributing to the activation of inflammatory cytokines the inflammasome intensifies the inflammatory cascade. The inflammasome can be activated through several pathways, which include the binding of pattern associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) to toll-like receptors (TLRs). Serum amyloid A (SAA), a non-specific acute-phase protein, can function as an endogenous DAMP by binding to pattern recognition receptors like TLRs on both breast cancer cells and cancer associated fibroblasts (CAFs). SAA can thus stimulate the production of IL-1β, thereby creating a favourable inflammatory environment to support tumour growth. The aim of this review is to highlight the possible role of SAA as an endogenous DAMP in the tumour microenvironment (TME) thereby promoting breast cancer growth through the activation of the NLRP3 inflammasome.https://www.sciencedirect.com/science/article/pii/S1359610120302203?via%3DihubPublishers versio

Serum Amyloid A Binds to Gibrin(ogen), Promoting Fibrin Amyloid Formation

Complex associations exist between inflammation and thrombosis, with the inflammatory state tending to promote coagulation. Fibrinogen, an acute phase protein, has been shown to interact with the amyloidogenic ß-amyloid protein of Alzheimer’s disease. However, little is known about the association between fibrinogen and serum amyloid A (SAA), a highly fibrillogenic protein that is one of the most dramatically changing acute phase reactants in the circulation. To study the role of SAA in coagulation and thrombosis, in vitro experiments were performed where purified human SAA, in concentrations resembling a modest acute phase response, was added to platelet-poor plasma (PPP) and whole blood (WB), as well as purified and fluorescently labelled fibrinogen. Results from thromboelastography (TEG) suggest that SAA causes atypical coagulation with a fibrin(ogen)-mediated increase in coagulation, but a decreased platelet/fibrin(ogen) interaction. In WB scanning electron microscopy analysis, SAA mediated red blood cell (RBC) agglutination, platelet activation and clumping, but not platelet spreading. Following clot formation in PPP, the presence of SAA increased amyloid formation of fibrin(ogen) as determined both with auto-fluorescence and with fluorogenic amyloid markers, under confocal microcopy. SAA also binds to fibrinogen, as determined with a fluorescent-labelled SAA antibody and correlative light electron microscopy (CLEM). The data presented here indicate that SAA can affect coagulation by inducing amyloid formation in fibrin(ogen), as well as by propelling platelets to a more prothrombotic state. The discovery of these multiple and complex effects of SAA on coagulation invite further mechanistic analyses

Theology at the University of Pretoria - 100 years: (1917-2017) Past, present and future

In this scholarly book, a century’s theology presented by the Faculty of Theology at the University of Pretoria, is celebrated. All authors are academics or research associates of the University of Pretoria. A historical and futuristic overview with perspectives from the past, present and future, are examined. The past is not only portrayed by means of societal and scientific contributions and achievements, but the authors also reflect on malfunctions, ill behaviour and disappointments of church and theology, presented at the University of Pretoria within the South African context over 100 years. The book commences with a chapter in which institutional transformation is discussed, as well as the changes that demonstrate the role of the Faculty of Theology within a secular state university. It includes an explanation of the importance of research impact, research productivity and research reputation. Among various discipline indicators, the category Theology and Religion Studies plays a significant role in the measurement of world university rankings of universities. With regard to scientific and encyclopaedic content, the book focuses on the theological disciplines presented in the academic curricula: first the biblical sciences (Old and New Testament Studies), then the historical disciplines (Systematic Theology, Church History and Church Polity), and finally the practical disciplines (Practical Theology, Science of Religion and Missiology). The role of Religion Studies in a newly established Faculty of Theology and Religion not only enhances the diversity of interreligious tolerance and an atmosphere of dialogue, but it serves as platform to interconnect with the fields of Humanities, Social and Natural Sciences and other academic disciplines. In the conclusive part of the book, contributions highlight the role of the centres in the Faculty (Centre for Contextual Ministry and Centre for Sustainable Communities), as well as the continental and international footprints of the two theological journals whose title ownership is attached to the Faculty of Theology of the University of Pretoria, namely HTS Theological Studies and Verbum et Ecclesia. The methodology comprised in all the chapters amounts to a literature and contextual study. Since the book describes the histories of formal academic departments, these texts are of a descriptive, interpretative and critical character. Reference is made in some chapters to exegetical methods, like the historical critical methods. The target audience of the book is academic scholars and theologians, who specialise in the different fields of Theology, the Humanities and other Social Sciences. The book is also accessible to scholars of other academic disciplines outside these disciplines. The book comprises original research by several authors and is not plagiarised from other scientific publications of this nature

Intestinal Epithelial Serum Amyloid A Modulates Bacterial Growth In Vitro and Pro-Inflammatory Responses in Mouse Experimental Colitis

<p>Abstract</p> <p>Background</p> <p>Serum Amyloid A (SAA) is a major acute phase protein of unknown function. SAA is mostly expressed in the liver, but also in other tissues including the intestinal epithelium. SAA reportedly has anti-bacterial effects, and because inflammatory bowel diseases (IBD) result from a breakdown in homeostatic interactions between intestinal epithelia and bacteria, we hypothesized that SAA is protective during experimental colitis.</p> <p>Methods</p> <p>Intestinal SAA expression was measured in mouse and human samples. Dextran sodium sulfate (DSS) colitis was induced in SAA 1/2 double knockout (DKO) mice and in wildtype controls. Anti-bacterial effects of SAA1/2 were tested in intestinal epithelial cell lines transduced with adenoviral vectors encoding the CE/J SAA isoform or control vectors prior to exposure to live <it>Escherichia coli</it>.</p> <p>Results</p> <p>Significant levels of SAA1/SAA2 RNA and SAA protein were detected by in situ hybridization and immunohistochemistry in mouse colonic epithelium. SAA3 expression was weaker, but similarly distributed. SAA1/2 RNA was present in the ileum and colon of conventional mice and in the colon of germfree mice. Expression of SAA3 was strongly regulated by bacterial lipopolysaccharides in cultured epithelial cell lines, whereas SAA1/2 expression was constitutive and not LPS inducible. Overexpression of SAA1/2 in cultured epithelial cell lines reduced the viability of co-cultured <it>E. coli</it>. This might partially explain the observed increase in susceptibility of DKO mice to DSS colitis. SAA1/2 expression was increased in colon samples obtained from Crohn's Disease patients compared to controls.</p> <p>Conclusions</p> <p>Intestinal epithelial SAA displays bactericidal properties in vitro and could play a protective role in experimental mouse colitis. Altered expression of SAA in intestinal biopsies from Crohn's Disease patients suggests that SAA is involved in the disease process..</p