Aberrantly Glycosylated IgA1 in IgA Nephropathy: What We Know and What We Don’t Know

IgA nephropathy (IgAN), the most common primary glomerular disease worldwide, is characterized by glomerular deposition of IgA1-containing immune complexes. The IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine usually with β1,3-linked galactose and variable sialylation. Circulating levels of IgA1 with abnormally O-glycosylated HR, termed galactose-deficient IgA1 (Gd-IgA1), are increased in patients with IgAN. Current evidence suggests that IgAN is induced by multiple sequential pathogenic steps, and production of aberrantly glycosylated IgA1 is considered the initial step. Thus, the mechanisms of biosynthesis of aberrantly glycosylated IgA1 and the involvement of aberrant glycoforms of IgA1 in disease development have been studied. Furthermore, Gd-IgA1 represents an attractive biomarker for IgAN, and its clinical significance is still being evaluated. To elucidate the pathogenesis of IgAN, it is important to deconvolute the biosynthetic origins of Gd-IgA1 and characterize the pathogenic IgA1 HR O-glycoform(s), including the glycan structures and their sites of attachment. These efforts will likely lead to development of new biomarkers. Here, we review the IgA1 HR O-glycosylation in general and the role of aberrantly glycosylated IgA1 in the pathogenesis of IgAN in particular.

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The Role of IgA and IgG Immune Complexes in IgA Nephropathy

Nephron ◽

10.1159/000183115 ◽

1984 ◽

Vol 36 (1) ◽

pp. 52-59 ◽

Cited By ~ 32

Author(s):

J. Egido ◽

J. Sancho ◽

F. Rivera ◽

L. Hernando

Keyword(s):

Iga Nephropathy ◽

Immune Complexes

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Clinical Significance and Biological Role of HuR in Head and Neck Carcinomas

Disease Markers ◽

10.1155/2018/4020937 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Georgia Levidou ◽

Ioly Kotta-Loizou ◽

Jason Tasoulas ◽

Thomas Papadopoulos ◽

Stamatios Theocharis

Keyword(s):

Head And Neck ◽

Clinical Significance ◽

Biological Role ◽

Current Evidence ◽

Biological Processes ◽

Head And Neck Carcinomas ◽

Present Information ◽

And Function ◽

Hu Antigen R

Background. Hu-antigen R (HuR) is a posttranscriptional regulator of several target mRNAs, implicated in carcinogenesis. This review aims to present the current evidence regarding the biological role and potential clinical significance of HuR in head and neck carcinomas. Methods. The existing literature concerning HuR expression and function in head and neck carcinomas is critically presented and summarised. Results. HuR is expressed in the majority of the examined samples, showing higher cytoplasmic levels in malignant or premalignant cases. Moreover, HuR modulates several genes implicated in biological processes important for malignant transformation, growth, and invasiveness. HuR seems to be an adverse prognosticator in patients with OSCCs, whereas a correlation with a more aggressive phenotype is reported in several types of carcinomas. Conclusions. A consistent role of HuR in the carcinogenesis and progression of head and neck carcinomas is suggested; nevertheless, further studies are warranted to expand the present information.

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From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms22136740 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6740

Author(s):

Silvia Vidal ◽

Lluís Puig ◽

José-Manuel Carrascosa-Carrillo ◽

Álvaro González-Cantero ◽

José-Carlos Ruiz-Carrascosa ◽

...

Keyword(s):

Immune Cells ◽

Crucial Role ◽

Th17 Cells ◽

Current Evidence ◽

Disease Development ◽

Receptor Complex ◽

Adaptive Immune ◽

Adaptive Immune Cells

The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural—containing a SEFIR/TILL domain—and functional—requiring ACT-1 for signaling—properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments.

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P0344NEFECON® (BUDESONIDE) SELECTIVELY REDUCES CIRCULATING LEVELS OF BAFF (BLYS) AND SOLUBLE BCMA AND TACI IN IGA NEPHROPATHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0344 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Karen Molyneux ◽

David Wimbury ◽

Jonathan Barratt

Keyword(s):

B Cell ◽

Iga Nephropathy ◽

Immune Complexes ◽

Distal Ileum ◽

Cell Maturation ◽

Specific Cell ◽

B Cell Maturation ◽

Luminex Technology ◽

Dose Dependent ◽

Circulating Levels

Abstract Background and Aims There is increasing evidence to support a pivotal role for the gut-associated lymphoid tissue (GALT) as a major source of the poorly O-galactosylated immunoglobulin A1 (IgA1) that triggers the formation of nephritogenic immune complexes in IgA nephropathy (IgAN). Critical to the regulation of IgA synthesis in GALT are two cytokines, which regulate B-cell maturation, function and survival: BAFF (B-cell activating factor [also known as BLyS (B-lymphocyte stimulator)]) and APRIL (A PRoliferation-inducing ligand). BAFF and APRIL bind to specific cell-surface receptors: TACI (transmembrane activator and calcium modulator and cyclophilin-ligand interactor), BCMA (B-cell maturation antigen) and the BAFF receptor. Several studies have shown elevated levels of BAFF and APRIL in IgAN linked to worse clinical outcomes. The therapeutic potential of selectively targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON®), designed to deliver budesonide to the GALT-rich distal ileum in patients with IgAN. The trial comprised a 6-month run-in, 9-month treatment and 3-month follow-up phase: 48 patients received NEFECON® 16 mg/day, 51 patients received NEFECON® 8 mg/day and 50 patients received placebo. The headline result of the study was that NEFECON® 16 mg/day, added to optimised renin–angiotensin system blockade, reduced proteinuria and stabilised estimated glomerular filtration rate in patients with IgAN. In this study, we aimed to determine whether NEFECON® treatment altered synthesis of the BAFF and APRIL B-cell maturation modulators. Method Serum levels of BAFF, APRIL, BCMA and TACI were measured using Luminex technology. Changes in the levels of each biomarker between randomisation (T0), end of treatment (T1) and the end of study (T2) and between treatments arms were compared using a one-way analysis of variance. Significance was set at p<0.05. Results A significant, dose-dependent reduction in serum BAFF levels was seen with NEFECON®, which reversed on cessation of NEFECON®. There were similar significant reductions in the levels of soluble BCMA and TACI with treatment but no effect was seen on circulating levels of APRIL. These changes were mirrored by parallel changes in soluble CD27 levels and are consistent with our previous reports describing a dose-dependent reduction in circulating IgA–IgG immune complexes, secretory IgA and galactose-deficient IgA levels with NEFECON®. Conclusion Delivering budesonide to the GALT-rich distal ileum modulates key regulators of GALT B-cell maturation in IgAN. Although the samples available are not sufficient to determine that the observed changes in serum BAFF, BCMA and TACI levels are due to a direct action on GALT, it is intriguing to note that BAFF-transgenic mice develop an IgAN-like disease, principally due to IgA overexpression in the intestinal lamina propria.

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Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment

Journal of Clinical Medicine ◽

10.3390/jcm10194501 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4501

Author(s):

Barbora Knoppova ◽

Colin Reily ◽

R. Glenn King ◽

Bruce A. Julian ◽

Jan Novak ◽

...

Keyword(s):

Iga Nephropathy ◽

Immune Complexes ◽

Mesangial Cells ◽

Specific Treatment ◽

Kidney Injury ◽

Pathogenic Potential ◽

Clinical Observations ◽

Circulating Levels ◽

Disease Specific

IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.

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Using serum biomarkers for identifying unstable carotid plaque: update of current evidence

Current Pharmaceutical Design ◽

10.2174/1381612826666201112094734 ◽

2020 ◽

Vol 26 ◽

Author(s):

Areti Sofogianni ◽

Konstantinos Tziomalos ◽

Triantafyllia Koletsa ◽

Apostolos G. Pitoulias ◽

Lemonia Skoura ◽

...

Keyword(s):

High Risk ◽

Great Proportion ◽

Current Literature ◽

Early Identification ◽

Carotid Plaque ◽

Potential Role ◽

Carotid Atherosclerosis ◽

Serum Biomarkers ◽

Current Evidence

: Carotid atherosclerosis is responsible for a great proportion of ischemic strokes. Early identification of unstable or vulnerable carotid plaques and therefore of patients at high risk for stroke is of significant medical and socioeconomical value. We reviewed the current literature and discuss the potential role of the most important serum biomarkers in identifying patients with carotid atherosclerosis who are at high risk for atheroembolic stroke.

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Patent Foramen Ovale, the Role of Antiplatelet Therapy Alone or Anticoagulant Therapy Alone Versus Device Closure for Cryptogenic Stroke: A Review of the Literature and Current Recommendations

Cardiovascular & Hematological Agents in Medicinal Chemistry ◽

10.2174/1871525718666200203111641 ◽

2020 ◽

Vol 18 (2) ◽

pp. 135-150

Author(s):

Harsha S. Nagarajarao ◽

Chandra P. Ojha ◽

Archana Kedar ◽

Debabrata Mukherjee

Keyword(s):

Patent Foramen Ovale ◽

Cryptogenic Stroke ◽

Narrow Channel ◽

Paradoxical Embolism ◽

Current Evidence ◽

Foramen Ovale ◽

The Right ◽

The Relationship ◽

Current Guidelines

: Cryptogenic stroke and its relation to the Patent Foramen Ovale (PFO) is a long-debated topic. Recent clinical trials have unequivocally established the relationship between cryptogenic strokes and paradoxical embolism across the PFO. This slit-like communication exists in everyone before birth, but most often closes shortly after birth. PFO may persist as a narrow channel of communication between the right and left atria in approximately 25-27% of adults. : In this review, we examine the clinical relevance of the PFO with analysis of the latest trials evaluating catheter-based closure of PFO’s for cryptogenic stroke. We also review the current evidence examining the use of antiplatelet medications versus anticoagulants for stroke prevention in those patients with PFO who do not qualify for closure per current guidelines.

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The application of virtual reality in health professions� digital education: a narrative review (Preprint)

10.2196/preprints.12220 ◽

2018 ◽

Author(s):

Lorraine Tudor Car ◽

Bhone Myint Kyaw ◽

Josip Car

Keyword(s):

Virtual Reality ◽

Professional Education ◽

Health Professions ◽

Health Professions Education ◽

Narrative Review ◽

Current Evidence ◽

Future Research ◽

Educational Content ◽

Potential Applications

BACKGROUND Digital technology called Virtual Reality (VR) is increasingly employed in health professions’ education. Yet, based on the current evidence, its use is narrowed around a few most applications and disciplines. There is a lack of an overview that would capture the diversity of different VR applications in health professions’ education and inform its use and research. OBJECTIVE This narrative review aims to explore different potential applications of VR in health professions’ education. METHODS The narrative synthesis approach to literature review was used to analyse the existing evidence. RESULTS We outline the role of VR features such as immersion, interactivity and feedback and explain the role of VR devices. Based on the type and scope of educational content VR can represent space, individuals, objects, structures or their combination. Application of VR in medical education encompasses environmental, organ and micro level. Environmental VR focuses on training in relation to health professionals’ environment and human interactions. Organ VR educational content targets primarily human body anatomy; and micro VR microscopic structures at the level of cells, molecules and atoms. We examine how different VR features and health professional education areas match these three VR types. CONCLUSIONS We conclude by highlighting the gaps in the literature and providing suggestions for future research.

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Institutions and the Embedded Entrepreneur

The Oxford Handbook of Entrepreneurship and Collaboration ◽

10.1093/oxfordhb/9780190633899.013.6 ◽

2019 ◽

pp. 115-134

Author(s):

Maryann Feldman ◽

Paige Clayton

Keyword(s):

Current Evidence ◽

Future Research ◽

Institutional Logic ◽

The Relationship ◽

Regional Resources

This chapter examines the relationship between entrepreneurs and the communities in which they are embedded. It argues that the actions of entrepreneurs and their firms are contextually situated in specific geographies that make their actions endogenous in the development of place and define a place-specific institutional logic. This argument is at odds with the view that industry clustering is due to the role of incumbent firms. This chapter reconciles these views by adopting a temporal view, allowing both incumbents and geography to co-occur and influence clustering. It then considers the current evidence of entrepreneurs’ effects on regional resources and capacity, and concludes with suggestions for future research.

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