scholarly journals New Insights into the Pathogenesis of IgA Nephropathy

2015 ◽  
Vol 1 (1) ◽  
pp. 8-18 ◽  
Author(s):  
Jan Novak ◽  
Dana Rizk ◽  
Kazuo Takahashi ◽  
XianWen Zhang ◽  
Qi Bian ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Iga Nephropathy ◽  
Immune Complexes ◽  
Molecular Mechanisms ◽  
Disease Risk ◽  
Disease Process ◽  
Contributing Factors ◽  
Specific Therapy ◽  
Risk Alleles ◽  
Disease Specific

Background: IgA nephropathy, a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli and induce renal injury. Multiple genetic loci associated with disease risk have been identified. The prevalence of risk alleles varies geographically: it is the highest in eastern Asia and northern Europe, lower in other parts of Europe and North America, and the lowest in Africa. IgA nephropathy is diagnosed by the pathological assessment of a renal biopsy specimen. Currently, therapy is not disease targeted but rather focused on maintaining control of blood pressure and proteinuria, ideally with suppression of angiotensin II. Possible additional approaches differ between countries. Disease-specific therapy as well as new tools for the diagnosis, prognosis, and assessment of responses to therapy are needed. Summary: Glycosylation pathways associated with aberrant O-glycosylation of IgA1 and, thus, production of autoantigen, have been identified. Furthermore, unique characteristics of the autoantibodies in IgA nephropathy have been uncovered. Many of these biochemical features are shared by patients with IgA nephropathy and Henoch-Schönlein purpura nephritis, suggesting that the two diseases may represent opposite ends of a spectrum of a disease process. Understanding the molecular mechanisms involved in the formation of pathogenic IgA1-containing immune complexes will enable the development of disease-specific therapies as well as diagnostic and prognostic biomarkers. Key Messages: IgA nephropathy is an autoimmune disease caused by the glomerular deposition of nephritogenic circulating immune complexes consisting of galactose-deficient IgA1 (autoantigen) bound by anti-glycan autoantibodies. A better understanding of the multi-step process of the pathogenesis of IgA nephropathy and the genetic and environmental contributing factors will lead to the development of biomarkers to identify patients with progressive disease who would benefit from a future disease-specific therapy.

scholarly journals CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Gabriel E. Hoffman ◽  
Jaroslav Bendl ◽  
Georgios Voloudakis ◽  
Kelsey S. Montgomery ◽  
Laura Sloofman ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Disease Risk ◽  
Genomic Data ◽  
Mental Illnesses ◽  
Rna Seq ◽  
Risk Alleles ◽  
Public Resource ◽  
Dorsolateral Prefrontal

Abstract Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org.

scholarly journals Cellular Signaling and Production of Galactose-Deficient IgA1 in IgA Nephropathy, an Autoimmune Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Colin Reily ◽  
Hiroyuki Ueda ◽  
Zhi-Qiang Huang ◽  
Jiri Mestecky ◽  
Bruce A. Julian ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Immune Complexes ◽  
Association Studies ◽  
Immunoglobulin A ◽  
Specific Treatment ◽  
Genome Wide Association Studies ◽  
Glomerular Injury ◽  
Stage Renal Disease ◽  
End Stage ◽  
Disease Specific

Immunoglobulin A (IgA) nephropathy (IgAN), the leading cause of primary glomerulonephritis, is characterized by IgA1-containing immunodeposits in the glomeruli. IgAN is a chronic disease, with up to 40% of patients progressing to end-stage renal disease, with no disease-specific treatment. Multiple studies of the origin of the glomerular immunodeposits have linked elevated circulating levels of aberrantly glycosylated IgA1 (galactose-deficient in someO-glycans; Gd-IgA1) with formation of nephritogenic Gd-IgA1-containing immune complexes. Gd-IgA1 is recognized as an autoantigen in susceptible individuals by anti-glycan autoantibodies, resulting in immune complexes that may ultimately deposit in the kidney and induce glomerular injury. Genetic studies have revealed that an elevated level of Gd-IgA1 in the circulation of IgAN patients is a hereditable trait. Moreover, recent genome-wide association studies have identified several immunity-related loci that associated with IgAN. Production of Gd-IgA1 by IgA1-secreting cells of IgAN patients has been attributed to abnormal expression and activity of several key glycosyltransferases. Substantial evidence is emerging that abnormal signaling in IgA1-producing cells is related to the production of Gd-IgA1. As Gd-IgA1 is the key autoantigen in IgAN, understanding the genetic, biochemical, and environmental aspects of the abnormal signaling in IgA1-producing cells will provide insight into possible targets for future disease-specific therapy.

Gene–environment interaction in autoimmune disease

2014 ◽  
Vol 16 ◽  
Author(s):  
Justine A Ellis ◽  
Andrew S Kemp ◽  
Anne-Louise Ponsonby
Keyword(s):  
Autoimmune Disease ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Disease Risk ◽  
Personalised Medicine ◽  
Current Evidence ◽  
Environment Interaction ◽  
Gene Environment ◽  
Genes And Environment ◽  
Genetic And Environmental Factors

Autoimmune disease manifests in numerous forms, but as a disease group is relatively common in the population. It is complex in aetiology, with genetic and environmental determinants. The involvement of gene variants in autoimmune disease is well established, and evidence for significant involvement of the environment in various disease forms is growing. These factors may act independently, or they may interact, with the effect of one factor influenced by the presence of another. Identifying combinations of genetic and environmental factors that interact in autoimmune disease has the capacity to more fully explain disease risk profile, and to uncover underlying molecular mechanisms contributing to disease pathogenesis. In turn, such knowledge is likely to contribute significantly to the development of personalised medicine, and targeted preventative approaches. In this review, we consider the current evidence for gene–environment (G–E) interaction in autoimmune disease. Large-scale G–E interaction research efforts, while well-justified, face significant practical and methodological challenges. However, it is clear from the evidence that has already been generated that knowledge on how genes and environment interact at a biological level will be crucial in fully understanding the processes that manifest as autoimmunity.

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

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.

The role of probiotics and natural bioactive compounds in modulation of the common molecular pathways in pathogenesis of atherosclerosis and cancer

Biologia ◽  
2012 ◽  
Vol 67 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Alojz Bomba ◽  
Andrea Brandeburová ◽  
Júlia Ričanyová ◽  
Ladislav Strojný ◽  
Anna Chmelárová ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Unsaturated Fatty Acids ◽  
Disease Risk ◽  
Disease Process ◽  
Experimental Models ◽  
Future Research ◽  
Molecular Pathways ◽  
Bioactive Substances

AbstractAtherosclerosis and cancer are ranked among the most serious health problems in human medicine. Various predictive and etiological factors, biomarkers and molecular pathways of disease development and progression common to atherosclerosis and cancer suggest that the two most common diseases in worldwide dimension are far more closely aligned than previously believed. It is hypothesized that atherosclerosis and cancer are variants of a similar disease process. Shared disease progression in atherosclerosis and cancer is the emergence of similar novel approaches to therapy. On previous knowledge, it may be hypothesized that not only common approaches to therapy but also preventive strategies could be efficacious in both diseases. The results of in vitro and in vivo animal experiments, clinical and epidemiological studies and also the results of our experiments using animal experimental models of atherosclerosis and carcinogenesis indicate that probiotics, prebiotics, plants and their extracts and poly-unsaturated fatty acids could be effectively used in prevention of both atherosclerosis and colorectal cancer and decrease the disease risk. Future research should answer the question whether probiotic microorganisms and natural bioactive substances could effectively influence the molecular mechanisms in pathogenesis of atherosclerosis and cancer.

Resolving Molecular Mechanisms of Autoimmune Disease In Primary CD4 T Cells

2019 ◽  
Author(s):  
Christophe Bourges ◽  
Abigail F. Groff ◽  
Oliver S. Burren ◽  
Chiara Gerhardinger ◽  
Kaia Mattioli ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Cd4 T Cells ◽  
Molecular Mechanisms

scholarly journals Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus

2021 ◽  
Vol 11 (8) ◽  
pp. 973
Author(s):  
Maria Cristina Petralia ◽  
Rosella Ciurleo ◽  
Alessia Bramanti ◽  
Placido Bramanti ◽  
Andrea Saraceno ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Clinical Manifestations ◽  
Antipsychotic Agents ◽  
Standards Of Care ◽  
Specific Gene ◽  
Contributing Factors ◽  
Healthy Donors ◽  
Dorsolateral Prefrontal ◽  
Inflammatory Processes ◽  
Disease Specific

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of β-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation. In the current study, we evaluated the expression levels of the galectin gene family in post-mortem samples of the hippocampus, associative striatum, and dorsolateral prefrontal cortex from SCZ patients. We found a significant downregulation of LGALS8 (Galectin-8) in the hippocampus of SCZ patients as compared to otherwise healthy donors. Interestingly, the reduction of LGALS8 was disease-specific, as no modulation was observed in the hippocampus from bipolar nor major depressive disorder (MDD) patients. Prediction analysis identified TBL1XR1, BRF2, and TAF7 as potential transcription factors controlling LGALS8 expression. In addition, MIR3681HG and MIR4296 were negatively correlated with LGALS8 expression, suggesting a role for epigenetics in the regulation of LGALS8 levels. On the other hand, no differences in the methylation levels of LGALS8 were observed between SCZ and matched control hippocampus. Finally, ontology analysis of the genes negatively correlated with LGALS8 expression identified an enrichment of the NGF-stimulated transcription pathway and of the oligodendrocyte differentiation pathway. Our study identified LGALS8 as a disease-specific gene, characterizing SCZ patients, that may in the future be exploited as a potential therapeutic target.

scholarly journals The Physiological Roles of Vitamin E and Hypovitaminosis E in the Transition Period of High-Yielding Dairy Cows

Animals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1088
Author(s):  
Satoshi Haga ◽  
Hiroshi Ishizaki ◽  
Sanggun Roh
Keyword(s):  
Dairy Cows ◽  
High Performance ◽  
Molecular Mechanisms ◽  
Transition Period ◽  
Disease Risk ◽  
Serum Vitamin ◽  
Physiological Role ◽  
Density Lipoprotein ◽  
Alpha Tocopherol ◽  
Transition Dairy Cows

Levels of alpha-tocopherol (α-Toc) decline gradually in blood throughout prepartum, reaching lowest levels (hypovitaminosis E) around calving. Despite numerous reports about the disease risk in hypovitaminosis E and the effect of α-Toc supplementation on the health of transition dairy cows, its risk and supplemental effects are controversial. Here, we present some novel data about the disease risk of hypovitaminosis E and the effects of α-Toc supplementation in transition dairy cows. These data strongly demonstrate that hypovitaminosis E is a risk factor for the occurrence of peripartum disease. Furthermore, a study on the effectiveness of using serum vitamin levels as biomarkers to predict disease in dairy cows was reported, and a rapid field test for measuring vitamin levels was developed. By contrast, evidence for how hypovitaminosis E occurred during the transition period was scarce until the 2010s. Pioneering studies conducted with humans and rodents have identified and characterised some α-Toc-related proteins, molecular players involved in α-Toc regulation followed by a study in ruminants from the 2010s. Based on recent literature, the six physiological factors: (1) the decline in α-Toc intake from the close-up period; (2) changes in the digestive and absorptive functions of α-Toc; (3) the decline in plasma high-density lipoprotein as an α-Toc carrier; (4) increasing oxidative stress and consumption of α-Toc; (5) decreasing hepatic α-Toc transfer to circulation; and (6) increasing mammary α-Toc transfer from blood to colostrum, may be involved in α-Toc deficiency during the transition period. However, the mechanisms and pathways are poorly understood, and further studies are needed to understand the physiological role of α-Toc-related molecules in cattle. Understanding the molecular mechanisms underlying hypovitaminosis E will contribute to the prevention of peripartum disease and high performance in dairy cows.

scholarly journals Degenerative Cervical Myelopathy: Insights into Its Pathobiology and Molecular Mechanisms

2021 ◽  
Vol 10 (6) ◽  
pp. 1214
Author(s):  
Ji Tu ◽  
Jose Vargas Castillo ◽  
Abhirup Das ◽  
Ashish D. Diwan
Keyword(s):  
Cervical Myelopathy ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Disease Process ◽  
Classification Systems ◽  
Molecular Features ◽  
Formidable Challenge ◽  
Long Term Treatment ◽  
Degenerative Cervical Myelopathy

Degenerative cervical myelopathy (DCM), earlier referred to as cervical spondylotic myelopathy (CSM), is the most common and serious neurological disorder in the elderly population caused by chronic progressive compression or irritation of the spinal cord in the neck. The clinical features of DCM include localised neck pain and functional impairment of motor function in the arms, fingers and hands. If left untreated, this can lead to significant and permanent nerve damage including paralysis and death. Despite recent advancements in understanding the DCM pathology, prognosis remains poor and little is known about the molecular mechanisms underlying its pathogenesis. Moreover, there is scant evidence for the best treatment suitable for DCM patients. Decompressive surgery remains the most effective long-term treatment for this pathology, although the decision of when to perform such a procedure remains challenging. Given the fact that the aged population in the world is continuously increasing, DCM is posing a formidable challenge that needs urgent attention. Here, in this comprehensive review, we discuss the current knowledge of DCM pathology, including epidemiology, diagnosis, natural history, pathophysiology, risk factors, molecular features and treatment options. In addition to describing different scoring and classification systems used by clinicians in diagnosing DCM, we also highlight how advanced imaging techniques are being used to study the disease process. Last but not the least, we discuss several molecular underpinnings of DCM aetiology, including the cells involved and the pathways and molecules that are hallmarks of this disease.

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