Omics & Immunoglobulin A Nephropathy

Over the past decade, advances in omics technology have provided new insights into the pathogenesis of various diseases. Genomics, epigenomics, transcriptomics, and proteomics have contributed to a better understanding of the causes and diversity of numerous diseases. Now, in a new study, researchers describe recent findings on the pathophysiology of immunoglobulin A nephropathy (IgAN), and they link omics studies to immune system dysregulation.

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, which leads to end-stage renal disease in up to 50% of cases. Primary glomerulonephritis refers to a group of kidney diseases that affect the glomeruli, which are tiny structures in the kidney responsible for filtering waste and excess fluid from the blood. These diseases are considered "primary" because they are not caused by another underlying condition such as diabetes or lupus. Although scientists first described IgAN more than half a century ago, a comprehensive understanding of its pathogenesis remains unknown.

In the study, the researchers talk about the pathophysiology of Immunoglubin A nephropathy and they explain the multi-hit pathogenesis model that describes IgAN as a systemic disease that consists of four steps. They also talks about the importance of omics technologies such as genomics, epigenomics, transcriptomics, and proteomics in providing insights into the disease's pathogenesis and the identification of potential targets for personalised treatment in the future. Although there is not yet a molecular diagnostic or prognostic biomarker derived and widely used from omics studies in IgAN, omics studies have helped to link the immune response in IgAN and provide data on the pathogenesis of IgAN – and with omics studies, we can continue to improve our understanding of IgAN.

IgA nephropathy (IgAN) is a polygenetic disease with a high locus heterogeneity, and recent studies suggest the involvement of immunological dysregulation in its pathogenesis. Several susceptibility loci for IgAN have been identified in case-control genome-wide association studies, including genes involved in immune processes, complement activation, mucosal IgA production, innate immunity against pathogens, and maintenance of the intestinal barrier integrity. Dysfunction of the immune system at multiple levels is needed for disease progression, and asymptomatic family members of IgAN patients have increased serum levels of IgA and IgA-IgG immunocomplexes. Epigenomics refers to the study of reversible changes in DNA structure or histones and structural proteins that affect DNA availability and consequently gene expression but do not alter the DNA sequence. One epigenomic study showed that the molecular chaperone of core1β1, 3galactosyl transferase (Cosmc), which has reduced expression in IgAN, can be regulated by methylation of one of the promotor regions and affect the level of Gd-IgA1.

Transcriptomics is a study of gene expression and its impact on defining the phenotype. It is a dynamic approach that shows the disease's progression compared to genomics. Transcriptomics can be used to study pathological changes in kidney biopsies, and it has potential as a biomarker for IgA nephropathy (IgAN). Single-cell RNA sequencing (sc-RNA-seq) is a promising technique used for studying IgAN pathogenesis. Sc-RNA-seq studies have discovered novel immune mechanisms involved in IgAN's onset and progression, such as complex gene expression alterations leading to IgAN symptoms, upregulated genes, inflammation-related genes, and WAP four-disulfide core domain 2. The sc-RNA-seq studies also suggest the potential for cross-talk between podocytes and macrophages, interactions between mesangial cells and other cells in IgAN, and high expression of Lymphotoxin Beta genes in kidney biopsies of IgAN and lupus nephritis patients. Although sc-RNA-seq provides new insights into IgAN's molecular background, the available studies are based on small-sample sizes.

Nanotechnology and gene editing are two promising therapeutic approaches for kidney disorders like IgA nephropathy (IgAN). Nanoparticles (NPs) can deliver drugs more effectively and specifically, reducing toxicity and systemic effects. CRISPR/Cas9, on the other hand, can assess the function of omic findings and could potentially be used as a treatment method. IgAN is characterized by four “hits” or steps leading to the disease, with the final step resulting in kidney damage. Hit 1 involves dysregulation of mucosal immunity and increased production of circulatory glycosylated IgA1 (Gd-IgA1) in response to antigens. Hit 2 involves the recognition of Gd-IgA1 by the adaptive immune system, leading to hit 3—immune complex (IC) formation. Finally, ICs are deposited in the kidneys (hit 4), leading to a local inflammatory process, mesangial cell activation, glomerulosclerosis, fibrosis, and renal injury.

In general, as we have already addressed, omics findings have revealed immune system dysregulation, including the role of the mucosal immune response and innate immunity in the pathogenesis of IgAN. Dysregulation of gut-associated lymphoid tissue (GALT) and mucosa-associated lymphoid tissue (MALT) is thought to lead to defective responses to microbiota and alimentary antigens, resulting in Gd-IgA1 production. Toll-like receptors (TLRs) play a crucial role in innate immunity, and their impaired function has been associated with IgAN. However, the findings about TLR involvement have not been confirmed by GWAS studies.