Omics are Getting Us Closer to Understanding IgA Nephropathy

Abstract

During the last decade, thanks to omics technologies, new light has been shed on the pathogenesis of many diseases. Genomics, epigenomics, transcriptomics, and proteomics have helped to provide a better understanding of the origin and heterogeneity of several diseases. However, the risk factors for most autoimmune diseases remain unknown. The successes and pitfalls of omics have also been observed in nephrology, including immunoglobulin A nephropathy (IgAN), the most common form of glomerulonephritis and a principal cause of end-stage renal disease worldwide. Unfortunately, the immense progress in basic research has not yet been followed by the satisfactory development of a targeted treatment. Although, most omics studies describe changes in the immune system, there is still insufficient data to apply their results in the constantly evolving multi-hit pathogenesis model and thus do to provide a complete picture of the disease. Here, we describe recent findings regarding the pathophysiology of IgAN and link omics studies with immune system dysregulation. This review provides insights into specific IgAN markers, which may lead to the identification of potential targets for personalised treatment in the future.

Keywords: Epigenomics; Genomics; IgA nephropathy; Immune system; Proteomics; Transcriptomics.

Fig. 1

Omics and mucosal immunity dysregulation in IgA nephropathy (hit 1). Dysregulation of mucosal immunity proceeds at various sites and involves both innate and adaptive mechanisms. A The aberrant response at MALT in the intestine and upper respiratory tract is triggered by bacterial, viral, and alimentary antigens. Risk variants of IgAN: DEFA1, DEFA3, DEFA5, DEFA6, ACCS are probably associated with lack of integrity of the mucosal membrane, promoting an excessive immune response. Overexpression of TLR4 and TLR9 enhances the recognition of pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP), respectively, triggering a first-line innate immune response to the antigens. The innate response and inflammation are provoked and mediated via two pathways hyperactivated in IgAN: WNT-β-catenin and PI3K/Akt. Additionally, several IgAN risk variants: ITGAM-ITGAX, LIF, OSM, HORMAD2 and MTMR3 are thought to play a role in inflammation and involvement of both innate and adaptive immunity. B HLA-DP, HLA-DQ, HLA-DR, TAP and PSMB are risk variants of genes crucial for antigen processing and presentation—a process that takes place at the MALT and is a bridge between innate and adaptive responses. Antigen presentation and stimulation of T-cell by antibody-presenting cells (APCs) leads to T-cell activation, proliferation and differentiation. One theory, supported by upregulation of miR133a and miR133b, downregulation of miR-155, the existence of risk variants: IFN-γ, CARD9 and PSMB8, assumes a shift towards Th2, T follicular helper, Th17, Th22, and gamma delta T cells. The second, supported by the downregulation of pre-miR-886, assumes an imbalance towards Th1 cells. C APRIL and BAFF, overexpressed in IgAN, are key molecules in B-cell activation and T-cell-independent IgA class switching; B-cell activation is also mediated via the nuclear factor kappa B pathway, which is upregulated in IgAN, and expression of the IgAN risk alleles vav guanine nucleotide exchange factor 3 (VAV3) and TNFRSF13B

Fig. 2

Omics and production of aberrantly glycosylated IgA, anti-IgA IgG, and immune complex formation (hits 1, 2, 3). Dysregulation of mucosal immunity coexists with the production of aberrantly glycosylated, Gd-IgA1 by overstimulated B cells. Gd-IgA1 reaches the circulatory system most likely via “misstrafficking” of plasma cells to the bone marrow. Aberrant glycosylation is a result of overexpression of miR-374b, miR let-7b, miR-148b; IgAN risk variants are associated with IgA production: C1GALT1, C1GALTC1, ST6GALT1, and methylation of Cosmc. IgAN risk variants of genes involved in antigen processing and presentation affect anti-Gd-IgA1 IgG production and along with the overexpression of sCD89 are crucial for immune complex formation

Fig. 3

Omics and immune complex deposition, complement activation, and organ damage (hit 4). Renal and organ damage in IgAN is mediated via complement system activation, of which several risk variants have been described including CFH, CFHR, and C1Q gene groups. IgAN risk variants, ITGAM-ITGAX and VAV3, are thought to play a role in glomerular inflammation and mesangial proliferation, as well as the upregulation of miR-1-5p, miR-199a-5p, miR-100-3p, and miR-877-3p in fibrosis and glomeruli sclerosis. For unknown reasons, immune complexes in some IgAN variants are also deposited in the intestine and skin