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      New developments in the genetics, pathogenesis, and therapy of IgA nephropathy

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          Recent years have brought notable progress in the field of IgA nephropathy. Here, we highlight important new directions and latest developments, including successful discovery of several genetic susceptibility loci, formulation of the multi-hit pathogenesis model that integrates findings from studies of galactose-deficient IgA1, anti-glycan response and immune complex-induced kidney injury, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines. We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geo-ethnic disparities in disease susceptibility. Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The concerted pattern of inter-population allelic differentiation across all Genome Wide Association Studies (GWAS) loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multi-locus adaptation might have shaped the present-day landscape of IgA nephropathy. Importantly, the “Intestinal Immune Network for IgA Production” emerged as one of the new targets for potential therapeutic intervention. We place these findings in the context of the multi-hit pathogenesis model and existing knowledge of IgA immunobiology. Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies.

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          Most cited references 153

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          Transglutaminases: crosslinking enzymes with pleiotropic functions.

          Blood coagulation, skin-barrier formation, hardening of the fertilization envelope, extracellular-matrix assembly and other important biological processes are dependent on the rapid generation of covalent crosslinks between proteins. These reactions--which are catalysed by transglutaminases--endow the resulting supramolecular structure with extra rigidity and resistance against proteolytic degradation. Some transglutaminases function as molecular switches in cytoskeletal scaffolding and modulate protein-protein interactions. Having knowledge of these enzymes is essential for understanding the aetiologies of diverse hereditary diseases of the blood and skin, and various autoimmune, inflammatory and degenerative conditions.
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            Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

            More than a thousand disease susceptibility loci have been identified via genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings generally remain to be defined. We utilize pooled next-generation sequencing to study 56 genes in regions associated to Crohn’s Disease in 350 cases and 350 controls. Follow up genotyping of 70 rare and low-frequency protein-altering variants (MAF ~ .001-.05) in nine independent case-control series (16054 CD patients, 12153 UC patients, 17575 healthy controls) identifies four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association to a novel, protective splice variant in CARD9 (p < 1e-16, OR ~ 0.29), as well as additional associations to coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by providing novel, rare, and likely functional variants that will empower functional experiments and predictive models.
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              Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5.

              The intestinal cell types responsible for defense against pathogenic organisms remain incompletely characterized. Here we identify a subset of CD11c(hi)CD11b(hi) lamina propria dendritic cells (LPDCs) that expressed Toll-like receptor 5 (TLR5) in the small intestine. When stimulated by the TLR5 ligand flagellin, TLR5(+) LPDCs induced the differentiation of naive B cells into immunoglobulin A-producing plasma cells by a mechanism independent of gut-associated lymphoid tissue. In addition, by a mechanism dependent on TLR5 stimulation, these LPDCs promoted the differentiation of antigen-specific interleukin 17-producing T helper cells and type 1 T helper cells. Unlike spleen DCs, the LPDCs specifically produced retinoic acid, which, in a dose-dependent way, supported the generation and retention of immunoglobulin A-producing cells in the lamina propria and positively regulated the differentiation interleukin 17-producing T helper cells. Our findings demonstrate unique properties of LPDCs and the importance of TLR5 for adaptive immunity in the intestine.

                Author and article information

                Kidney Int
                Kidney Int.
                Kidney international
                3 August 2015
                16 September 2015
                November 2015
                01 May 2016
                : 88
                : 5
                : 974-989
                [1 ]Division of Nephrology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA
                [2 ]Division of Nephrology Dialysis and Transplantation, Department of Surgery, Medicine, Dentistry, Morphologic Science, Transplantation, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Italy
                [3 ]Division of Renal Pathology, Department of Pathology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
                Author notes
                Corresponding Author: Krzysztof Kiryluk, M.D., M.S., Department of Medicine, Division of Nephrology, Columbia University, 1150 St Nicholas Ave, Russ Berrie Pavilion # 411, New York, NY 10032, Tel: 212-851-5559, Fax: 212-851-5520, kk473@

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