Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy

Yamada, Koshi; Huang, Zhi; Raška, Milan; Reily, Colin; Anderson, Joshua C.; Suzuki, Hitoshi; Kiryluk, Krzysztof; Gharavi, Ali G.; Julian, Bruce A.; Willey, Christopher D.; Novák, Jan

doi:10.1159/000505748

Cited by 29 publications

(19 citation statements)

References 68 publications

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“…Leukemia inhibitory factor (LIF) exhibits similar effects as IL-6 on IgA1-producing cells from IgAN patients, except that the signaling is mediated by STAT1. These cytokine effects underscore the role of aberrant signaling and cellular activation in Gd-IgA1 production in IgAN [ 84 ].…”

Section: Galactose-deficient Iga1 (Hit #1)mentioning

confidence: 99%

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

Knoppová

Reily

King

et al. 2021

JCM

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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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Section: Galactose-deficient Iga1 (Hit #1)mentioning

confidence: 99%

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

Knoppová

Reily

King

et al. 2021

JCM

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“…Aberrant IL-6 activates the JAK2/STAT3 signaling pathway through its receptor protein coupling gp130, and the enhanced phosphorylation of STAT3 further downregulates the transcription of C1GALT1 , thereby mediating the production of Gd-IgA1 ( 41 ). Furthermore, another member of the IL-6 family, leukemia inhibitory factor (LIF), upon receptor binding, leads to the overproduction of Gd-IgA1 via the LIF/STAT1 pathway ( 42 ). In addition to the IL-6 family, B-cell activating factor (BAFF), a tumor necrosis factor (TNF) superfamily member, is also involved in the synthesis of Gd-IgA1.…”

Section: Pathogenesismentioning

confidence: 99%

IgA vasculitis update: Epidemiology, pathogenesis, and biomarkers

2022

Front. Immunol.

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Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is the most common systemic vasculitis in children, characterized by diverse clinical manifestations with a wide spectrum ranging from isolated cutaneous vasculitis to systemic involvement. The incidence of IgAV is geographically and ethnically variable, with a prevalence in autumn and winter, suggesting a driving role that genetic and environmental factors play in the disease. Although IgAV has a certain degree of natural remission, it varies widely among individuals. Some patients can suffer from severe renal involvement and even progress to end-stage renal disease. Its pathogenesis is complex and has not been fully elucidated. The formation of galactose-deficient IgA1 (Gd-IgA1) and related immune complexes plays a vital role in promoting the occurrence and development of IgAV nephritis. In addition, neutrophil activation is stimulated through the binding of IgA to the Fc alpha receptor I expressed on its surface, resulting in systemic vascular inflammation and tissue damage. Starting from the epidemiological characteristics, this article will review the role of immunological factors such as Gd-IgA1, autoantibodies, circulating immune complexes, complement system, cellular immunization, and the contributions of environmental and genetic factors in the pathogenesis of IgAV, and conclude with the major biomarkers for IgAV.

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“…IL-4 and, even more so, IL-6 enhance production of Gd-IgA1 due to further dysregulation of expression and activities of specific targets, including C1GALT1, C1GALT1C1, and ST6GALNAC2 [64]. Leukemia inhibitory factor (LIF), an IL-6-related cytokine, also enhances Gd-IgA1 production [119]. Notably, both IL-6 and LIF enhance production of Gd-IgA1 in IgA1-secreting cell lines derived from IgAN patients due to abnormal signaling in JAK-STAT pathways that leads to further dysregulation of key glycosyltransferases [38,[119][120][121][122].…”

Section: Alteration Of Mucosal Immunity Associated With Gd-iga1 Productionmentioning

confidence: 99%

“…Leukemia inhibitory factor (LIF), an IL-6-related cytokine, also enhances Gd-IgA1 production [119]. Notably, both IL-6 and LIF enhance production of Gd-IgA1 in IgA1-secreting cell lines derived from IgAN patients due to abnormal signaling in JAK-STAT pathways that leads to further dysregulation of key glycosyltransferases [38,[119][120][121][122]. Furthermore, a proliferation-inducing ligand (APRIL), known to play an important role in T cell-independent IgA class switching, is overproduced by CD19 + B cells in tonsil germinal centers in IgAN [118].…”

Section: Alteration Of Mucosal Immunity Associated With Gd-iga1 Productionmentioning

confidence: 99%

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

Ohyama

Renfrow

Novák

et al. 2021

JCM

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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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Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy

Cited by 29 publications

References 68 publications

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

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

IgA vasculitis update: Epidemiology, pathogenesis, and biomarkers

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

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