Somatic Mutations Modulate Autoantibodies against Galactose-Deficient IgA1 in IgA Nephropathy

Huang, Zhi; Raška, Milan; Stewart, Tyler J; Reily, Colin; King, R. Glenn; Crossman, David K.; Crowley, Michael R.; Hargett, Audra A.; Zhang, Zhixin; Suzuki, Hitoshi; Hall, Stacy; Wyatt, Robert; Julian, Bruce A.; Renfrow, Matthew B.; Gharavi, Ali G.; Novák, Jan

doi:10.1681/asn.2014101044

Cited by 31 publications

(18 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These autoantibodies share an unusual sequence in the complementarity-determining region 3 of the variable region of their heavy chains that enhances binding to galactose-deficient glycans,[ 8 ] apparently as a result of a somatic mutation. [ 28 ] The clinical observation that many IgAN patients have renal biopsies without mesangial IgG by standard immunofluorescence staining may seem at odds with our current findings. However, glomerular IgG can be found frequently in these biopsy specimens when using high-resolution confocal microscopy imaging coupled with immunofluorescence staining.…”

Section: Discussioncontrasting

confidence: 54%

Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy

et al. 2018

Self Cite

View full text Add to dashboard Cite

IgA nephropathy is an autoimmune disease characterized by IgA1-containing glomerular immune deposits. We previously proposed a multi-hit pathogenesis model in which patients with IgA nephropathy have elevated levels of circulatory IgA1 with some O-glycans deficient in galactose (Gd-IgA1, autoantigen). Gd-IgA1 is recognized by anti-glycan IgG and/or IgA autoantibodies, resulting in formation of pathogenic immune complexes. Some of these immune complexes deposit in the kidney, activate mesangial cells, and incite glomerular injury leading to clinical presentation of IgA nephropathy. Several studies have demonstrated that elevated circulatory levels of either Gd-IgA1 or the corresponding autoantibodies predict progressive loss of renal clearance function. In this study we assessed a possible association between serum levels of Gd-IgA1 and IgG or IgA autoantibodies specific for Gd-IgA1 in serum samples from 135 patients with biopsy-proven IgA nephropathy, 76 patients with other renal diseases, and 106 healthy controls. Our analyses revealed a correlation between the concentrations of the autoantigen and the corresponding IgG autoantibodies in sera of patients with IgA nephropathy, but not of disease or healthy controls. Moreover, our data suggest that IgG is the predominant isotype of Gd-IgA1-specific autoantibodies in IgA nephropathy. This work highlights the importance of both initial hits in the pathogenesis of IgA nephropathy.

show abstract

Section: Discussioncontrasting

confidence: 54%

Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, these antibodies are susceptible to bacteria-derived proteases (13). Recent data suggest that anti-glycan autoantibodies may be targeting IgA VH gene segments that occur as a result of somatic hypermutation, and not sequences present in the host germline (14).…”

Section: Disease Pathogenesis In Iganmentioning

confidence: 99%

IgA Nephropathy

Rodrigues

Haas

Reich

2017

CJASN

453

326

View full text Add to dashboard Cite

IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.

show abstract

“…Conversely, introducing Ser residue in the third position of CDR3 of the heavy chains of IgG from a healthy control increased the binding of the IgG to Gd-IgA1 ( 182 ). Recent study has shown that Ser in CDR3 in the heavy chains of IgG autoantibodies originates from somatic mutations rather than from rare variants of VH genes ( 183 ).…”

Section: Autoantibodies Against Galactose-deficient Iga1 In Iga Nephrmentioning

confidence: 99%

The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy

et al. 2016

Self Cite

View full text Add to dashboard Cite

IgA nephropathy (IgAN) is the most common primary glomerulonephritis, frequently leading to end-stage renal disease, as there is no disease-specific therapy. IgAN is diagnosed from pathological assessment of a renal biopsy specimen based on predominant or codominant IgA-containing immunodeposits, usually with complement C3 co-deposits and with variable presence of IgG and/or IgM. The IgA in these renal deposits is galactose-deficient IgA1, with less than a full complement of galactose residues on the O -glycans in the hinge region of the heavy chains. Research from the past decade led to the definition of IgAN as an autoimmune disease with a multi-hit pathogenetic process with contributing genetic and environmental components. In this process, circulating galactose-deficient IgA1 (autoantigen) is bound by antiglycan IgG or IgA (autoantibodies) to form immune complexes. Some of these circulating complexes deposit in glomeruli, and thereby activate mesangial cells and induce renal injury through cellular proliferation and overproduction of extracellular matrix components and cytokines/chemokines. Glycosylation pathways associated with production of the autoantigen and the unique characteristics of the corresponding autoantibodies in patients with IgAN have been uncovered. Complement likely plays a significant role in the formation and the nephritogenic activities of these complexes. Complement activation is mediated through the alternative and lectin pathways and probably occurs systemically on IgA1-containing circulating immune complexes as well as locally in glomeruli. Incidence of IgAN varies greatly by geographical location; the disease is rare in central Africa but accounts for up to 40% of native-kidney biopsies in eastern Asia. Some of this variation may be explained by genetically determined influences on the pathogenesis of the disease. Genome-wide association studies to date have identified several loci associated with IgAN. Some of these loci are associated with the increased prevalence of IgAN, whereas others, such as deletion of complement factor H-related genes 1 and 3, are protective against the disease. Understanding the molecular mechanisms and genetic and biochemical factors involved in formation and activities of pathogenic IgA1-containing immune complexes will enable the development of future disease-specific therapies as well as identification of non-invasive disease-specific biomarkers.

show abstract

Somatic Mutations Modulate Autoantibodies against Galactose-Deficient IgA1 in IgA Nephropathy

Cited by 31 publications

References 30 publications

Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy

Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy

IgA Nephropathy

The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy

Contact Info

Product

Resources

About