# Characterizing the proteome of pathogenic IgA1-containing immune complexes in IgA Nephropathy

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $37,767

## Abstract

Project Abstract
IgA Nephropathy (IgAN) is an autoimmune glomerulonephritis that frequently results in kidney failure. IgAN is
characterized by elevated production of galactose-deficient immunoglobulin A1 (Gd-IgA1) being bound by an
immunoglobulin G (IgG) autoantibody specific for Gd-IgA1 to form IgA1-associated immune complexes (IgA1-
ICs) with additional proteins in blood. These complexes deposit in the glomerulus and cause kidney injury by
activating mesangial cell proliferation and breakdown of glomerular capillaries allowing protein or blood in the
urine. There is no worldwide screening and can only be diagnosed by renal biopsy. We know that the
immunoglobulins and the undefined blood proteins are necessary to the nephritogenic activity of the high
molecular weight IgA1-ICs, but we do not know what concentration, and variability of each protein nor the ratio
of immunoglobulins necessary for complex formation. The primary goal of my study is to quantify and establish
the ratios of immunoglobulins and blood proteins in the composition of IgA1-ICs in the serum of patients with
IgAN of opposing clinical spectrum in comparison to healthy controls. Our collaborative team has observed that
the addition of serum to the immunoglobulin nucleating factors is necessary for the formation of pathogenic ICs
that activate human cultured mesangial cells. The overarching goal of this proposal is that quantitative analysis
of serum IgA1-ICs will determine stoichiometry of immunoglobulins and other blood proteins involved in the
formation of IgA1-ICs in both progressing and stable disease patients with IgAN. In my recently submitted
manuscript, I identified 21 high-quality blood protein targets specifically enriched in IgA1-ICs isolated from IgAN
patient serum. When comparing the identification of proteins and their corresponding enrichment in the IgA1-ICs
to the other uncomplexed forms of IgA1 control fractions (monomeric and polymeric IgA), we observed that each
fraction clustered by molecular form, showing the value of our sample prep and innovative fractionation of serum.
Based on preliminary data, I hypothesize the ratio of IgA1 to IgG autoantibody is discreet and can be determined
by targeted LC-MS quantitative analysis, polymeric IgA1 is the predominant molecular form of IgA1 involved in
complex formation and complement cascade activation factors are present in complex composition at a higher
ratio than immunoglobulins before deposition into the kidney. Throughout the global pandemic, the world has
learned of the importance of disease screening, the variability of disease presentation, and the daily fear that
immunocompromised populations live in. Being a researcher in IgA Nephropathy, I have been aware of these
realities in IgAN patient populations prior to COVID-19. This has fueled my dedication to answering important
questions in the IgAN field and understanding this crucial part of pathogenesis of IgA1-IC formation for the sake
of future development ...

## Key facts

- **NIH application ID:** 10536410
- **Project number:** 1F31DK127833-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Mary Cunningham
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,767
- **Award type:** 1
- **Project period:** 2022-07-15 → 2024-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536410

## Citation

> US National Institutes of Health, RePORTER application 10536410, Characterizing the proteome of pathogenic IgA1-containing immune complexes in IgA Nephropathy (1F31DK127833-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10536410. Licensed CC0.

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