All ETDs from UAB

Advisory Committee Chair

Terje Dokland

Advisory Committee Members

Todd J Green

R Glenn King

Jan Novak

Dana Rizk

Mark R Walter

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) School of Medicine

Abstract

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world, yet there is no cure and treatment options are limited. Advances in understanding of the molecular basis of this pathology may lead to potential novel therapeutics, but there is still much we don’t know about the disease and the underlying biology. The current paradigm explaining the molecular stages leading to IgAN is called the “multi-hit hypothesis,” which involves the following four hits: (1) Elevated levels of circulating IgA1 with some O-linked glycans deficient in galactose moieties (galactose-deficient IgA1, Gd-IgA1). (2) Circulating IgG autoantibodies (autoAbs) specific to the Gd-IgA1 autoantigen. (3) Formation of immune complexes containing Gd-IgA1 and IgG, along with other proteins. (4) Deposition of Gd-IgA1-IgG complexes in the glomeruli, which leads to kidney injury. Up to 40% of patients progress to kidney failure within 20 years of diagnosis, underscoring the need to pursue a cure. In the work described in this dissertation, we used X-ray crystallography paired with site-directed mutagenesis and binding assays to structurally characterize the antigen-binding fragments (Fabs) of an IgG autoAb and IgG engineered to mimic autoAbs, addressing hit #2 of the multi-hit hypothesis. In our studies, we identify residues and structural features on the putative binding regions of the autoantibody that contribute to Gd-IgA1 binding. In doing so, we provide a proof-of-concept model for future studies investigating the properties of antibodies specific for Gd-IgA1. This information may guide the rational design of iv antibody-based therapeutics engineered to interfere with disease progression of IgAN by preventing interaction of Gd-IgA1 and IgG autoAbs.

Available for download on Monday, September 01, 2025

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