Dissertation
Novel insights into the genetic and immunologic drivers of C3 glomerulopathy
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2021
DOI: 10.17077/etd.006346
Abstract
C3 Glomerulopathy (C3G) is a family of ultra-rare, multifactorial diseases mediated by dysregulation of the complement system. The complement system is a critical part of the innate immune response that initiates and amplifies an immune response in the presence of pathogenic or unwanted material. A common pattern of complement-mediated diseases is damage to host tissue. C3G is distinguished by complement component C3 deposition localized to the glomerular basement membrane (GBM) of the kidney. In approximately 50% of patients, this deposition will result in progressive renal failure within the first 10 years of diagnosis. No standard, effective treatments are available for the C3G population. Given the characteristic C3 protein deposition in the GBM, the alternative pathway of complement is the primary focus in understanding the pathophysiology of C3G. The alternative pathway is unique in its spontaneous activation via the hydrolysis of an internal thioester bond of the C3 protein. Once activated, C3 will form a C3 convertase to amplify alternative pathway activation by cleaving C3 into its active fragments, C3a and C3b. Subsequently, a C5 convertase is formed by the association of an active C3b fragment with an active C3 convertase and triggers the terminal complement cascade. Terminal complement activity ultimately results in cell lysis and opsonization. Signs of ongoing, systemic complement activity, such as depleted levels of C3, are frequently (but not always) identified in the serum of patients with C3G.
Factors associated with alternative pathway dysregulation in C3G include rare and novel genetic variation in complement genes and autoantibodies which target complement proteins and protein complexes such as the C3 and C5 convertases. These factors are thought to drive complement dysregulation in C3G and are identified in 55-65% of patients, but their interpretation and clinical consequences are not yet well understood. In 35-45% of patients with C3G, no disease-associated factors are identified. Unraveling the specific causes of alternative pathway dysregulation is a prerequisite for developing effective therapeutics to mitigate the C3G phenotype. This thesis will describe several studies performed in pursuit of two major goals in C3G: 1) the characterization of known disease-associated factors, in particular the role of autoantibodies as potential drivers of disease progression in C3G, and 2) the investigation of novel drivers of local (rather than systemic) complement dysregulation mediated by the glomerular microenvironment.
The data presented here progress our understanding of C3G. We identify distinct patient subsets within C3G based on the presence or absence of systemic complement dysregulation. In patients with systemic dysregulation, we present data which strongly suggest that autoantibodies to complement proteins and complexes are robust drivers of complement dysregulation in vivo. In addition to systemic drivers of disease, a mechanism of local complement dysregulation within the glomerular microenvironment is proposed and 3 genes are identified as potential genetic drivers of disease which warrant further investigation. These findings are critical pieces of the C3G pathophysiology and provide insight into our basic understanding of complement activity, further our ability to precisely treat disease and offer new therapeutic targets for improving patient outcome.
Details
- Title: Subtitle
- Novel insights into the genetic and immunologic drivers of C3 glomerulopathy
- Creators
- Jill Hauer
- Contributors
- Richard Smith (Advisor)Jacob Michaelson (Committee Member)Michael Schnieders (Committee Member)Val Sheffield (Committee Member)Kai Wang (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Autumn 2021
- DOI
- 10.17077/etd.006346
- Publisher
- University of Iowa
- Number of pages
- xvi, 122 pages
- Copyright
- Copyright 2021 Jill Hauer
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 107-122).
- Public Abstract (ETD)
The innate immune system is the first line of defense between the human body and harmful pathogens in the environment. A major part of innate immunity is the complement system – a complicated system of proteins which helps identify unwanted material in the body and efficiently get rid of it by initiating a larger immune response. There are many processes in place to keep complement inactive when a large immune response is not needed, but, when those processes break down, disease may arise. C3 Glomerulopathy (C3G) is the focus of this thesis and is caused by dysregulation of the complement system. Chronic, unnecessary complement activity in persons with C3G results in damage to the kidney and causes kidney failure in ~50% of the C3G population. Unfortunately, there are no standard, effective treatments available.
In order to provide better patient care and develop treatments for C3G, we first have to understand on a molecular level what is driving this unwanted complement dysregulation. Genetic sequencing has led to the discovery that changes in complement genes (which lead to misfunctioning complement proteins) are found in about 20% of the C3G population. Tests of patient serum have also identified autoantibodies which interact with complement proteins and likely contribute to the disrupted complement function observed in C3G. The first goal of the studies presented in this thesis was to get a better understanding of these known factors associated with complement dysregulation. We discovered that most patients who have these disease-associated genetic and immunologic factors, also have massively dysregulated complement activity, and the degree of this over-activity correlates with the rate at which patients progress to kidney failure.
- Academic Unit
- Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9984210527602771
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