Date of Award
Doctor of Philosophy (PhD)
The complement system is an ancient and powerful form of innate immunity. The alternative pathway (AP), a positive feedback loop, is at the core of the complement system. Activating components and regulators of the AP are genetically implicated in atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). aHUS features kidney failure, and often affects young children, but may occur throughout life and can be precipitated by pregnancy. aHUS associated variants are extremely rare and are considered highly penetrant. At the opposite end of the spectrum, AMD affects the retina leading to loss of central vision with a late age of onset. Risk variants in AMD are common in the population and have smaller effect sizes.
I endeavored to understand the role of rare variants of large effect, similar to those causative in aHUS, in common diseases involving the kidney, specifically preeclampsia and lupus nephritis. I also examined the role of such variants in AMD. Because thousands of people must be studied to assess the impact of rare variation, I developed novel approaches allowing these experiments to be done with 10- to 100-fold reductions in both cost and labor.
aHUS-like variants are present in preeclampsia, a syndrome that affects pregnant women and shares multiple pathologic findings with aHUS. These variants are present in ~1% of preeclamptic individuals. Additionally, aHUS-like rare variants are found in severe AMD patients. A diversity of variants in factor H and factor I are enriched in AMD cases. Subsets of these alleles have high penetrance in families and defective function.
To study the effect of unregulated AP activation in vivo I studied a mouse deficient for the ubiquitous membrane regulator of complement Crry. Embryos that lack Crry are not viable due to attack by the maternal AP early in development. Damage in this model is unrelated to traditional forms of complement-mediated inflammation such as neutrophil activation or anaphylatoxin signaling.
The findings of this body of work are an important step forward in understanding the risk individuals have of the common diseases PE and AMD and has implications for how these patients could be treated.
Chair and Committee
John P Atkinson
Alison Goate, Timothy Ley, Robi Mitra, D. Michael Nelson, John Rice
Triebwasser, Michael, "Excessive Complement Activation Due to Genetic Haploinsufficiency of Regulators in Multiple Human Diseases" (2015). Arts & Sciences Electronic Theses and Dissertations. 427.