Anuja Java, M.D.
ABSTRACT:
Preeclampsia (PE) is the leading cause of maternal and fetal morbidity and mortality. It
is characterized by new-onset hypertension often associated with proteinuria after 20-weeks of
gestation. Disease manifestations include HELLP (Hemolysis, Elevated Liver enzymes, Low
Platelets), kidney failure, seizures (eclampsia), stroke and cardiovascular complications. The only
current treatment for PE is delivery, and labor is usually induced early to prevent systemic
complications. The pathology of PE involves endothelial injury and morphological alterations in uterine
spiral arteries. This process is strikingly reminiscent of a kidney disease known as atypical hemolytic
uremic syndrome (aHUS) in which endothelial injury results in hemolytic anemia, thrombocytopenia,
and kidney failure. aHUS is caused by genetic mutations in complement proteins. Complement
system is a component of the immune system that is used to fight infections and dispose of cellular
debris. Complement activation needs to be tightly regulated to prevent damage to healthy host cells.
In aHUS, the complement system activates inappropriately due to genetic mutations and damages the
kidney. Because of the similarity between PE and aHUS, we speculated that PE may also be caused
by complement activation secondary to the presence of genetic variants. To investigate this, we
conducted whole exome sequencing (WES) in PE patients with an initial analysis of complement
genes. Our results have revealed pathogenic variants and variants of uncertain significance (VUS) in
known complement proteins. Several of these variants are in a distinct set of complement regulators
called CSMD (CUB and Sushi Multiple Domains) 1,2 and 3. This is a novel and intriguing finding since
complete loss-of-function due to homozygous mutations in CSMD 1 have been reported to cause
gonadal dysfunction due to complement overactivation. This led us to postulate that partial loss of
function due to heterozygous variants in CSMD may lead to PE. We further hypothesize that the
majority of VUS identified in complement proteins in our cohort are deleterious. Therefore, in Aim 1,
we will functionally characterize the VUS to determine their clinical significance and in Aim 2, we will
utilize the WES data available for an additional 154 PE patients from the Preeclampsia RegistryTM to
determine if CSMD variants are a unique risk factor for PE. This work will establish the role of
complement proteins and regulators in PE and will define the subset of high-risk patients who should
be treated with anti-complement therapy to prevent short and long-term complications and will further
open the door for development of novel complement therapeutics.
SUMMARY AND DESCRIPTION IN LAY LANGUAGE
An intact immune system is important for a successful normal pregnancy to ensure proper
development of the placenta and baby. Preeclampsia is a severe complication of human pregnancy
characterized by high blood pressure and signs of damage to other organ systems, most often the
heart and kidneys. It is one of the leading causes of maternal and fetal death. Despite intensive
research efforts, the cause of preeclampsia is not well understood. The complement system is a key
component of the immune system that enhances the ability of antibodies to clear microbes and
damaged cells from an organism. However, the complement system has the potential to be damaging
to healthy host tissues thus its activation must be tightly regulated. The findings in preeclampsia
resemble a genetic kidney disease, called atypical hemolytic uremic syndrome (aHUS) that occurs
due to poorly controlled complement activation and causes blood clots to form in small blood vessels
in the kidney. The excessive complement activation in aHUS occurs due to genetic mutations in
complement proteins and we speculated maybe associated with preeclampsia as well. Therefore, we
conducted genetic testing on blood and placental samples from mother and baby in patients with
preeclampsia. Our results have revealed mutations in complement proteins. Some of these mutations
are known to be damaging, while others are novel, and their significance is unclear. We will now study
these novel mutations to determine if they are indeed damaging and therefore the likely cause of
preeclampsia in our patients. Complement genetic studies in aHUS paved the way for the successful
development of therapies that prevent overactivation of the complement system and have
revolutionized the treatment of aHUS. Therefore, a clearer understanding of the role of the
complement system in preeclampsia will help to identify patients who would benefit from
anticomplement therapy, thereby improving short-and long-term health for both mother and child and
further facilitate the development of newer medications for treatment.
