Dana Rizk, M.D., professor of Medicine in the Division of Nephrology and medical director for UAB’s Clinical Trials Administrative Office, is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates important research from School of Medicine faculty members.
Dr. Rizk’s study, “Glomerular Immunodeposits of Patients with IgA Nephropathy Are Enriched for IgG Autoantibodies Specific for Galactose-Deficient IgA1,” was recently published in the Journal of the American Society of Nephrology. The study found that IgG is a crucial part of the pathogenic immunodeposits in glomeruli of patients with IgA nephropathy. Dr. Rizk worked with professors in the Division of Nephrology, the Department of Microbiology, and the Department of Pathology on the study.
IgA nephropathy is the most common form of a kidney disease called glomerulonephritis. IgA nephropathy is believed to be caused by IgA1-containing immune complexes formed in the blood that ultimately deposit in the glomeruli—the filtering apparatus of the kidneys.
Previous studies surrounding IgA nephropathy showed that IgA1 immunodeposits in IgA nephropathy are enriched for galactose-deficient IgA1, likely originating from the IgA1-IgG complexes formed in the circulation. This study thus provided a key piece of evidence for the pathogenic role of IgG autoantibodies in IgA nephropathy.
Dr. Rizk and her team’s study has confirmed the hypothesis that a second immunoglobulin, IgG, is a crucial part of the pathogenic immunodeposits in glomeruli of patients with IgA nephropathy. Initially, she hypothesized that the IgA1 was blocking the IgG from being detected in routine immunofluorescence microscopy. When a different reagent, a small nanobody that detects the very end of the IgG molecule was used, IgG was detected in all biopsy specimens, including those that did not show IgG by routine immunofluorescence. Moreover, a highly sensitive confocal microscopy showed co-localization of the IgA1 and IgG in glomerular deposits of the biopsy-tissue specimens.
This study validates the four-hit hypothesis of IgA nephropathy pathogenesis: 1) Patients with IgA nephropathy have elevated levels of circulatory galactose-deficient IgA1; 2) This leads to development of autoantibodies, mostly of the IgG subclass; 3) The IgG autoantibodies bind galactose-deficient IgA1 to form pathogenic immune complexes; and 4) Those pathogenic immune complexes deposit in glomeruli to induce kidney injury.
This knowledge is crucial to understanding and developing new kidney disease treatments and cultivating new therapies. Read more about Dr. Rizk’s study from UAB News here.
The School of Medicine communications staff sat down with Dr. Rizk to gain insights about her research, UAB, and the science community.
Q: What compelled you to pursue this research?
For the past 6 years, I have been working with a team of researchers (led by Drs. Bruce A. Julian and Jan Novak) at UAB who have dedicated most of their lives trying to understand the pathogenesis of IgA nephropathy (IgAN)—the most common glomerular disease worldwide. Thanks to work done at UAB, the proposed disease process involved the overproduction of an abnormally glycosylated immunoglobulin A1 (galactose-deficient IgA1), which in turn was recognized as a foreign antigen against which the body starts forming autoantibodies, mostly of IgG subtype. The autoantibody binding to galactose-deficient IgA1 leads to the formation of circulating immune complexes that deposit in the kidneys and cause inflammation and ultimately scarring. The surprising thing was that when we looked at kidney biopsies of patient with IgAN, up to 50% of them did not reveal IgG based on routine immunofluorescence staining used for clinical purposes. This prompted us to ask whether IgG was present but just not detected by our current technology used for routine care? And if we were to extract this IgG from renal immunodeposits, could we show that it can specifically recognize galactose-deficient IgA1? Answering these questions would confirm our proposed mechanism for the disease pathogenesis.
Q: How do you feel your research will impact the science community?
Our research lends support to the currently proposed IgAN disease mechanism. Understanding the disease pathogenesis in medicine is always the first step towards offering disease-specific therapies and, hopefully, a cure. Additionally, confirming the universal involvement of the IgG autoantibodies in IgAN and their important role identifies a potential biomarker that could be used in the future to monitor for disease activity as well as response to treatment.
Q: What is your research’s relevance to human disease (if applicable)?
IgAN is the most common primary glomerulonephritis in the world and affects predominantly young individuals. It imparts significant morbidity as it can lead to chronic kidney disease and, ultimately, end-stage renal disease. Additionally, IgAN is associated with increased mortality. Finding a treatment, or better yet a cure, is a necessity. In recent years, there has been an increased interest in re-purposing existing drugs or developing new ones to treat IgAN. Our study confirms the autoimmune nature of IgAN and the paramount role of the IgG autoantibodies, thus providing critical information for the design of clinical trials testing therapeutics targeting IgG antibodies with specificity for galactose-deficient IgA1.
Another challenge in the diagnosis and monitoring of IgAN is the silent nature of the disease, especially in its early stages. The discovery of biomarkers such as the IgG autoantibodies and development of reliable tests based on these biomarkers would allow risk stratification of patients. Therapeutic interventions could therefore be reserved for the patient population at high risk of disease progression. Moreover, a biomarker would allow treating physicians to follow disease activity and response to treatment.
Q: How has being at UAB and living in Birmingham affected your research?
My main interest in nephrology has been glomerular diseases. By coming to UAB, I have had the unique opportunity of working with Dr. Julian in the Division of Nephrology, whose life’s work has been around IgAN. He and Dr. Novak (Department of Microbiology) have successfully collaborated for over two decades on elucidating the disease pathogenesis. This unique opportunity at UAB allowed me to pursue my research interest and be part of an outstanding network of scientists with a wide breadth of expertise that contributes to the success of my research endeavors.
Q: What do you find makes the science community here unique?
When I came to UAB I was struck by the collegial collaborations on campus across divisions, as well as departments. Our research is a perfect example of the type of multi-disciplinary teamwork that makes the UAB science community unique. Our interdisciplinary team of clinicians and scientists from multiple departments has been successfully studying all aspects of IgAN for many years. Our current research discovery highlights this translational effort from the bench to the bedside and back.