The Falk Labs
Dr. Falk's research probes questions focused on immune mediated kidney diseases, especially glomerulonephritis. His clinical and basic science interests include both ANCA glomerulonephritis and small vessel vasculitis (SVV). A central objective of Falk's research is elucidating the causes of ANCA necrotizing and crescentic glomerulonephritis. Unraveling the cause of this disease requires considering a number of factors involved in the devolpment of ANCA glomerulonephritis. Falk conceptualizes this process as opening the vasculitis lock with a key that has a number of "ridges and valleys" analogous to those factors that contribute to the development of this autoimmune disease. He participates in a research group that, in a large study over the last four years has revealed a number of avenues of investigation and new approaches to ongoing questions that pertain not only to ANCA glomerulonephritis, but to the general fields of autoimmunity, inflammation and basic neutrophil and monocyte biology.
Dr. Jennette's current research focuses on inflammatory vascular disease (vasculitis and glomerulonephritis) caused by anti-neutrophil cytoplasmic autoantibodies (ANCA), which are a major cause for the most common form of aggressive glomerulonephritis and systemic small vessel vasculitis in adults.
In collaboration with Dr. Hong Xiao and Dr. Peiqi Hu, he utilizes animal models of ANCA disease discovered in their laboratory that is induced by mouse anti-myeloperoxidase (anti-MPO) antibodies and is mediated primarily by activation of neutrophils. Activation of the alternative complement pathway is critically involved in the pathogenesis of disease in this model. ANCA-activated neutrophils release factors that activate complement, which in turn primes neutrophils for further activation by ANCA. These effects and other ANCA-mediated pathogenic events depend on generation of C5a by alternative pathway activation and on engagement of C5a receptors on neutrophils. Blockade of this critical pathogenic step abrogates disease induction, which suggests a possible novel therapeutic strategy in humans, which is currently under investigation in patients with ANCA disease. Current studies include investigations of the genes responsible for differences in disease severity, the role of epitope specificity in the pathogenicity of ANCA, the roles of Fc gamma receptors and other innate immune factors in modulating disease phenotype, and studies using a mouse model to elucidate the pathogenesis of ANCA-induced necrotizing pulmonary granulomatosis.
Dr. Bunch’s research focuses on dissecting the role of B cells and the autoantibodies they produce in autoimmune diseases affecting the kidney. She investigates how normal regulatory mechanisms are circumvented to allow production of pathogenic antibodies and how these autoantibodies interact with immune cells to generate microparticles or cause the release of cytokines and other cellular factors leading to disease. Dr. Bunch and her co-workers discovered similar B cell aberrations in two autoimmune diseases that affect the kidney, antineutrophil cytoplasmic autoantibodies (ANCA) vasculitis and systemic lupus erythematosus (SLE). She is particularly interested in elucidating the mechanisms by which regulatory B cells help maintain immunological balance and promote disease remission. Her lab group identified a CD5+ B regulatory cell population that decreases during active disease and can serve as an indicator of clinical relapse. Whether these regulatory B cells, when normalized, are protective of future relapse is currently being tested in a randomized, proof-of-concept trial.
Her lab also investigates potential risk factors for thrombosis including anti-plasminogen antibodies and microparticle tissue factor activity in patients with glomerulonephritis and membranous nephropathy. Dr. Bunch’s goal is to translate our understanding of disease pathogenesis into better clinical tools for predicting relapse or other disease complications such as thrombosis and better therapies for management of diseases affecting the kidney.
Dr. Ciavatta studies anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) to identify the genetic and epigenetic drivers contributing to disease susceptibility and severity. Large-scale genetic studies in humans have identified HLA variants (proteins that present antigens to T cells) more frequently in patients with AAV than healthy individuals, suggesting variants in HLA genes predispose individuals to AAV. Currently his lab is investigating how the HLA variants linked with AAV interact with patient’s T cells. Using a mouse model of AAV, they observed differences in glomerular damage among inbred strains of mice, indicating a genetic component influences disease severity.
Dr. Ciavatta and colleagues also found that patients with AAV differ from healthy individuals at the level of epigenetics--that is, changes that regulate gene activity, independent of the DNA sequence. Epigenetic modifications to DNA and histones (proteins used to compact DNA into a cell’s nucleus) associated with inactive genes are deficient at key genes in patients with AAV. Intriguingly, patients that restore the DNA modifications are less likely to relapse, which suggests a patient’s epigenetic status may predict disease progression. Dr. Ciavatta's lab is examining genome wide epigenetic changes in patients to understand molecular mechanisms regulating gene activation that are disrupted in AAV.
Dr. Free’s research is focused on deciphering the role of T cells in autoimmune glomerulonephritis. One type of autoimmune kidney disease, called anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, has already demonstrated numerous abnormalities in the CD4+ T cell pool. Dr. Free has already determined, along with other collaborating labs, that regulatory T cells do not function properly in patients with ANCA vasculitis. These regulatory T cells are responsible for keeping other effector T cells “in check” to prevent excessive inflammation. Without functional regulatory T cells, excess inflammation ensues alongside autoreactive T cells. Currently, Dr. Free is examining a potential role of myeloid-derived suppressor cells (MDSCs) in ANCA vasculitis. MDSCs have been extensively researched in the cancer field, but are relatively unknown in autoimmunity. Also potent suppressors of T cell function, her hope is that MDSCs represent a potential source of T cell regulation in patients.
Another disease of interest to Dr. Free is minimal change disease (MCD), the most common cause of nephrotic syndrome in children. The immunopathogenesis of MCD is virtually unknown, although many hypotheses have emerged over the years. She is currently investigating the roles of T cells and other circulating immune components and their contributions to disease progression and relapse.
Dr. Lardinois’ major research interest lies in the field of mass spectrometry and its application to the analysis of antigens/antibodies involved in a variety of renal auto-immune diseases, with a special emphasis on ANCA (AntiNeutrophilicCytoplasmic Autoantibodies) and autoimmune vasculitides (inflammations of blood vessels). Antibodies are major components of the immune systems and ANCAs are a group of autoantibodies directed against constituents of neutrophil granulocytes (the most common type of white blood cells) and monocytes (another type of white blood cell). A body of evidence point to a crucial role for ANCA in the disease process for several types of small-vessel vasculitides; Wegener's granulomatosis, Churg-Strauss syndrome, and Microscopic polyangiitis. Intriguingly, however, ANCA levels do not correlate or correlate only moderately with disease activity. ANCAs are normally of the IgG type. IgGs are glycoproteins (molecules that consist of a carbohydrate – a “sugar”- plus a protein). Typically, more than 30 IgG glycovariants (molecular forms varying in their carbohydrate composition and structure) can be detected in human serum and the proportion of individual IgG glycovariants in patients with active ANCA-associated vasculitides differ from healthy individual.
Dr. Lardinois is currently investigating whether changes in the abundance of certain glycovariants of ANCA could affect their pathogenicity and be correlated with disease activity. Another focus is the development of LC-MS/MS based methods to identify and characterize new antigens/antibodies involved in renal auto-immune diseases.