International Law Colloquia, Spring 2007 Series

Spring 2007 Presenters: February 9: Curtis A. Bradley (Duke Law School), Unratified Treaties, Domestic Politics and the U.S. Constitution February 16: Melissa A. Waters (Washington & Lee University School of Law), “Foreign Authority” Through a Narrow Lens: Interpretive Incorporation of Treaties February 23: Joost Pauwelyn (Duke Law School), Optimal Protection of International Law: Navigating between ‘European Absolutism’ and ‘American Voluntarism’ March 2: Jacob Katz Cogan (University of Cincinnati College of Law), Competition and Control in International Adjudication March 23: Janet Koven Levit (University of Tulsa College of Law), A Bottom-Up Approach to International Lawmaking: The Tale of Three Trade Finance Instruments April 13: Derek Jinks (University of Texas School of Law), Hamdan and the Law of War: The Applicability of the Geneva Conventions to the “Global War on Terrorism” April 20: Diane Marie Amann (University of California-Davis School of Law): Slave Trafficking, Crimes against Humanit

IgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cells.

BackgroundFamily screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons.MethodsWe performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2.ResultsThe three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD.ConclusionsThe presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease