Exposure to occupational antigens might predispose to IgG4‐related disease
Authors: Lucas J. Maillette de Buy Wenniger, Emma L. Culver, Ulrich Beuers
Journal: Hepatology (2014)

IgG4-associated cholangitis (IAC) and autoimmune pancreatitis are the predominant manifestations of IgG4-related diseases (IgG4-RD); their pathogenesis is enigmatic.1, 2 Serum IgG4 concentrations are generally elevated in IgG4-RD but the biological implications thereof have not been explained.3 IgG4, traditionally regarded as a regulatory antibody, has been consistently reported to be upregulated in chronic immune stimulation, as illustrated by an elevation of bee-venom-specific IgG4 in beekeepers.4 As reported in this journal, we recently found clonal expansions of IgG4-switched B-cells in patients with IAC, using a novel next-generation sequencing protocol.5 That led us to speculate that chronic antigenic stimulation underlies the often tremendously elevated levels of serum IgG4 in IgG4-RD. As it was our clinical impression that blue-collar workers were dominating our cohort of IAC patients, we hypothesized that chronic occupational antigen exposure could play a crucial pathogenetic role for the mainly elderly male IgG4-RD patients. Using a questionnaire, we carefully investigated the job history of our mostly retired IgG4-RD patients. Of 25 patients with IAC and/or autoimmune pancreatitis, 88% had a history of blue-collar work of at least 1 year, but often of a whole career (Table 1: e.g., building contractors, plumbers), much more than could be expected on the basis of historical Dutch occupational records. Chronic exposure to solvents, industrial and metal dusts, and pigments and oils used in the automotive industry were among the most frequent potential occupational hazards. In comparison, among a disease control cohort of 21 patients with primary sclerosing cholangitis (PSC), a male-predominant disease with similar clinical characteristics, only 14% reported a history of working in a blue-collar profession. Using the same questionnaire, a trial nurse blinded to our hypothesis and the Amsterdam results replicated this investigation among the Oxford cohort of 44 patients with established IgG4-RD. It was found that 61% of the patients had blue-collar professions and recalled chronic exposures to potentially harmful compounds. Again, intensive and prolonged exposure to solvents, industrial dusts, pesticides, or industrial oils or polymers was reported by 52% of IgG4-RD patients. In a control cohort of 27 PSC patients from Oxford with elevated serum IgG4 (>1.4 g/L) and no histological evidence of IAC, the percentage of blue-collar workers was 22%. Among the PSC patients, 7% reported any (often incidental) exposure to these compounds. Our earlier finding of clonal expansions of IgG4-switched B cells in patients with IgG4-RD5 is compatible with the presence of an antigen-driven immune process in these individuals. Given our observed high rate of chronic occupational exposure of two independent cohorts of IgG4-RD patients suggests that chronic exposure to occupational antigens may play a role in the initiation and/or maintenance of IgG4-RD in susceptible individuals. Lucas J. Maillette de Buy Wenniger, M.D.1* Emma L. Culver, M.D.2* Ulrich Beuers, M.D.1 1Department of Gastroenterology and Hepatology Tytgat Institute for Liver and Intestinal Research Academic Medical Center, University of Amsterdam Amsterdam, The Netherlands 2Department of Gastroenterology and Hepatology Oxford University Oxford, UK