Characterization of pathological IgE-mediated mast cell activation in Lyme disease

Abstract

Lyme disease, caused by the bacteria Borrelia burgdorferi, is the most common and rapidly growing vector-borne infectious disease in the United States and Europe. High variability in disease burden among Lyme patients suggests that individual immune responses may be key drivers of clinical presentation and patient outcomes. Use of high resolution flow-based immunosorbent profiling revealed that a subset of Lyme patients with persistent symptoms were producing high concentrations of IgE specific to B. burgdorferi. Comparing C57B/6 mice, which are tolerant to B. burgdorferi, and C3H/HeJ mice, which are susceptible to disease, we find high levels of IgE specific for B. burgdorferi in C3H/HeJ but not C57B/6 mice. Furthermore, IgE was found to target Borrelia peptidoglycan in both acute and chronic infection models. Histologic analysis of mouse Lyme arthritic ankle tissue showed mast cells, which release highly immunogenic effectors upon activation by bound IgE, degranulating at significantly higher rates compared to uninfected controls. Forced mast cell degranulation exacerbated Lyme arthritis in infected mice. This data suggests that a subset of Lyme patients with persistent symptoms may have developed an allergic response to conserved bacterial antigens from a B. burgdorferi infection, as opposed to an autoimmune type response. Inclusion of IgE reactivity in diagnostic testing and examination of pathological immune responses to bacterial antigens could assist clinicians in patient care and effective treatments. Research reported in this publication was supported by the Fairbairn family foundation; Bay Area Lyme Foundation; the Younger family foundation; the Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation; the Virginia and D. K. Ludwig Fund for Cancer Research; M.C.T. was supported by Stanford Immunology training grant 5T32AI007290, and the NIH NRSA 1 F32 AI124558-01 award. L.B.T.D. was supported by a Stanford Diversifying Academia Recruiting Excellence fellowship. S.D.G was supported by the California Institute for Regenerative Medicine Bridges 2.0 Training Program grant EDUC2-08397. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.