Summary
Lyme disease (Borrelia burgdorferi infection) is increasingly recognized as a significant worldwide illness. This study provides insights into important immune mechanisms involved in Borrelia burgdorferi clearance in human Lyme disease. By studying B cell subsets in blood, robust plasmablast levels are found to predict more rapid resolution of clinical symptoms whereas poor plasmablast responses are associated with a longer duration of symptoms in Lyme disease patients following doxycycline treatment. Plasmablasts are cells that lead to antibody production, and a strong plasmablast response is shown to produce antibodies that inhibit Borrelia burgdorferi growth. These Bb-inhibiting antibodies could provide the basis for next-generation diagnostics and therapeutics for Lyme disease.
Why was the study done?
Many Lyme disease patients suffer from significant ongoing severe pain, fatigue, musculoskeletal pain, sleep disturbance, heart, and cognitive problems. This study was done to provide insights into biologic mechanisms driving the resolution of clinical symptoms and determine if B cell immune responses to Borrelia burgdorferi correlated with variable outcomes following treatment with doxycycline. Improving the understanding of human immune responses can help inform new approaches to improved diagnostics and treatments for Lyme disease.
How was the study done?
Utilizing advanced immune profiling the study examined B cell responses to Borrelia burgdorferi infection, including how responses change over time following doxycycline treatment and vary among different clinical subsets of well characterized Lyme disease patients. Peripheral blood mononuclear cells (PBMCs) from Bb-infected patients were analyzed over a range of time points spanning the initial (untreated) visit through 2 years following treatment. PBMCs were also collected from healthy controls in the same geographic region (the Mid-Atlantic United States). The prevalence and characterization of B cells were assessed using flow cytometry and antibody repertoire sequencing including single-cell plasmablast antibody sequencing as well as unique molecular identifier (UMI) barcode-based bulk heavy-chain sequencing.
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What were the major findings?
The study found robust B cell plasmablast responses that encode Bb-inhibiting antibodies were associated with faster resolution of symptoms following Lyme disease treatment, and poor plasmablast responses were associated with a longer symptom duration.
Recombinantly expressed antibodies from expanded lineages of these Bb-inhibiting antibodies were found to bind Bb antigens, confirming that these clones were driven by the infection. Furthermore, recombinantly expressed antibodies were shown to inhibit Bb growth in vitro.
What is the impact of this work?
Presently, immune mechanisms for human Lyme disease recovery are not well understood and biomarkers to measure treatment success are lacking in Lyme disease patient care. This study provides insight into an important immune mechanism of Bb clearance and identifies a potential biomarker associated with return to health following treatment for Bb infection. The study shows that in patients who lack a strong B cell response, doxycycline treatment alone does not ensure full resolution of symptoms. Robust plasmablast responses that encode Bb-inhibiting antibodies are shown to be associated with more rapid resolution of Lyme disease and could provide the basis for next-generation diagnostics and therapeutics for Lyme disease.
Who did this study?
Johns Hopkins, Stanford