Researchers have identified a distinct set of anti-lipid antibodies that could improve the early diagnosis of Lyme disease while also helping distinguish patients who develop persistent symptoms after treatment from those who recover fully.
The study, published in Infection and Immunity, found that antibodies against specific phospholipids appear before conventional Lyme disease antibodies in some patients and persist in a subset of individuals with post-treatment Lyme disease (PTLD). The findings suggest these immune markers could eventually complement existing diagnostic tests and provide new clues about the biology underlying chronic symptoms.
Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne infection in North America and Europe. Although most patients respond well to a two- to three-week course of antibiotics, an estimated 10% to 20% continue to experience fatigue, pain, cognitive impairment, and other nonspecific symptoms long after treatment. The biological basis for these persistent symptoms remains poorly understood, and clinicians currently lack objective biomarkers to identify affected patients.
Current diagnostic testing also has significant limitations. Standard two-tier serologic testing relies on antibodies directed against Borrelia proteins, but these antibodies often do not appear until several weeks after infection and can remain detectable long after the bacteria have been eliminated. As a result, existing tests have limited sensitivity during early infection and cannot reliably distinguish active infection from previous exposure or persistent post-treatment illness.
The new study builds on earlier work showing that B. burgdorferi scavenges lipids from its human host and incorporates them into its outer membrane. The researchers hypothesized that this unusual biology could trigger immune responses against host lipids that might serve as biomarkers of disease activity.
To test that idea, investigators analyzed serum samples from patients with acute Lyme disease and PTLD collected from two independent biobanks. Together, the cross-sectional and longitudinal cohorts allowed researchers to follow antibody responses from the day of diagnosis through one year after treatment.
Among numerous lipid targets examined, only three antiphospholipid antibodies were consistently elevated following infection. Two antibodies—anti-phosphatidic acid (αPA) and anti-phosphatidylserine (αPS)—were significantly elevated at diagnosis, including in patients with erythema migrans before they had seroconverted on conventional Lyme disease testing.
Longitudinal analyses showed that antibody levels followed distinct patterns over time. Both αPA and αPS peaked approximately three to six months after diagnosis before declining in most patients. However, αPS remained persistently elevated in a subset of individuals with PTLD, distinguishing them from healthy controls and from patients with autoimmune and chronic illnesses that often resemble post-treatment Lyme disease, including systemic lupus erythematosus, multiple sclerosis, fibromyalgia, long COVID, and chronic fatigue syndrome.
The researchers propose that persistent αPS elevations may reflect an abnormal immune response rather than ongoing infection. While the precise mechanism remains unknown, they suggest that dysregulated activation of innate-like B cells or continued exposure to phosphatidylserine antigens could sustain antibody production in susceptible individuals.
Importantly, the authors note that whether these antibodies actively contribute to disease or simply mark immune dysfunction remains uncertain. “The presence of autoantibodies does not always drive autoimmune disease,” the authors write, emphasizing that further mechanistic studies are needed.
The investigators also draw parallels with syphilis, another spirochete infection. In syphilis, lipid-directed antibody tests are routinely used alongside pathogen-specific assays to monitor disease activity and treatment response. The authors suggest a similar strategy could eventually enhance Lyme disease diagnostics.
“The addition of antilipid antibodies to these panels may improve sensitivity while retaining the more specific diagnostic antibodies,” the authors write. They note that anti-lipid antibodies could potentially function both as adjuncts for early diagnosis and as biomarkers for monitoring recovery following treatment.
The study has several limitations, including relatively modest sample sizes and the use of specimens collected from multiple biobanks with differing collection protocols. Nevertheless, the consistency of findings across independent cohorts strengthens confidence in the observations.
Ultimately, the authors conclude that “the antibodies described here may be valuable biomarkers of early or persistent disease and suggest another mechanism linking B. burgdorferi infection and pathologic autoimmunity.” Larger prospective studies will be needed to determine whether these antibodies can be incorporated into clinical practice for diagnosing Lyme disease or identifying patients at risk for persistent symptoms.
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