Plain language summary
Borrelia burgdorferi (BD) specific Immunoglobulin (Ig) antibodies are a diagnostic key for infection and Lyme’s disease. Generally, IgM is reflective of recent infection and converts to IgG after several weeks during disease progression or inadequate treatment. Yet, in the early phase of infection, not all cases present with antibodies and at the same time, both IgM and IgG can persist in healthy people after tick exposure or treatment. This study sought to investigate further the common phenomenon of persistence of IgM, regardless of symptomatic BD infection. The study examined the serum of 59 predominantly female patients, that showed persistent IgM antibodies in the absence of IgG. The majority of subjects experienced non-specific symptoms, and half of them had a history of antibiotic treatment, yet IgM persisted. The observation went on for >6 months, thus excluding the likelihood of any acute infection. The results showed that in people with lower IgM count a greater improvement of non-specific symptoms was observed as opposed to those with higher IgM count. Furthermore, the assay identified multiple cross-reactivity patterns from other plants, bacteria and human tissue to the antigen-binding receptor OspC typically used for BD testing. The authors postulate that the phenomena of IgM persistence potentially originates from a previous infection with BD, but may be maintained in some individuals by continuous stimulation with cross-reactive antigens from other sources. This is important knowledge for the interpretation and improvement of testing for BD. Of clinical interest here is that IgM persistence, beyond the acute phase, maybe no longer be reflective of the original BD infection. And in such cases, non-specific symptoms may be sustained by other triggers such as foods, other microorganisms and autoimmunity.
Abstract
The aim of the study was to investigate the etiology of persistent IgM antibodies against Borrelia burgdorferi sensu lato (sl) and to analyze their association with nonspecific symptoms. The study group comprised individuals with persistent IgM antibodies in the absence of IgG. The relation between ELISA values and time elapsed since past erythema migrans (EM) was analyzed. Previous antibiotic treatments were assessed. The association between persistent IgM and nonspecific symptoms was evaluated statistically. Specificity of IgM antibodies for outer surface protein C (OspC) of B. burgdorferi sl was examined by immunoblotting. Further, we investigated the cross-reactivity with Borrelia-unrelated proteins. Fifty-nine patients (46 women; 78%) were included in the study group. The mean IgM-ELISA values did not change significantly during follow-up (median 6.2 months). The mean ELISA value in the study group was dependent on time elapsed since past EM. Nonspecific symptoms improved significantly more often in patients with lower IgM ELISA results. Persistent IgM antibodies were specific for the C-terminal PKKP motif of OspC. Cross-reacting C-terminal PKKP antigens from both human and prokaryotic origins were identified. We demonstrate that the C-terminal PKKP motif plays a main role for the reactivity of persistent Borrelia IgM toward OspC. However, cross-reactivity to other eukaryotic and/or prokaryotic antigens may hamper the specificity of OspC in the serological diagnosis of Lyme borreliosis. Lack of improvement of nonspecific symptoms was associated with higher IgM ELISA values. IMPORTANCE The reactivity of human IgM with the outer surface protein C (OspC) of Borrelia burgdorferi sensu lato is frequently used to detect Borrelia specific IgM in commercial immunoassays, and such antibodies usually occur in the early phase of the infection. We identified a group of individuals with persistent Borrelia IgM without symptoms of Lyme borreliosis. We used their sera to demonstrate that the C-terminal epitope of OspC binds the IgM. Strikingly, we found that the same epitope occurs also in certain proteins of human and environmental origin; the latter include other bacteria and food plants. Our experimental data show that these Borrelia-unrelated proteins cross-react with the OpsC-specific IgM. This knowledge is important for the development of serologic assays for Lyme borreliosis and provides a cross-reactive explanation for the persistence of Borrelia-IgM.
Methodological quality
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