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.