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. 2020 May;39(5):855-862.
doi: 10.1007/s10096-019-03807-5. Epub 2019 Dec 31.

Complement activation in individuals with previous subclinical Lyme borreliosis and patients with previous Lyme neuroborreliosis

Hanna Carlsson  1 , Kerstin Sandholm  2 , Haben Woldu Haddish  3 , Lars Brudin  4 , Kristina Nilsson Ekdahl  2   5 , Ivar Tjernberg  6
Affiliations

Complement activation in individuals with previous subclinical Lyme borreliosis and patients with previous Lyme neuroborreliosis

Hanna Carlsson et al. Eur J Clin Microbiol Infect Dis. 2020 May.

Abstract

Lyme borreliosis (LB) is caused by Borrelia burgdorferi and infection may lead to not only a large variety of clinical manifestations but also a subclinical outcome. The aim of the present study was to investigate if there is a constitutional difference in complement activation between individuals with previous subclinical Lyme borreliosis (SB) and patients previously diagnosed with Lyme neuroborreliosis (LNB).Lepirudin plasma for activation studies was collected from 60 SB individuals and from 22 patients pre-diagnosed with LNB. The plasma was incubated with live Borrelia spirochetes of two strains (complement sensitive B. garinii Lu59 and complement resistant B. afzelii ACA1).Complement factor C3 was measured in non-activated lepirudin plasma with immune-nephelometry and C3a and sC5b-9 generated during complement activation were measured by enzyme-linked immunosorbent assay.We found that the complement sensitive Lu59 induced higher complement activation than the complement resistant ACA1 when measuring activation products C3a and sC5b-9 in SB and LNB patients, p < 0.0001. No significant difference was found between SB and LNB patients in systemic levels of C3. Furthermore, SB individuals generated a higher activation of C3 cleavage to C3a (C3a/C3 ratio) than LNB patients after activation with ACA1, p < 0.001, but no significant differences were found in response to Lu59. In conclusion, Lu59 induced higher complement activation than ACA1 and individuals with previous SB showed increased generation of C3a compared with patients with previous LNB. In our study population, this mechanism could lead to less elimination of spirochetes in LNB patients and thereby be a factor contributing to the clinical outcome.

Keywords: C3a; Complement activation; Innate immune system; Lyme borreliosis; Lyme neuroborreliosis; Subclinical Lyme borreliosis.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Flow-chart of complement activation in lepirudin plasma with live Borrelia spirochetes and following determination of C3a and sC5b-9 with enzyme linked immunosorbent assay. We performed our complement activation experiments in duplicates. When determining C3a and sC5b-9, we ran each activation duplicate in duplicates. The average concentration of each complement marker minus the background were thereafter used in the statistical analysis. SB, subclinical individuals; LNB, Lyme neuroborreliosis patients; 0, negative/background control; lepirudin plasma without addition of spirochetes
Fig. 2
Fig. 2
Complement factor C3 in non-activated lepirudin plasma. No significant differences were observed in constitutionally expressed complement factor C3 between SB and LNB patients, p = 0.743. SB; subclinical individuals, LNB; Lyme neuroborreliosis patients
Fig. 3
Fig. 3
Complement activation in vitro in lepirudin plasma activated with Borrelia strain ACA1 and Lu59 from subclinical Lyme borreliosis individuals and patients with previous Lyme neuroborreliosis. Complement activation in lepirudin plasma activated with Borrelia strain ACA1 and Lu59 were assessed by measurement of generated C3a and sC5b-9 with ELISA. Sample data were normalized against lepirudin plasma run in parallel, but without addition of spirochetes in the activation step. Boxes represent minimum and maximum with line at median. a Generated C3a from SB (n = 60) and LNB patients (n = 22). b Generated sC5b-9 from SB (n = 59) and LNB patients (n = 22). SB, Subclinical individuals; LNB, Lyme neuroborreliosis. ****p < 0.0001
Fig. 4
Fig. 4
Complement activation in vitro monitored as the ratio of C3a to intact C3 in lepirudin plasma from subclinical Lyme borreliosis individuals and patients with previous Lyme neuroborreliosis. SB generated a higher C3a/C3 ratio in lepirudin plasma after activation with Borrelia strain ACA1, ***p < 0.001. SB, subclinical individuals; LNB; Lyme neuroborreliosis
Fig. 5
Fig. 5
Complement activation in vitro monitored as the ratio of C3a to intact C3 in lepirudin plasma from subclinical Lyme borreliosis individuals and patients with previous Lyme neuroborreliosis with or without concomitant Borrelia-specific antibodies in serum. SB generated higher C3a/C3 ratio after activation with Borrelia strain ACA1 than LNB patients with Borrelia-specific serum antibodies and without Borrelia-specific serum antibodies at the time of activation, *p = 0.03 and **p = 0.006 respectively. SB, subclinical individuals; LNB AB−, Lyme neuroborreliosis patients without Borrelia-specific serum antibodies at the time of study inclusion; LNB AB+, Lyme neuroborreliosis patients with Borrelia-specific serum antibodies at the time of study inclusion
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