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. 2017 Apr 1;64(7):930-938.
doi: 10.1093/cid/cix002.

T-Helper 17 Cell Cytokine Responses in Lyme Disease Correlate With Borrelia Burgdorferi Antibodies During Early Infection and With Autoantibodies Late in the Illness in Patients With Antibiotic-Refractory Lyme Arthritis

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Free PMC article

T-Helper 17 Cell Cytokine Responses in Lyme Disease Correlate With Borrelia Burgdorferi Antibodies During Early Infection and With Autoantibodies Late in the Illness in Patients With Antibiotic-Refractory Lyme Arthritis

Klemen Strle et al. Clin Infect Dis. .
Free PMC article

Abstract

Background: Control of Lyme disease is attributed predominantly to innate and adaptive T-helper 1 cell (TH1) immune responses, whereas the role of T-helper 17 cell (TH17) responses is less clear. Here we characterized these inflammatory responses in patients with erythema migrans (EM) or Lyme arthritis (LA) to elucidate their role early and late in the infection.

Methods: Levels of 21 cytokines and chemokines, representative of innate, TH1, and TH17 immune responses, were assessed by Luminex in acute and convalescent sera from 91 EM patients, in serum and synovial fluid from 141 LA patients, and in serum from 57 healthy subjects. Antibodies to Borrelia burgdorferi or autoantigens were measured by enzyme-linked immunosorbent assay.

Results: Compared with healthy subjects, EM patients had significantly higher levels of innate, TH1, and TH17-associated mediators (P ≤ .05) in serum. In these patients, the levels of inflammatory mediators, particularly TH17-associated cytokines, correlated directly with B. burgdorferi immunoglobulin G antibodies (P ≤ .02), suggesting a beneficial role for these responses in control of early infection. Late in the disease, in patients with LA, innate and TH1-associated mediators were often >10-fold higher in synovial fluid than serum. In contrast, the levels of TH17-associated mediators were more variable, but correlated strongly with autoantibodies to endothelial cell growth factor, matrix metalloproteinase 10, and apolipoprotein B-100 in joints of patients with antibiotic-refractory LA, implying a shift in TH17 responses toward an autoimmune phenotype.

Conclusions: Patients with Lyme disease often develop pronounced TH17 immune responses that may help control early infection. However, late in the disease, excessive TH17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory LA.

Keywords: Lyme arthritis; Lyme disease; TH17; antibodies; erythema migrans.

Figures

Figure 1.
Figure 1.
Cytokine and chemokine levels in acute and convalescent serum samples from patients with erythema migrans (EM). Protein levels of 21 mediators associated with innate, T-helper 1 cell (TH1), or T-helper 17 cell (TH17) immune responses were assessed in 91 culture-positive patients with EM using bead-based Luminex assays. A, Comparison of cytokine and chemokine levels in matched acute and convalescent serum samples from patients with EM or in healthy controls. Black bars represent acute serum samples obtained prior to antibiotic therapy, a period of active infection. Gray bars represent convalescent samples obtained at the conclusion of antibiotic therapy, approximately 3 weeks after study entry. White bars represent values in healthy controls. The bars represent the mean values and I-bars represent the standard error of the mean. P values for comparison of acute and convalescent samples are indicated above the bars; P values for comparison with healthy controls are indicated by an asterisk (*P ≤ .05, **P ≤ .01, ***P ≤ .001). B, Cytokine and chemokine values in EM patients stratified according to the presence of symptoms: patients with no associated symptoms (n = 21, white box plots), 1–5 symptoms (n = 29, light gray box plots), or 6–20 symptoms (n = 41, dark-gray box plots) at first visit. The box represents 25th–75th percentiles, the line inside the box represents the median value, and I-bars represent the 10th–90th percentiles. P values for comparison of patients with 1–5 symptoms vs 6–12 symptoms are indicated above the box plots; P values for comparison of patients with 1–5 symptoms or 6–20 symptoms to those with no symptoms are indicated by an asterisk (*P ≤ .05, **P ≤ .01, ***P ≤ .001). Abbreviations: EM, erythema migrans; IFN, interferon; IL, interleukin; TH1, T-helper cell 1; TH17, T-helper cell 17; TNF, tumor necrosis factor.
Figure 2.
Figure 2.
Cytokine and chemokine levels in patients with Lyme arthritis (LA). Protein levels of 21 mediators associated with innate, T-helper 1 cell (TH1), or T-helper 17 cell (TH17) immune responses were assessed in serum and synovial fluid from 141 patients with LA using bead-based Luminex assays. A, Comparison of cytokine and chemokine values in serum or synovial fluid samples from patients with LA or in healthy controls. Black bars represent synovial fluid samples, gray bars represent serum samples, and white bars represent values in healthy subjects. The bars represent the mean values and I-bars represent the standard error of the mean. P values for comparison of synovial fluid and serum are indicated above the bars; P values for comparison with healthy controls are indicated by an asterisk (*P ≤ .05, **P ≤ .01, ***P ≤ .001). B, Cytokine and chemokine values in serum (upper panel) or synovial fluid (lower panel) in LA patients stratified according to antibiotic-responsive (white box plots, n = 60) or antibiotic-refractory (gray box plots, n = 81) course. The box represents the 25th–75th percentiles, the line inside the box represents median values, and I-bars represent the 10th–90th percentiles. Because of the large range in interferon-γ and interleukin 23 levels, the highest values for these mediators may be listed in parentheses above the graphs. P values for comparison of patients with antibiotic-responsive or refractory LA are indicated by an asterisk (*P ≤ .05, **P ≤ .01). Abbreviations: IFN, interferon; IL, interleukin; LA, Lyme arthritis; TH1, T-helper cell 1; TH17, T-helper cell 17; TNF, tumor necrosis factor.

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