Background/Purpose

Lyme disease usually begins with an expanding skin lesion, erythema migrans (EM), whereas arthritis is a late disease manifestation. The infection usually resolves with appropriate antibiotic therapy, but post-infectious symptoms following EM or persistent synovitis despite antibiotic therapy (antibiotic-refractory arthritis) may occur. Control of the infection in humans is attributed predominantly to innate and adaptive T_H1 immune responses, whereas the role of T_H17 responses is not yet well characterized. We recently showed that high levels of IL-23, a T_H17-associated cytokine, occur in a subset of European patients with EM, and are associated with more frequent post-infectious symptoms and autoantibody responses. Here, we characterized these responses in a large cohort of American patients with EM or Lyme arthritis to elucidate the role of T_H17-mediated immunity throughout the infection.

Methods

The levels of 20 cytokines and chemokines, representative of innate and adaptive T_H1 and T_H17 immune responses, were assessed by Luminex in matched acute and convalescent serum samples from 106 culture-positive patients with EM, in matched serum and synovial fluid (SF) samples from 159 patients with antibiotic-responsive or antibiotic-refractory arthritis, and in serum samples from 57 healthy control subjects.

Results

Compared with healthy subjects, acute-phase sera from EM patients contained significantly higher levels of the T_H17-associated mediators (IL-6, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25 and IL-27; P≤0.01). With the exception of IL-27, which down-regulates T_H17 responses, the levels of other T_H17-associated mediators remained elevated in convalescent sera obtained at the conclusion of antibiotic therapy. The levels of IL-23, the most highly induced T_H17 cytokine, correlated directly with antibody levels to the B. burgdorferi VlsE antigen (P=0.04) in both acute and convalescent samples, suggesting a role for T_H17-associated mediators in control of the infection. In patients with Lyme arthritis, the serum levels of IL-23 and other T_H17-associated mediators were generally lower than in patients with EM, and the levels of these mediators were only minimally concentrated, if at all, in SF. In contrast, innate (IL-8) and T_H1 mediators (CXCL9 and CXCL10) were >50-fold higher in SF than in serum. Compared with antibiotic-responsive patients, there was a trend toward higher levels of most of the T_H17-associated mediators, particularly IL-23, in SF in patients with antibiotic-refractory arthritis, and toward a greater frequency of autoantibody responses to human endothelial cell growth factor, the first known target of T and B cell responses in this disease. 

Conclusion

A subset of patients with Lyme disease develops T_H17 immune responses. T_H17-associated mediators seem to be highest early in the infection and may play a role in control of the infection. In addition, T_H17 mediators may be one factor in shaping an immune response early in the illness in which autoantibody responses are more common, thereby contributing to subsequent antibiotic refractory Lyme arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/th17-inflammatory-responses-occur-in-a-subset-of-patients-with-erythema-migrans-or-lyme-arthritis-but-are-not-predominant-responses-in-joints/