Comment; This article reviews the search for various biomarkers associated with acute Lyme, unfortunately, it does not conclusively find anything. Immunologic markers of the reaction to Lyme disease have many false negatives complicating the diagnosis of this complex, illness with many confusing presentations.
Mark J. Soloski, 1 , * Lauren A. Crowder, 4 Lauren J. Lahey, 3 Catriona A. Wagner, 3 William H. Robinson,# 3 andJohn N. Aucott# 2 , *Eui-Cheol Shin, EditorAuthor informationArticle notesCopyright and License informationDisclaimerThis article has been cited by other articles in PMC.
Associated Data
Abstract
Chemokines and cytokines are key signaling molecules that orchestrate the trafficking of immune cells, direct them to sites of tissue injury and inflammation and modulate their states of activation and effector cell function. We have measured, using a multiplex-based approach, the levels of 58 immune mediators and 7 acute phase markers in sera derived from of a cohort of patients diagnosed with acute Lyme disease and matched controls. This analysis identified a cytokine signature associated with the early stages of infection and allowed us to identify two subsets (mediator-high and mediator-low) of acute Lyme patients with distinct cytokine signatures that also differed significantly (p<0.0005) in symptom presentation. In particular, the T cell chemokines CXCL9 (MIG), CXCL10 (IP-10) and CCL19 (MIP3B) were coordinately increased in the mediator-high group and levels of these chemokines could be associated with seroconversion status and elevated liver function tests (p = 0.027 and p = 0.021 respectively). There was also upregulation of acute phase proteins including CRP and serum amyloid A. Consistent with the role of CXCL9/CXCL10 in attracting immune cells to the site of infection, CXCR3+ CD4 T cells are reduced in the blood of early acute Lyme disease (p = 0.01) and the decrease correlates with chemokine levels (p = 0.0375). The levels of CXCL9/10 did not relate to the size or number of skin lesions but elevated levels of serum CXCL9/CXCL10 were associated with elevated liver enzymes levels. Collectively these results indicate that the levels of serum chemokines and the levels of expression of their respective chemokine receptors on T cell subsets may prove to be informative biomarkers for Lyme disease and related to specific disease manifestations.Go to:
Introduction
Lyme disease is the most frequently reported vector-borne disease in the United States, with approximately 30,000 cases reported to the CDC in 2012 [1]. The average annual rate in 2003–2005 (29.2 cases per 100,000 population) was approximately three times the Healthy People 2010 target of 9.7 new cases per 100,000 [2], [3]. Reports likely underestimate the incidence of Lyme disease and it has been suggested that there are up to 10 times more cases than those reported to the CDC [4], [5]. The rising incidence of Lyme disease demands a more complete understanding of the disease process and particularly the disease mechanisms underlying long term outcomes of Borrelia burgdorferi infection such as Post-Treatment Lyme disease Syndrome (PTLDS) [6].
Lyme disease is an inflammatory disease initiated by infection with B. burgdorferi following a bite from an infected tick [7]. Symptoms of early acute Lyme disease can include erythema migrans (EM) with or without systemic symptoms such as fever, chills and malaise. Signs of disseminated infection may occur early or late in the disease process and can involve the skin, musculoskeletal and nervous system [8]. Pathology of EM skin lesions shows a mononuclear cell infiltrate of lymphocytes, plasma cells, and macrophages [9], [10]. Although patients will resolve the EM with or without antibiotic therapy, as the early immune response develops in response to the infection, a significant fraction of patients who receive antibiotics early in infection do not develop detectable antibodies on convalescent testing [11], [12]. In the absence of early antibiotic treatment, the host immune response does not completely eradicate the infection and a significant fraction of patients develop late-onset arthritis [7]. While the infection and late-onset arthritis can largely be controlled by antibiotic therapy, in a subset of patients, Lyme arthritis with inflammation is antibiotic-refractory, persisting up to 12 months or more. An ongoing pathologic host immune response is thought to be the primary etiology in those with persistent arthritis [13]. Circulating inflammatory markers that may be associated with this secondary complication have not been identified.
To study the immunological processes that are initiated following B. burgdorferi infection, we have utilized samples generated from a large cohort of Lyme disease patients that have been followed longitudinally for two years from the time of diagnosis and treatment. In this report, we measured the levels of a comprehensive panel of cytokines and chemokines to identify inflammatory mediators associated with acute Lyme disease as well as long-term outcomes of B. burgdorferi infection. Interestingly, mediator levels allow us to distinguish two populations of Lyme disease patients that display significant differences in the number of disease symptoms, seroconversion rates, lymphopenia and serum liver enzyme levels. Several T cell chemokines were coordinately upregulated while chemokines that drive other immune cell types were not. This work suggests that the complexity and levels of mediators present in the serum may be informative in understanding the various pathophysiological outcomes that occur in acute B. burgdorferiinfection and that are associated with subsequent development of PTLDS.
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