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CCL19 as a Chemokine Risk Factor for Posttreatment Lyme Disease

ABSTRACT: Approximately 10% to 20% of patients optimally treated for early Lyme disease develop persistent symptoms of unknown pathophysiology termed posttreatment Lyme disease syndrome (PTLDS). The objective of this study was to investigate associations between PTLDS and immune mediator levels during acute illness and at several time points following treatment. Seventy-six participants with physician-documented erythema migrans and 26 healthy controls with no history of Lyme disease were enrolled. Sixty-four cytokines, chemokines, and inflammatory markers were measured at each visit for a total of 6 visits over 1 year. An operationalized definition of PTLDS incorporating symptoms and functional impact was applied at 6 months and 1 year following treatment completion, and clinical outcome groups were defined as the return-to-health, symptoms-only, and PTLDS groups. Significance analysis of microarrays identified 7 of the 64 immune mediators to be differentially regulated by group. Generalized logit regressions controlling for potential confounders identified posttreatment levels of the T-cell chemokine CCL19 to be independently associated with clinical outcome group. Receiver operating characteristic analysis identified a CCL19 cutoff of >111.67 pg/ml at 1 month following treatment completion to be 82% sensitive and 83% specific for later PTLDS. We speculate that persistently elevated CCL19 levels among participants with PTLDS may reflect ongoing, immune-driven reactions at sites distal to secondary lymphoid tissue. Our findings suggest the relevance of CCL19 both during acute infection and as an immunologic risk factor for PTLDS during the posttreatment phase. Identification of a potential biomarker predictor for PTLDS provides the opportunity to better understand its pathophysiology and to develop early interventions in the context of appropriate and specific clinical information.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE84479 | GEO | 2016/07/20

SECONDARY ACCESSION(S): PRJNA329638

REPOSITORIES: GEO

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Project description: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. A total of 65 immune and inflammatory mediators were profiled in serum samples derived from early Lyme disease patients and age- and sex-matched controls. These samples have been generated as part of a prospective cohort study that includes a well-defined cohort of patients with acute Lyme disease enrolled from a Lyme endemic area of the mid-Atlantic United States. Only patients with untreated, confirmed early Lyme disease manifesting an active EM skin lesion at the time of enrollment, as defined by CDC case criteria are eligible. Patients with a history of prior Lyme disease or the presence of confounding preexisting medical conditions associated with prolonged fatigue, pain or neurocognitive symptoms are excluded. Controls are nonhospitalized age- and sex-matched and have no prior history of Lyme disease or any exclusionary medical conditions including lack of inflammatory disorders.

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CCL19 as a Chemokine Risk Factor for Posttreatment Lyme Disease

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