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      Innate and Th1/Th17 adaptive immunity in acute and convalescent Brazilian borreliosis disease

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          Abstract

          Introduction

          Brazilian borreliosis (BB) disease is an infectious disease transmitted by ticks that mimics Lyme disease (LD) from the Northern Hemisphere. The BB clinical picture is characterized by a pathognomonic skin lesion (migratory erythema) and joint, neurological, cardiac and psychiatric symptoms. Innate and Th1/Th17 adaptive immunity seem to play an important role in the pathogenesis of Lyme disease.

          Objective

          The aim of this study was to characterize the role of innate and Th1/Th17 adaptive immunity in BB patients with acute (<3 months) and convalescent (>3 months) disease.

          Methods

          Fifty BB patients (28 with acute and 22 with convalescent disease) without treatment and 30 healthy subjects were evaluated. Levels of 20 cytokines or chemokines associated with innate and Th1/Th17 adaptive immunity were analyzed using Luminex (Millipore Corp., Billerica, MA).

          Results

          Overall, BB patients had increased levels of IL-8 (6.29 vs 2.12 p = 0.002) and MIP-1α/CCL3 (5.20 vs 2.06, p = 0.030), associated with innate immunity, and MIP3B/CCL19 (Th1; 297.86 vs 212.41, p = 0.031) and IL-17A (Th17; 3.11 vs 2.20, p = 0.037), associated with adaptive immunity, compared with the levels of healthy controls. When comparing acute BB vs. convalescent BB subjects vs. healthy controls, IL-1β, IL-8 and MIP-1α/CCL3 (innate mediators) levels were highest in patients in the acute phase of disease (p < 0.05). TNF-α was associated with disseminated symptoms and with humoral reactivity against Borrelia burgdorferi. IL-10 was significantly correlated with IL-6 (r = 0.59, p = 0.003), IL-8 (r = 0.51, p < 0.001), MIP-1α/CCL3 (r = 0.42, p < 0.001) and MIP-3β/CCL19 (r = 0.40, p = 0.002) in all BB patients.

          Conclusions

          This is the first study describing that innate and Th1/Th17 adaptive immunity play a crucial role in BB disease. Furthermore, innate mediators are particularly important in acute BB disease, and TNF-α is associated with evolution of BB symptoms.

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          Multisite comparison of high-sensitivity multiplex cytokine assays.

          Rose M. Reynolds, Persephone Borrow, Joseph Margolick … (2011)
          The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1β was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important.
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            Clinical practice. Lyme disease.

            Eugene D Shapiro (2014)
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              Borrelia burgdorferi RST1 (OspC type A) genotype is associated with greater inflammation and more severe Lyme disease.

              Klemen Strle, Kathryn Jones, Elise Drouin … (2011)
              Evidence is emerging for differential pathogenicity among Borrelia burgdorferi genotypes in the United States. By using two linked genotyping systems, ribosomal RNA intergenic spacer type (RST) and outer surface protein C (OspC), we studied the inflammatory potential of B. burgdorferi genotypes in cells and patients with erythema migrans or Lyme arthritis. When macrophages were stimulated with 10 isolates of each RST1, RST2, or RST3 strain, RST1 (OspC type A)-stimulated cells expressed significantly higher levels of IL-6, IL-8, chemokine ligand (CCL) 3, CCL4, tumor necrosis factor, and IL-1β, factors associated with innate immune responses. In peripheral blood mononuclear cells, RST1 strains again stimulated significantly higher levels of these mediators. Moreover, compared with RST2, RST1 isolates induced significantly more interferon (IFN)-α, IFN-γ, and CXCL10, which are needed for adaptive immune responses; however, OspC type I (RST3) approached RST1 (OspC type A) in stimulating these adaptive immune mediators. Similarly, serum samples from patients with erythema migrans who were infected with the RST1 genotype had significantly higher levels of almost all of these mediators, including exceptionally high levels of IFN-γ-inducible chemokines, CCL2, CXCL9, and CXCL10; and this pronounced inflammatory response was associated with more symptomatic infection. Differences among genotypes were not as great in patients with Lyme arthritis, but those infected with RST1 strains more often had antibiotic-refractory arthritis. Thus, the B. burgdorferi RST1 (OspC type A) genotype, followed by the RST3 (OspC type I) genotype, causes greater inflammation and more severe disease, establishing a link between spirochetal virulence and host inflammation. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Virginia Lucia Nazario Bonoldi
                Journal
                Journal ID (nlm-ta): Braz J Infect Dis
                Journal ID (iso-abbrev): Braz J Infect Dis
                Title: The Brazilian Journal of Infectious Diseases
                Publisher: Elsevier
                ISSN (Print): 1413-8670
                ISSN (Electronic): 1678-4391
                Publication date PMC-release: 10 April 2021
                Publication date Collection: Mar-Apr 2021
                Publication date (Electronic): 10 April 2021
                Volume: 25
                Issue: 2
                Electronic Location Identifier: 101575
                Affiliations
                [a ]Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
                [b ]Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brazil
                [c ]Instituto Butantan, São Paulo, SP, Brazil
                Author notes
                [* ] Corresponding author at: Virginia Lucia Nazario Bonoldi, Faculdade de Medicina da Universidade de São Paulo, Av. Doutor Arnaldo, 455 sala 3143, CEP: 01246-903, São Paulo, SP, Brazil. virginia.bonoldi@ 123456hc.fm.usp.br
                Article
                Publisher Item ID: S1413-8670(21)00044-1 Publisher ID: 101575
                DOI: 10.1016/j.bjid.2021.101575
                PMC ID: 9392183
                PubMed ID: 33848504
                SO-VID: 698e6ea4-a18e-4741-9884-9a926152b505
                Copyright © © 2021 Published by Elsevier España, S.L.U. on behalf of Sociedade Brasileira de Infectologia.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 23 September 2020
                Date accepted : 27 March 2021
                Categories
                Subject: Original Article

                Keywords: brazilian borreliosis,th1,th17,inflammatory cytokines,inflammatory chemokines,tnf-α
                Data availability:
                Keywords: brazilian borreliosis, th1, th17, inflammatory cytokines, inflammatory chemokines, tnf-α

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