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      Borrelia burgdorferi-specific IgA in Lyme Disease

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          Abstract

          The laboratory diagnosis of Lyme disease is currently dependent on the detection of IgM and IgG antibodies against Borrelia burgdorferi, the causative agent of the disease. The significance of serum IgA against B. burgdorferi remains unclear. The production of intrathecal IgA has been noted in patients with the late Lyme disease manifestation, neuroborreliosis, but production of antigen-specific IgA during early disease has not been evaluated. In the current study, we assessed serum IgA binding to the B. burgdorferi peptide antigens, C6, the target of the FDA-cleared C6 EIA, and FlaB(211-223)-modVlsE(275-291), a peptide containing a Borrelia flagellin epitope linked to a modified VlsE sequence, in patients with early and late Lyme disease. Specific IgA was detected in 59 of 152 serum samples (38.8%) from early Lyme disease patients. Approximately 50% of early Lyme disease patients who were seropositive for peptide-specific IgM and/or IgG were also seropositive for peptide-specific IgA. In a subpopulation of patients, high peptide-specific IgA could be correlated with disseminated disease, defined as multiple erythema migrans lesions, and neurological disease complications. These results suggest that there may be an association between elevated levels of antigen-specific IgA and particular disease manifestations in some patients with early Lyme disease.

          Highlights

          • Approximately one-third of all patients diagnosed with early Lyme disease have significant levels of antigen-specific IgA

          • Approximately one-half of patients seropositive for IgM and/or IgG are also seropositive for IgA

          • Antigen-specific IgA correlated with disseminated disease and neurological symptoms in patients with early Lyme disease

          The significance of serum IgA production in patients with early Lyme disease has not been previously evaluated. In the present study, we demonstrated that IgA antibodies against Borrelia burgdorferi, the causative agent of Lyme disease, were present in ~ 33% of patients diagnosed with early disease. Anti- B. burgdorferi IgA production correlated with disseminated disease as well as neurological manifestations in a subset of these patients. Though further study is necessary, these results suggest that monitoring serum IgA could have potential diagnostic and/or prognostic value in early Lyme disease.

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          Most cited references29

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          Diagnosis of lyme borreliosis.

          A large amount of knowledge has been acquired since the original descriptions of Lyme borreliosis (LB) and of its causative agent, Borrelia burgdorferi sensu stricto. The complexity of the organism and the variations in the clinical manifestations of LB caused by the different B. burgdorferi sensu lato species were not then anticipated. Considerable improvement has been achieved in detection of B. burgdorferi sensu lato by culture, particularly of blood specimens during early stages of disease. Culturing plasma and increasing the volume of material cultured have accomplished this. Further improvements might be obtained if molecular methods are used for detection of growth in culture and if culture methods are automated. Unfortunately, culture is insensitive in extracutaneous manifestations of LB. PCR and culture have high sensitivity on skin samples of patients with EM whose diagnosis is based mostly on clinical recognition of the lesion. PCR on material obtained from extracutaneous sites is in general of low sensitivity, with the exception of synovial fluid. PCR on synovial fluid has shown a sensitivity of up to >90% (when using four different primer sets) in patients with untreated or partially treated Lyme arthritis, making it a helpful confirmatory test in these patients. Currently, the best use of PCR is for confirmation of the clinical diagnosis of suspected Lyme arthritis in patients who are IgG immunoblot positive. PCR should not be used as the sole laboratory modality to support a clinical diagnosis of extracutaneous LB. PCR positivity in seronegative patients suspected of having late manifestations of LB most likely represents a false-positive result. Because of difficulties in direct methods of detection, laboratory tests currently in use are mainly those detecting antibodies to B. burgdorferi sensu lato. Tests used to detect antibodies to B. burgdorferi sensu lato have evolved from the initial formats as more knowledge on the immunodominant antigens has been collected. The recommendation for two-tier testing was an attempt to standardize testing and improve specificity in the United States. First-tier assays using whole-cell sonicates of B. burgdorferi sensu lato need to be standardized in terms of antigen composition and detection threshold of specific immunoglobulin classes. The search for improved serologic tests has stimulated the development of recombinant protein antigens and the synthesis of specific peptides from immunodominant antigens. The use of these materials alone or in combination as the source of antigen in a single-tier immunoassay may someday replace the currently recommended two-tier testing strategy. Evaluation of these assays is currently being done, and there is evidence that certain of these antigens may be broadly cross-reactive with the B. burgdorferi sensu lato species causing LB in Europe.
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            Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group.

            The risk of acquiring Lyme disease is high in areas in which the disease is endemic, and the development of a safe and effective vaccine is therefore important. We conducted a multicenter, double-blind, randomized trial involving 10,936 subjects who lived in areas of the United States in which Lyme disease is endemic. Participants received an injection of either recombinant Borrelia burgdorferi outer-surface lipoprotein A (OspA) with adjuvant or placebo at enrollment and 1 and 12 months later. In cases of suspected Lyme disease, culture of skin lesions, polymerase-chain-reaction testing, or serologic testing was done. Serologic testing was performed 12 and 20 months after study entry to detect asymptomatic infections. In the first year, after two injections, 22 subjects in the vaccine group and 43 in the placebo group contracted definite Lyme disease (P=0.009); vaccine efficacy was 49 percent (95 percent confidence interval, 15 to 69 percent). In the second year, after the third injection, 16 vaccine recipients and 66 placebo recipients contracted definite Lyme disease (P<0.001); vaccine efficacy was 76 percent (95 percent confidence interval, 58 to 86 percent). The efficacy of the vaccine in preventing asymptomatic infection was 83 percent in the first year and 100 percent in the second year. Injection of the vaccine was associated with mild-to-moderate local or systemic reactions lasting a median of three days. Three injections of vaccine prevented most definite cases of Lyme disease or asymptomatic B. burgdorferi infection.
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              Cerebrospinal fluid--physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases.

              The state of the art in routine CSF analysis is reviewed with particular reference to multiple sclerosis regarding: (1) The physiology and pathophysiology of blood-CSF barrier function and dysfunction with the CSF flow rate as main modulator of blood- and brain-derived protein concentrations in CSF; (2) The neuroimmunological aspects regarding (a) patterns of disease-related immunoglobulin class response (IgG, IgA, IgM) in actual Reiber graphs with reference to specific parameters and optional tests, and (b) the oligoclonal, polyspecific antibody synthesis in brain; (3) Particular marker proteins in CSF and blood for differential diagnosis of neurological diseases; (4) Mathematical base for evaluations of CSF data with an example of a multiple sclerosis patient for calculation of intrathecal immunoglobulin and antibody synthesis as well as Antibody Index.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                21 April 2017
                May 2017
                21 April 2017
                : 19
                : 91-97
                Affiliations
                [a ]Department of Microbiology and Immunology, School of Medicine, New York Medical College, Valhalla, NY 10595, United States
                [b ]Biopeptides, Corp., East Setauket, NY 11733, United States
                Author notes
                [* ]Corresponding author at: Department of Microbiology and Immunology, New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY 12563, United States.Department of Microbiology and ImmunologyNew York Medical College40 Sunshine Cottage RoadValhallaNY12563United States paul_arnaboldi@ 123456nymc.edu
                Article
                S2352-3964(17)30180-9
                10.1016/j.ebiom.2017.04.025
                5440658
                28457619
                1c6063af-1aca-4d14-9b49-6c5404250e4e
                © 2017 The Authors

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

                History
                : 17 February 2017
                : 18 April 2017
                : 18 April 2017
                Categories
                Research Paper

                lyme disease,iga,borrelia burgdorferi,lyme neuroborreliosis,erythema migrans

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