scholarly journals Macrophage Polarization during Murine Lyme Borreliosis

2015 ◽  
Vol 83 (7) ◽  
pp. 2627-2635 ◽  
Author(s):  
Carrie E. Lasky ◽  
Rachel M. Olson ◽  
Charles R. Brown
Keyword(s):  
Lyme Disease ◽  
Time Course ◽  
Macrophage Polarization ◽  
Lyme Arthritis ◽  
Macrophage Phenotype ◽  
Content Type ◽  
C3h Mice ◽  
Inflammatory Site ◽  
Macrophage Subset ◽  
Inflammatory Infiltrates

Infection of C3H mice withBorrelia burgdorferi, the causative agent of Lyme disease, reliably produces an infectious arthritis and carditis that peak around 3 weeks postinfection and then spontaneously resolve. Macrophage polarization has been suggested to drive inflammation, the clearance of bacteria, and tissue repair and resolution in a variety of infectious disease models. During Lyme disease it is clear that macrophages are capable of clearingBorreliaspirochetes and exhausted neutrophils; however, the role of macrophage phenotype in disease development or resolution has not been studied. Using classical (NOS2) and alternative (CD206) macrophage subset-specific markers, we determined the phenotype of F4/80+macrophages within the joints and heart throughout the infection time course. Within the joint, CD206+macrophages dominated throughout the course of infection, and NOS2+macrophage numbers became elevated only during the peak of inflammation. We also found dual NOS2+CD206+macrophages which increased during resolution. In contrast to findings for the ankle joints, numbers of NOS2+and CD206+macrophages in the heart were similar at the peak of inflammation. 5-Lipoxygenase-deficient (5-LOX−/−) mice, which display a failure of Lyme arthritis resolution, recruited fewer F4/80+cells to the infected joints and heart, but macrophage subset populations were unchanged. These results highlight differences in the inflammatory infiltrates during Lyme arthritis and carditis and demonstrate the coexistence of multiple macrophage subsets within a single inflammatory site.

scholarly journals Regulatory T Cells Contribute to Resistance against Lyme Arthritis

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Emily M. Siebers ◽  
Elizabeth S. Liedhegner ◽  
Michael W. Lawlor ◽  
Ronald F. Schell ◽  
Dean T. Nardelli
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lyme Disease ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Interleukin 10 ◽  
Lyme Arthritis ◽  
Interleukin 17 ◽  
Content Type

ABSTRACT The symptoms of Lyme disease are caused by inflammation induced by species of the Borrelia burgdorferi sensu lato complex. The various presentations of Lyme disease in the population suggest that differences exist in the intensity and regulation of the host response to the spirochete. Previous work has described correlations between the presence of regulatory T cells and recovery from Lyme arthritis. However, the effects of Foxp3-expressing CD4+ T cells existing prior to, and during, B. burgdorferi infection have not been well characterized. Here, we used C57BL/6 “depletion of regulatory T cell” mice to assess the effects these cells have on the arthritis-resistant phenotype characteristic of this mouse strain. We showed that depletion of regulatory T cells prior to infection with B. burgdorferi resulted in sustained swelling, as well as histopathological changes, of the tibiotarsal joints that were not observed in infected control mice. Additionally, in vitro stimulation of splenocytes from these regulatory T cell-depleted mice resulted in increases in gamma interferon and interleukin-17 production and decreases in interleukin-10 production that were not evident among splenocytes of infected mice in which Treg cells were not depleted. Depletion of regulatory T cells at various times after infection also induced rapid joint swelling. Collectively, these findings provide evidence that regulatory T cells existing at the time of, and possibly after, B. burgdorferi infection may play an important role in limiting the development of arthritis.

scholarly journals Induction of Interleukin 10 byBorrelia burgdorferiIs Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling

2018 ◽  
Vol 86 (4) ◽  
Author(s):  
Bikash Sahay ◽  
Kathleen Bashant ◽  
Nicole L. J. Nelson ◽  
Rebeca L. Patsey ◽  
Shiva Kumar Gadila ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Lyme Borreliosis ◽  
Human Peripheral Blood ◽  
Interleukin 10 ◽  
Mapk Signaling ◽  
Lyme Arthritis ◽  
Mitogen Activated Protein Kinase ◽  
Content Type ◽  
C3h Mice ◽  
Mitogen Activated Protein

ABSTRACTHost genotype influences the severity of murine Lyme borreliosis, caused by the spirochetal bacteriumBorrelia burgdorferi. C57BL/6 (B6) mice develop mild Lyme arthritis, whereas C3H/HeN (C3H) mice develop severe Lyme arthritis. Differential expression of interleukin 10 (IL-10) has long been associated with mouse strain differences in Lyme pathogenesis; however, the underlying mechanism(s) of this genotype-specific IL-10 regulation remained elusive. Herein we reveal a cAMP-mediated mechanism of IL-10 regulation in B6 macrophages that is substantially diminished in C3H macrophages. Under cAMP and CD14-p38 mitogen-activated protein kinase (MAPK) signaling, B6 macrophages stimulated withB. burgdorferiproduce increased amounts of IL-10 and decreased levels of arthritogenic cytokines, including tumor necrosis factor (TNF). cAMP relaxes chromatin, while p38 increases binding of the transcription factors signal transducer and activator of transcription 3 (STAT3) and specific protein 1 (SP1) to the IL-10 promoter, leading to increased IL-10 production in B6 bone marrow-derived monocytes (BMDMs). Conversely, macrophages derived from arthritis-susceptible C3H mice possess significantly less endogenous cAMP, produce less IL-10, and thus are ill equipped to mitigate the damaging consequences ofB. burgdorferi-induced TNF. Intriguingly, an altered balance between anti-inflammatory and proinflammatory cytokines and CD14-dependent regulatory mechanisms also is operative in primary human peripheral blood-derived monocytes, providing potential insight into the clinical spectrum of human Lyme disease. In line with this notion, we have demonstrated that cAMP-enhancing drugs increase IL-10 production in myeloid cells, thus curtailing inflammation associated with murine Lyme borreliosis. Discovery of novel treatments or repurposing of FDA-approved cAMP-modulating medications may be a promising avenue for treatment of patients with adverse clinical outcomes, including certain post-Lyme complications, in whom dysregulated immune responses may play a role.

scholarly journals Infection of Interleukin 17 Receptor A-Deficient C3H Mice with Borrelia burgdorferi Does Not Affect Their Development of Lyme Arthritis and Carditis

2015 ◽  
Vol 83 (7) ◽  
pp. 2882-2888 ◽  
Author(s):  
Carrie E. Lasky ◽  
Kara E. Jamison ◽  
Darcie R. Sidelinger ◽  
Carmela L. Pratt ◽  
Guoquan Zhang ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Lyme Borreliosis ◽  
Heart Tissue ◽  
Lyme Arthritis ◽  
Mouse Strains ◽  
Interleukin 17 ◽  
Content Type ◽  
C3h Mice ◽  
A Subunit

Recently, a number of studies have reported the presence of interleukin 17 (IL-17) in patients with Lyme disease, and several murine studies have suggested a role for this cytokine in the development of Lyme arthritis. However, the role of IL-17 has not been studied using the experimental Lyme borreliosis model of infection of C3H mice withBorrelia burgdorferi. In the current study, we investigated the role of IL-17 in the development of experimental Lyme borreliosis by infecting C3H mice devoid of the common IL-17 receptor A subunit (IL-17RA) and thus deficient in most IL-17 signaling. Infection of both C3H and C3H IL-17RA−/−mice led to the production of high levels of IL-17 in the serum, low levels in the heart tissue, and no detectable IL-17 in the joint tissue. The development and severity of arthritis and carditis in the C3H IL-17RA−/−mice were similar to what was seen in wild-type C3H mice. In addition, development of antiborrelia antibodies and clearance of spirochetes from tissues were similar for the two mouse strains. These results demonstrate a limited role for IL-17 signaling through IL-17RA in the development of disease following infection of C3H mice withB. burgdorferi.

scholarly journals A Multiplexed Serologic Test for Diagnosis of Lyme Disease for Point-of-Care Use

2019 ◽  
Vol 57 (12) ◽  
Author(s):  
Siddarth Arumugam ◽  
Samiksha Nayak ◽  
Taylor Williams ◽  
Francesco Serra di Santa Maria ◽  
Mariana Soares Guedes ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Confidence Interval ◽  
Point Of Care ◽  
Laboratory Diagnosis ◽  
Lyme Arthritis ◽  
Disease Stage ◽  
Serologic Test ◽  
Content Type ◽  
Disease Stages ◽  
Late Stages

ABSTRACT Single multiplexed assays could replace the standard 2-tiered (STT) algorithm recommended for the laboratory diagnosis of Lyme disease if they perform with a specificity and a sensitivity superior or equal to those of the STT algorithm. We used human serum rigorously characterized to be sera from patients with acute- and convalescent-phase early Lyme disease, Lyme arthritis, and posttreatment Lyme disease syndrome, as well as the necessary controls (n = 241 samples), to select the best of 12 Borrelia burgdorferi proteins to improve our microfluidic assay (mChip-Ld). We then evaluated its serodiagnostic performance in comparison to that of a first-tier enzyme immunoassay and the STT algorithm. We observed that more antigens became positive as Lyme disease progressed from early to late stages. We selected three antigens (3Ag) to include in the mChip-Ld: VlsE and a proprietary synthetic 33-mer peptide (PepVF) to capture sensitivity in all disease stages and OspC for early Lyme disease. With the specificity set at 95%, the sensitivity of the mChip-Ld with 3Ag ranged from 80% (95% confidence interval [CI], 56% to 94%) and 85% (95% CI, 74% to 96%) for two panels of serum from patients with early Lyme disease and was 100% (95% CI, 83% to 100%) for serum from patients with Lyme arthritis; the STT algorithm detected early Lyme disease in the same two panels of serum from patients with early Lyme disease with a sensitivity of 48.5% and 75% and Lyme arthritis in serum from patients with Lyme arthritis with a sensitivity of 100%, and the specificity was 97.5% to 100%. The mChip-Ld platform outperformed the STT algorithm according to sensitivity. These results open the door for the development of a single, rapid, multiplexed diagnostic test for point-of-care use that can be designed to identify the Lyme disease stage.

scholarly journals Misdiagnosis of Late-Onset Lyme Arthritis by Inappropriate Use of Borrelia burgdorferi Immunoblot Testing with Synovial Fluid

2012 ◽  
Vol 19 (11) ◽  
pp. 1806-1809 ◽  
Author(s):  
Sam S. Barclay ◽  
Michael T. Melia ◽  
Paul G. Auwaerter
Keyword(s):  
Lyme Disease ◽  
Synovial Fluid ◽  
Borrelia Burgdorferi ◽  
Late Onset ◽  
Medical Center ◽  
Academic Medical Center ◽  
Primary Objective ◽  
Lyme Arthritis ◽  
Serum Samples ◽  
Content Type

ABSTRACTThe primary objective of this study was to determine whether patients with putative late-onset Lyme arthritis based upon synovial fluidBorrelia burgdorferiIgM and IgG immunoblot testing offered by commercial laboratories satisfied conventional criteria for the diagnosis of Lyme arthritis. Secondary objectives included assessing the prior duration and responsiveness of associated antibiotic therapy. We conducted a retrospective analysis of 11 patients referred to an academic medical center infectious disease clinic during the years 2007 to 2009 with a diagnosis of Lyme disease based upon previously obtained synovial fluidB. burgdorferiimmunoblot testing. Ten of the 11 (91%) patients with a diagnosis of late-onset Lyme arthritis based upon interpretation of synovial fluidB. burgdorferiimmunoblot testing were seronegative and did not satisfy published criteria for the diagnosis of late-onset Lyme arthritis. None of the 10 patients had a clinical response to previously received antibiotics despite an average course of 72 days. Diagnosis of Lyme arthritis should not be based on synovial fluidB. burgdorferiimmunoblot testing. This unvalidated test does not appear useful for the diagnosis of Lyme disease, and this study reinforces the longstanding recommendation to useB. burgdorferiimmunoblot testing only on serum samples and not other body fluids. Erroneous interpretations of “positive” synovial fluid immunoblots may lead to inappropriate antibiotic courses and delays in diagnosis of other joint diseases.

scholarly journals MyD88- and TRIF-Independent Induction of Type I Interferon Drives Naive B Cell Accumulation but Not Loss of Lymph Node Architecture in Lyme Disease

2014 ◽  
Vol 82 (4) ◽  
pp. 1548-1558 ◽  
Author(s):  
Christine J. Hastey ◽  
Jennine Ochoa ◽  
Kimberley J. Olsen ◽  
Stephen W. Barthold ◽  
Nicole Baumgarth
Keyword(s):  
Lymph Node ◽  
B Cells ◽  
Lyme Disease ◽  
Lymph Nodes ◽  
B Cell ◽  
Time Course ◽  
Type I Interferon ◽  
Type I ◽  
Content Type ◽  
Specific Immunity

ABSTRACTRapidly after infection, liveBorrelia burgdorferi, the causative agent of Lyme disease, is found within lymph nodes, causing rapid and strong tissue enlargement, a loss of demarcation between B cell follicles and T cell zones, and an unusually large accumulation of B cells. We sought to explore the mechanisms underlying these changes, as lymph tissue disruption could be detrimental for the development of robustBorrelia-specific immunity. A time course study demonstrated that the loss of the normal lymph node structure was a distinct process that preceded the strong increases in B cells at the site. The selective increases in B cell frequencies were due not to proliferation but rather to cytokine-mediated repositioning of B cells to the lymph nodes, as shown with various gene-targeted and bone marrow irradiation chimeras. These studies demonstrated thatB. burgdorferiinfection induced type I interferon receptor (IFNR) signaling in lymph nodes in a MyD88- and TRIF-independent manner and that type I IFNR indirect signaling was required for the excessive increases of naive B cells at those sites. It did not, however, drive the observed histopathological changes, which occurred independently also from major shifts in the lymphocyte-homing chemokines, CXCL12, CXCL13, and CCL19/21, as shown by quantitative reverse transcription-PCR (qRT-PCR), flow cytometry, and transwell migration experiments. Thus,B. burgdorferiinfection drives the production of type I IFN in lymph nodes and in so doing strongly alters the cellular composition of the lymph nodes, with potential detrimental effects for the development of robustBorrelia-specific immunity.

scholarly journals Arthritis and Diagnostics in Lyme Disease

2021 ◽  
Vol 6 (1) ◽  
pp. 18
Author(s):  
Javier A. Quintero ◽  
Raluchukwu Attah ◽  
Reena Khianey ◽  
Eugenio Capitle ◽  
Steven E. Schutzer
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Diagnostic Tests ◽  
Laboratory Tests ◽  
Diagnostic Methods ◽  
Lyme Arthritis ◽  
Differential Diagnoses ◽  
Antibody Testing ◽  
Active Infection ◽  
Indirect Measure

The diagnosis of Lyme disease, caused by Borrelia burgdorferi, is clinical but frequently supported by laboratory tests. Lyme arthritis is now less frequently seen than at the time of its discovery. However, it still occurs, and it is important to recognize this, the differential diagnoses, and how laboratory tests can be useful and their limitations. The most frequently used diagnostic tests are antibody based. However, antibody testing still suffers from many drawbacks and is only an indirect measure of exposure. In contrast, evolving direct diagnostic methods can indicate active infection.

Preoperative and postoperative cognitive functioning in patients with frontal meningiomas

2003 ◽  
Vol 98 (1) ◽  
pp. 21-31 ◽  
Author(s):  
Oliver Tucha ◽  
Christian Smely ◽  
Michael Preier ◽  
Georg Becker ◽  
Geraldine M. Paul ◽  
...  
Keyword(s):  
Executive Functions ◽  
Cognitive Functioning ◽  
Time Course ◽  
Lesion Size ◽  
Test Battery ◽  
Surgical Removal ◽  
Specific Information ◽  
Content Type ◽  
Before And After ◽  
Fine Print

Object. There is presently no specific information available concerning the nature and course of cognitive deficits caused by intracranial meningiomas. In this prospective study the authors examined the cognitive functioning of patients with frontal meningiomas. Methods. Fifty-four patients with frontal meningiomas were examined neuropsychologically before and after neurosurgery. The test battery consisted of standardized instruments including those assessing memory, attention, visuoconstructive abilities, and executive functions. The time period between pre-and postoperative assessment ranged from 4 to 9 months. The patients' performance was compared with the results in 54 healthy adults who were also assessed twice by using the same test battery in a period ranging from 4 to 9 months. In addition, the effect on cognition of meningioma lateralization, localization, lesion size, edema, brain compression, time course, and the occurrence of preoperative seizures was analyzed. Conclusions. Except in the case of working memory, comparisons of pre- and postoperative assessments of cognition revealed no differences in memory, visuoconstructive abilities, or executive functions, although a postoperative improvement in attentional functions was observed. The results of this study indicate that the surgical removal of frontal meningiomas does not impair patients' cognitive functioning. Furthermore, improvements in attentional functions may occur in these patients.

scholarly journals The Western Progression of Lyme Disease: Infectious and NonclonalBorrelia burgdorferi Sensu LatoPopulations in Grand Forks County, North Dakota

2014 ◽  
Vol 81 (1) ◽  
pp. 48-58 ◽  
Author(s):  
Brandee L. Stone ◽  
Nathan M. Russart ◽  
Robert A. Gaultney ◽  
Angela M. Floden ◽  
Jefferson A. Vaughan ◽  
...  
Keyword(s):  
Lyme Disease ◽  
16S Rrna ◽  
16S Rrna Gene ◽  
North Dakota ◽  
Intergenic Spacer ◽  
Rrna Gene ◽  
Content Type ◽  
Intergenic Spacer Region ◽  
Grand Forks ◽  
The 16S Rrna Gene

ABSTRACTScant attention has been paid to Lyme disease,Borrelia burgdorferi,Ixodes scapularis, or reservoirs in eastern North Dakota despite the fact that it borders high-risk counties in Minnesota. Recent reports ofB. burgdorferiandI. scapularisin North Dakota, however, prompted a more detailed examination. Spirochetes cultured from the hearts of five rodents trapped in Grand Forks County, ND, were identified asB. burgdorferi sensu latothrough sequence analyses of the 16S rRNA gene, the 16S rRNA gene-ileTintergenic spacer region,flaB,ospA,ospC, andp66. OspC typing revealed the presence of groups A, B, E, F, L, and I. Two rodents were concurrently carrying multiple OspC types. Multilocus sequence typing suggested the eastern North Dakota strains are most closely related to those found in neighboring regions of the upper Midwest and Canada. BALB/c mice were infected withB. burgdorferiisolate M3 (OspC group B) by needle inoculation or tick bite. Tibiotarsal joints and ear pinnae were culture positive, andB. burgdorferiM3 was detected by quantitative PCR (qPCR) in the tibiotarsal joints, hearts, and ear pinnae of infected mice. Uninfected larvalI. scapularisticks were able to acquireB. burgdorferiM3 from infected mice; M3 was maintained inI. scapularisduring the molt from larva to nymph; and further, M3 was transmitted from infectedI. scapularisnymphs to naive mice, as evidenced by cultures and qPCR analyses. These results demonstrate that isolate M3 is capable of disseminated infection by both artificial and natural routes of infection. This study confirms the presence of unique (nonclonal) and infectiousB. burgdorferipopulations in eastern North Dakota.

Application of magnetic resonance neurography in the evaluation of patients with peripheral nerve pathology

1996 ◽  
Vol 85 (2) ◽  
pp. 299-309 ◽  
Author(s):  
Aaron G. Filler ◽  
Michel Kliot ◽  
Franklyn A. Howe ◽  
Cecil E. Hayes ◽  
Dawn E. Saunders ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Time Course ◽  
Spin Echo ◽  
Fast Spin Echo ◽  
Mr Neurography ◽  
Magnetic Resonance Neurography ◽  
Cross Sectional ◽  
Content Type ◽  
Direct Nerve ◽  
Fine Print

✓ Currently, diagnosis and management of disorders involving nerves are generally undertaken without images of the nerves themselves. The authors evaluated whether direct nerve images obtained using the new technique of magnetic resonance (MR) neurography could be used to make clinically important diagnostic distinctions that cannot be readily accomplished using existing methods. The authors obtained T2-weighted fast spin—echo fat-suppressed (chemical shift selection or inversion recovery) and T1-weighted images with planes parallel or transverse to the long axis of nerves using standard or phased-array coils in healthy volunteers and referred patients in 242 sessions. Longitudinal and cross-sectional fascicular images readily distinguished perineural from intraneural masses, thus predicting both resectability and requirement for intraoperative electrophysiological monitoring. Fascicle pattern and longitudinal anatomy firmly identified nerves and thus improved the safety of image-guided procedures. In severe trauma, MR neurography identified nerve discontinuity at the fascicular level preoperatively, thus verifying the need for surgical repair. Direct images readily demonstrated increased diameter in injured nerves and showed the linear extent and time course of image hyperintensity associated with nerve injury. These findings confirm and precisely localize focal nerve compressions, thus avoiding some exploratory surgery and allowing for smaller targeted exposures when surgery is indicated. Direct nerve imaging can demonstrate nerve continuity, distinguish intraneural from perineural masses, and localize nerve compressions prior to surgical exploration. Magnetic resonance neurography can add clinically useful diagnostic information in many situations in which physical examinations, electrodiagnostic tests, and existing image techniques are inconclusive.

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