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Allen C Steere - One of the best experts on this subject based on the ideXlab platform.
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robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious borrelia burgdorferi induced Lyme Arthritis
Cellular Microbiology, 2019Co-Authors: Robert B Lochhead, Sheila L Arvikar, Klemen Strle, John M Aversa, Ruslan I Sadreyev, Allen C SteereAbstract:In most patients with Lyme Arthritis (LA), antibiotic therapy results in Borrelia burgdorferi pathogen elimination, tissue repair, and return to homeostasis. However, despite spirochetal killing, some patients develop proliferative synovitis, characterised by synovial hyperplasia, inflammation, vascular damage, and fibrosis that persists for months to several years after antibiotic treatment, called postinfectious LA. In this study, we characterised the transcriptomes of postinfectious LA patients' synovial tissue, the target tissue of the immune response. High-throughput RNA sequencing to a depth of ~30 million reads per sample was used to profile gene expression in synovial tissue from 14 patients with postinfectious LA, compared with eight patients with other types of chronic inflammatory Arthritis and five with minimally inflammatory osteoArthritis (OA). Synovium from postinfectious LA and other inflammatory arthritides shared gene signatures associated with antigen presentation, innate immune responses, and cell-mediated immune activation, whereas these responses were diminished in OA synovium. Unique to postinfectious LA was a particularly robust interferon-gamma (IFNγ) signature. Moreover, this heightened IFNγ signature inversely correlated with expression of genes involved in repair of damaged tissue, including genes associated with stromal cell proliferation and differentiation, neovascularisation, and extracellular matrix synthesis, which were markedly suppressed in postinfectious LA. Transcriptional observations were confirmed by cytokine profiling, histologic analyses, and clinical correlations. We propose that in patients with postinfectious LA, overexpression of IFNγ in synovium prevents appropriate repair of tissue damaged by B. burgdorferi infection, blocking return to tissue homeostasis long after completion of antibiotic therapy and resolution of active infection.
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interferon gamma production in Lyme Arthritis synovial tissue promotes differentiation of fibroblast like synoviocytes into immune effector cells
Cellular Microbiology, 2019Co-Authors: Robert B Lochhead, Allen C Steere, Sheila L Arvikar, John M Aversa, David Ordonez, Benton E Heyworth, Ruslan I Sadreyev, Klemen StrleAbstract:Lyme Arthritis (LA), a late disease manifestation of Borrelia burgdorferi infection, usually resolves with antibiotic therapy. However, some patients develop proliferative synovitis lasting months to several years after spirochetal killing, called postinfectious LA. In this study, we phenotyped haematopoietic and stromal cell populations in the synovial lesion ex vivo and used these findings to generate an in vitro model of LA using patient-derived fibroblast-like synoviocytes (FLS). Ex vivo analysis of synovial tissue revealed high abundance of IFNγ-producing T cells and NK cells. Similar to marked IFNγ responses in tissue, postinfectious LA synovial fluid also had high levels of IFNγ. HLA-DR-positive FLS were present throughout the synovial lesion, particularly in areas of inflammation. FLS stimulated in vitro with B. burgdorferi, which were similar to conditions during infection, expressed 68 genes associated primarily with innate immune activation and neutrophil recruitment. In contrast, FLS stimulated with IFNγ, which were similar to conditions in the postinfectious phase, expressed >2,000 genes associated with pathogen sensing, inflammation, and MHC Class II antigen presentation, similar to the expression profile in postinfectious synovial tissue. Furthermore, costimulation of FLS with B. burgdorferi and IFNγ induced greater expression of IL-6 and other innate immune response proteins and genes than with IFNγ stimulation alone. These results suggest that B. burgdorferi infection, in combination with IFNγ, initiates the differentiation of FLS into a highly inflammatory phenotype. We hypothesise that overexpression of IFNγ by lymphocytes within synovia perpetuates these responses in the postinfectious period, causing proliferative synovitis and stalling appropriate repair of damaged tissue.
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microrna expression shows inflammatory dysregulation and tumor like proliferative responses in joints of patients with postinfectious Lyme Arthritis
Arthritis & Rheumatism, 2017Co-Authors: Robert B Lochhead, Sheila L Arvikar, Klemen Strle, John M Aversa, Nancy D Kim, Minna J Kohler, Allen C SteereAbstract:Objective Lyme Arthritis (LA) is caused by infection with Borrelia burgdorferi and usually resolves following spirochetal killing with antibiotics. However, in some patients, Arthritis persists after antibiotic therapy. To provide insights into underlying pathogenic processes associated with antibiotic-refractory LA (postinfectious LA), we analyzed differences in microRNA (miRNA) expression between LA patients with active infection and those with postinfectious LA. Methods MicroRNA expression was assayed in synovial fluid (SF) from LA patients before and after oral and intravenous antibiotic therapy, and in synovial tissue obtained months after antibiotic therapy from patients with postinfectious LA. SF and tissue from patients with other forms of Arthritis, such as rheumatoid Arthritis (RA) and osteoArthritis, were used for comparison. Results SF from LA patients during active infection had marked elevations of white blood cells, particularly polymorphonuclear leukocytes, accompanied by elevated levels of microRNA-223 (miR-223). In contrast, SF from postantibiotic LA patients contained greater percentages of lymphocytes and mononuclear cells. SF from postantibiotic LA patients also exhibited marked inflammatory (miR-146a, miR-155), wound repair (miR-142), and proliferative (miR-17–92) miRNA signatures, and higher levels of these miRNAs correlated with longer Arthritis duration. Levels of miR-146a, miR-155, miR-142, miR-223, and miR-17–92 were also elevated in synovial tissue in late postinfectious LA, and levels of let-7a were reduced, similar to RA. Conclusion During active infection, miRNA expression in SF reflected an immune response associated with bacterial killing, while in postinfectious LA, miRNA expression in SF and synovial tissue reflected chronic inflammation, synovial proliferation, and breakdown of wound repair processes, showing that the nature of the Arthritis was altered after spirochetal killing.
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t helper 17 cell cytokine responses in Lyme disease correlate with borrelia burgdorferi antibodies during early infection and with autoantibodies late in the illness in patients with antibiotic refractory Lyme Arthritis
Clinical Infectious Diseases, 2017Co-Authors: Klemen Strle, Annalisa Pianta, Jameson T Crowley, Sheila L Arvikar, Ruslan I Sadreyev, Katherine B Sulka, Anthony Anselmo, Allen C SteereAbstract:Background Control of Lyme disease is attributed predominantly to innate and adaptive T-helper 1 cell (TH1) immune responses, whereas the role of T-helper 17 cell (TH17) responses is less clear. Here we characterized these inflammatory responses in patients with erythema migrans (EM) or Lyme Arthritis (LA) to elucidate their role early and late in the infection. Methods Levels of 21 cytokines and chemokines, representative of innate, TH1, and TH17 immune responses, were assessed by Luminex in acute and convalescent sera from 91 EM patients, in serum and synovial fluid from 141 LA patients, and in serum from 57 healthy subjects. Antibodies to Borrelia burgdorferi or autoantigens were measured by enzyme-linked immunosorbent assay. Results Compared with healthy subjects, EM patients had significantly higher levels of innate, TH1, and TH17-associated mediators (P ≤ .05) in serum. In these patients, the levels of inflammatory mediators, particularly TH17-associated cytokines, correlated directly with B. burgdorferi immunoglobulin G antibodies (P ≤ .02), suggesting a beneficial role for these responses in control of early infection. Late in the disease, in patients with LA, innate and TH1-associated mediators were often >10-fold higher in synovial fluid than serum. In contrast, the levels of TH17-associated mediators were more variable, but correlated strongly with autoantibodies to endothelial cell growth factor, matrix metalloproteinase 10, and apolipoprotein B-100 in joints of patients with antibiotic-refractory LA, implying a shift in TH17 responses toward an autoimmune phenotype. Conclusions Patients with Lyme disease often develop pronounced TH17 immune responses that may help control early infection. However, late in the disease, excessive TH17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory LA.
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immunogenic hla dr presented self peptides identified directly from clinical samples of synovial tissue synovial fluid or peripheral blood in patients with rheumatoid Arthritis or Lyme Arthritis
Journal of Proteome Research, 2017Co-Authors: Qi Wang, Allen C Steere, Elise E Drouin, Chunxiang Yao, Jiyang Zhang, Yu Huang, Deborah R Leon, Catherine E. CostelloAbstract:Human leukocyte antigen–antigen D related (HLA-DR) molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory forms of Arthritis. Here, we used LC-MS/MS to identify HLA-DR-presented self-peptides in cells taken directly from clinical samples: ST, synovial fluid mononuclear cells (SFMC), or peripheral blood mononuclear cells (PBMC) from five patients with rheumatoid Arthritis (RA) and eight with Lyme Arthritis (LA). We identified 1593 non-redundant HLA-DR-presented peptides, derived from 870 source proteins. A total of 67% of the peptides identified in SFMC and 55% of those found in PBMC were found in ST, but analysis of SFMC/PBMC also revealed new antigen-presented peptides. Peptides were synthesized and examined for reactivity with the patients’ PBMC. To date, three autoantigens in RA and four novel autoantigens in LA, presented in ST and/or PBMC, were shown to be targets of T- and B-cell responses in these diseases; ongoing analyses may add to this ...
Elise E Drouin - One of the best experts on this subject based on the ideXlab platform.
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immunogenic hla dr presented self peptides identified directly from clinical samples of synovial tissue synovial fluid or peripheral blood in patients with rheumatoid Arthritis or Lyme Arthritis
Journal of Proteome Research, 2017Co-Authors: Qi Wang, Allen C Steere, Elise E Drouin, Chunxiang Yao, Jiyang Zhang, Yu Huang, Deborah R Leon, Catherine E. CostelloAbstract:Human leukocyte antigen–antigen D related (HLA-DR) molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory forms of Arthritis. Here, we used LC-MS/MS to identify HLA-DR-presented self-peptides in cells taken directly from clinical samples: ST, synovial fluid mononuclear cells (SFMC), or peripheral blood mononuclear cells (PBMC) from five patients with rheumatoid Arthritis (RA) and eight with Lyme Arthritis (LA). We identified 1593 non-redundant HLA-DR-presented peptides, derived from 870 source proteins. A total of 67% of the peptides identified in SFMC and 55% of those found in PBMC were found in ST, but analysis of SFMC/PBMC also revealed new antigen-presented peptides. Peptides were synthesized and examined for reactivity with the patients’ PBMC. To date, three autoantigens in RA and four novel autoantigens in LA, presented in ST and/or PBMC, were shown to be targets of T- and B-cell responses in these diseases; ongoing analyses may add to this ...
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matrix metalloproteinase 10 is a target of t and b cell responses that correlate with synovial pathology in patients with antibiotic refractory Lyme Arthritis
Journal of Autoimmunity, 2016Co-Authors: Jameson T Crowley, Catherine E. Costello, Elise E Drouin, Annalisa Pianta, Sheila L Arvikar, Klemen Strle, Qi Wang, Allen C SteereAbstract:Infection-induced autoimmunity is thought to be a contributing factor in antibiotic-refractory Lyme Arthritis, but studies of autoimmunity have been hindered by difficulty in identifying relevant autoantigens. We developed a novel approach that begins with the identification of T cell epitopes in synovial tissue using tandem mass spectrometry. Herein, we identified an immunogenic HLA-DR-presented peptide (T cell epitope) derived from the source protein matrix metalloproteinase-10 (MMP-10) from the synovium of a patient with antibiotic-refractory Arthritis. This finding provided a bridge for the identification of autoantibody responses to MMP-10, the "first autoimmune hit" in a subgroup of patients with erythema migrans, the initial skin lesion of the infection. Months later, after priming of the immune response to MMP-10 in early infection, a subset of patients with antibiotic-responsive or antibiotic-refractory Arthritis had MMP-10 autoantibodies, but only patients with antibiotic-refractory Arthritis had both T and B cell responses to the protein, providing evidence for a "second autoimmune hit". Further support for a biologically relevant autoimmune event was observed by the positive correlation of anti-MMP-10 autoantibodies with distinct synovial pathology. This experience demonstrates the power of new, discovery-based methods to identify relevant autoimmune responses in chronic inflammatory forms of Arthritis.
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annexin a2 is a target of autoimmune t and b cell responses associated with synovial fibroblast proliferation in patients with antibiotic refractory Lyme Arthritis
Clinical Immunology, 2015Co-Authors: Annalisa Pianta, Catherine E. Costello, Elise E Drouin, Jameson T Crowley, Sheila L Arvikar, Klemen Strle, Allen C SteereAbstract:In this study, autoantibody responses to annexin A2 were found in 11–15% of 278 patients with Lyme disease, including in those with erythema migrans (EM), an early sign of the illness, and in those with antibiotic-responsive or antibiotic-refractory Lyme Arthritis (LA), a late disease manifestation. In contrast, robust T cell reactivity to annexin A2 peptides was found only in patients with responsive or refractory LA. In LA patients, annexin A2 protein levels, which were higher in the refractory group, correlated with annexin A2 antibody levels in sera and synovial fluid. In addition, in patients with antibiotic-refractory LA who had anti-annexin A2 antibodies, synovial tissue had intense staining for annexin A2 protein, greater synovial fibroblast proliferation and more tissue fibrosis. Thus, a subset of LA patients had T and B cell responses to annexin A2, and in the refractory group, annexin A2 autoantibodies were associated with specific pathologic findings.
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antibodies to endothelial cell growth factor and obliterative microvascular lesions in the synovium of patients with antibiotic refractory Lyme Arthritis
Arthritis & Rheumatism, 2014Co-Authors: Diana Londono, Gail Mchugh, Elise E Drouin, Klemen Strle, Diego Cadavid, John M Aversa, Allen C SteereAbstract:Lyme disease in the northeastern United States is caused by the tick-transmitted spirochete, Borrelia burgdorferi (1). The most common late manifestation of the infection is Lyme Arthritis, which often affects one or both knees (2). Most patients can be treated successfully with a 1-month course of oral or intravenous (IV) antibiotic therapy (3,4), called antibiotic-responsive Lyme Arthritis. However, a small percentage of patients have persistent synovitis despite treatment with 1–2 months of oral antibiotics and 1 month of IV antibiotics, termed antibiotic-refractory Lyme Arthritis (5). After antibiotic therapy, these patients are often treated with disease modifying anti-rheumatic drugs (DMARDs), such as hydroxychloroquine or methotrexate. If the response to DMARDs is incomplete, arthroscopic synovectomy is an option. Antibiotic-refractory Lyme Arthritis is associated with infection with highly inflammatory strains of B. burgdorferi (6). However, persistent infection seems not to be the explanation for persistent synovitis after oral and IV antibiotic therapy (7). Culture and PCR results for B. burgdorferi in synovial tissue have been uniformly negative after this therapy (8), and treatment with immunosuppressive DMARDs has not led to reactivation of infection (5). Instead, excessive inflammation in joints (9,10), associations with specific HLA-DR alleles (11), and difficulty down-regulating inflammatory responses (12,13) appear to result in post-infectious inflammatory immune phenomena that lead to persistent synovitis after spirochetal killing. In MyD88−/− mice, which have high pathogen loads, B. burgdorferi antigens are retained near cartilage surfaces after antibiotic therapy, and patellar homogenates induce macrophages to secrete TNF-α (14). However, patients with Lyme Arthritis have low pathogen loads (8), and the extensive proliferative synovitis found in patients with antibiotic-refractory Arthritis (15–17) is not replicated in mice. Thus, the role of retained spirochetal antigens in post-infectious immune responses in the human disease is not yet clear. We recently identified human, platelet-derived endothelial cell growth factor (ECGF) as the first autoantigen known to be a target of T and B cell responses in about 20% of patients with Lyme Arthritis, particularly in those with antibiotic-refractory Arthritis (18). In addition, about 15% of patients with erythema migrans (EM), the initial skin lesion of the infection, also had autoantibody responses to ECGF. When archival serum samples were tested from 27 non-antibiotic-treated patients who were followed from EM through the course of Arthritis during the 1970s before the cause of the disease was known, 7 (26%) had ECGF antibody responses, which often appeared early in the illness, prior to the onset of Arthritis. Moreover, the total duration of attacks of active Arthritis in these patients was significantly longer than in those who lacked ECGF reactivity (median, 67 versus 17 weeks, P=0.004). Additionally, ECGF, an IFN-γ-inducible protein (19), was expressed at significantly higher levels in synovial fluid (SF) in patients with antibiotic-refractory Arthritis than in those with antibiotic-responsive Arthritis, and patients with antibiotic-refractory Arthritis often had moderate-to-intense staining for ECGF in the lining and sublining areas of synovial tissue (18). Although the ECGF protein is also found in synovial tissue and SF from patients with rheumatoid Arthritis (RA) (20), it seems to be immunogenic only in Lyme Arthritis. Thus, anti-ECGF antibodies appear to be a marker for a disadvantageous immune response that is associated with more persistent Lyme Arthritis. However, it is not yet known whether autoantibodies to ECGF cause synovial pathology. To investigate this issue, we examined synovial tissue samples, which were obtained at synovectomy, months after antibiotic treatment, from 14 patients with antibiotic-refractory Lyme Arthritis. To blind the investigators to diagnosis and clinical data, synovial samples were also included from 6 patients with other forms of chronic inflammatory Arthritis, primarily RA. In each of these diseases, synovial tissue often showed synovial hypertrophy, vascular proliferation, immune cell infiltrates, and fibrosis. However, obliterative microvascular lesions were found only in Lyme Arthritis. Five of the 14 patients (36%) with this disease had positive antibody responses to ECGF, and all 5 had extensive obliterative microvascular lesions. Moreover, the magnitude of ECGF antibody responses correlated directly with the extent of obliterative microvascular lesions, suggesting that these autoantibodies have specific pathologic consequences in antibiotic-refractory Lyme Arthritis.
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dysregulation of cd4 cd25 high t cells in the synovial fluid of patients with antibiotic refractory Lyme Arthritis
Arthritis & Rheumatism, 2013Co-Authors: Nalini K Vudattu, Allen C Steere, Klemen Strle, Elise E DrouinAbstract:There is increasing interest in the role of infection in triggering autoimmune diseases (1, 2). With infection, a pro-inflammatory response is induced to protect the host which includes the activation and expansion of innate and adaptive immune cells. However, this pro-inflammatory response must be properly down-regulated once the pathogen is controlled or eliminated to maintain tolerance and limit tissue pathology. In some individuals, these regulatory mechanisms do not work optimally, leading to pathogenic autoimmunity. Therefore, identifying quantitative and qualitative differences in immune cells between patients who can properly down-regulate their immune response after infection from those who cannot is critical to our understanding of infection-induced autoimmunity. Lyme Arthritis, a late stage manifestation of infection with the tick-borne spirochete Borrelia burgdorferi (Bb) (3), provides a human model of infection that may lead to these two alternative outcomes (4). Most patients can be treated successfully with antibiotics, called antibiotic-responsive Arthritis (5, 6). However, in a small percentage of patients, proliferative synovitis persists for months or years after ≥3 months of oral and IV antibiotics, called antibiotic-refractory Arthritis (7). This outcome is postulated to result from persistent infection, retained spirochetal antigens, infection-induced autoimmunity, or a combination of these factors. In animal models, a small number of attenuated spirochetes may survive despite 1 month of antibiotic therapy (8), but in patients with antibiotic-refractory Arthritis, culture and PCR results for Bb in synovial tissue have been uniformly negative after ≥3 months of antibiotics (9). Additionally, in MyD88−/− mice, which have a high pathogen load, spirochetal antigens are retained near cartilage surfaces after antibiotic therapy (10), but the relevance of this finding to human antibiotic-refractory Arthritis is not yet clear. In the human disease, data supports the infection-induced autoimmunity model (7, 11, 12). For example, antibiotic-refractory Arthritis is associated with specific HLA-DR alleles (particularly DRB1*0101 and 0401) (11), a risk factor commonly associated with autoimmune diseases. We postulate that these patients are unable to properly down-regulate their immune response with antibiotic therapy and apparent spirochetal killing leading to immune dysregulation and antibiotic-refractory Arthritis. Previously, we showed that in patients with antibiotic-refractory Arthritis, the percentage of CD4+FOXP3+ Treg cells in SF correlated inversely with the post-antibiotic duration of Arthritis (13), implying that lower numbers of Treg led to slower Arthritis resolution. Furthermore, suppression assays using cells from 2 patients with refractory Arthritis showed that CD25-positive T cells (Treg) from PB and SF suppressed the proliferation of CD25-negative T cells (Teff) at a 1-to-1 ratio equally well, but CD25-negative T cells (Teff) from SF were more resistant to suppression than from PB. However, in this study, the expression of FOXP3 within various CD4+CD25 T cell subpopulations, the expression of activating or inhibitory T cell co-receptors, and the ability of these patients’ Treg cells to suppress cytokine secretion were not determined. In our current study, we compared the frequency, phenotype and function of immune cells in PB and SF from patients with antibiotic-responsive or antibiotic-refractory Lyme Arthritis. Critical differences between the 2 patient groups were found in the CD4+CD25hi+ T cell population in SF. This cell population in the refractory group often had lower frequencies of Treg, higher expression of activation co-receptors, and less effective inhibition of pro-inflammatory responses, leading to immune dysregulation and persistent synovitis.
Klemen Strle - One of the best experts on this subject based on the ideXlab platform.
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borrelia burgdorferi peptidoglycan is a persistent antigen in patients with Lyme Arthritis
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Brandon L Jutras, Robert B Lochhead, Klemen Strle, Zachary A Kloos, Jacob Biboy, Carmen J Booth, Sander K Govers, Joe Gray, Peter Schumann, Waldemar VollmerAbstract:Lyme disease is a multisystem disorder caused by the spirochete Borrelia burgdorferi A common late-stage complication of this disease is oligoarticular Arthritis, often involving the knee. In ∼10% of cases, Arthritis persists after appropriate antibiotic treatment, leading to a proliferative synovitis typical of chronic inflammatory arthritides. Here, we provide evidence that peptidoglycan (PG), a major component of the B. burgdorferi cell envelope, may contribute to the development and persistence of Lyme Arthritis (LA). We show that B. burgdorferi has a chemically atypical PG (PGBb) that is not recycled during cell-wall turnover. Instead, this pathogen sheds PGBb fragments into its environment during growth. Patients with LA mount a specific immunoglobulin G response against PGBb, which is significantly higher in the synovial fluid than in the serum of the same patient. We also detect PGBb in 94% of synovial fluid samples (32 of 34) from patients with LA, many of whom had undergone oral and intravenous antibiotic treatment. These same synovial fluid samples contain proinflammatory cytokines, similar to those produced by human peripheral blood mononuclear cells stimulated with PGBb In addition, systemic administration of PGBb in BALB/c mice elicits acute Arthritis. Altogether, our study identifies PGBb as a likely contributor to inflammatory responses in LA. Persistence of this antigen in the joint may contribute to synovitis after antibiotics eradicate the pathogen. Furthermore, our finding that B. burgdorferi sheds immunogenic PGBb fragments during growth suggests a potential role for PGBb in the immunopathogenesis of other Lyme disease manifestations.
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interferon gamma production in Lyme Arthritis synovial tissue promotes differentiation of fibroblast like synoviocytes into immune effector cells
Cellular Microbiology, 2019Co-Authors: Robert B Lochhead, Allen C Steere, Sheila L Arvikar, John M Aversa, David Ordonez, Benton E Heyworth, Ruslan I Sadreyev, Klemen StrleAbstract:Lyme Arthritis (LA), a late disease manifestation of Borrelia burgdorferi infection, usually resolves with antibiotic therapy. However, some patients develop proliferative synovitis lasting months to several years after spirochetal killing, called postinfectious LA. In this study, we phenotyped haematopoietic and stromal cell populations in the synovial lesion ex vivo and used these findings to generate an in vitro model of LA using patient-derived fibroblast-like synoviocytes (FLS). Ex vivo analysis of synovial tissue revealed high abundance of IFNγ-producing T cells and NK cells. Similar to marked IFNγ responses in tissue, postinfectious LA synovial fluid also had high levels of IFNγ. HLA-DR-positive FLS were present throughout the synovial lesion, particularly in areas of inflammation. FLS stimulated in vitro with B. burgdorferi, which were similar to conditions during infection, expressed 68 genes associated primarily with innate immune activation and neutrophil recruitment. In contrast, FLS stimulated with IFNγ, which were similar to conditions in the postinfectious phase, expressed >2,000 genes associated with pathogen sensing, inflammation, and MHC Class II antigen presentation, similar to the expression profile in postinfectious synovial tissue. Furthermore, costimulation of FLS with B. burgdorferi and IFNγ induced greater expression of IL-6 and other innate immune response proteins and genes than with IFNγ stimulation alone. These results suggest that B. burgdorferi infection, in combination with IFNγ, initiates the differentiation of FLS into a highly inflammatory phenotype. We hypothesise that overexpression of IFNγ by lymphocytes within synovia perpetuates these responses in the postinfectious period, causing proliferative synovitis and stalling appropriate repair of damaged tissue.
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robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious borrelia burgdorferi induced Lyme Arthritis
Cellular Microbiology, 2019Co-Authors: Robert B Lochhead, Sheila L Arvikar, Klemen Strle, John M Aversa, Ruslan I Sadreyev, Allen C SteereAbstract:In most patients with Lyme Arthritis (LA), antibiotic therapy results in Borrelia burgdorferi pathogen elimination, tissue repair, and return to homeostasis. However, despite spirochetal killing, some patients develop proliferative synovitis, characterised by synovial hyperplasia, inflammation, vascular damage, and fibrosis that persists for months to several years after antibiotic treatment, called postinfectious LA. In this study, we characterised the transcriptomes of postinfectious LA patients' synovial tissue, the target tissue of the immune response. High-throughput RNA sequencing to a depth of ~30 million reads per sample was used to profile gene expression in synovial tissue from 14 patients with postinfectious LA, compared with eight patients with other types of chronic inflammatory Arthritis and five with minimally inflammatory osteoArthritis (OA). Synovium from postinfectious LA and other inflammatory arthritides shared gene signatures associated with antigen presentation, innate immune responses, and cell-mediated immune activation, whereas these responses were diminished in OA synovium. Unique to postinfectious LA was a particularly robust interferon-gamma (IFNγ) signature. Moreover, this heightened IFNγ signature inversely correlated with expression of genes involved in repair of damaged tissue, including genes associated with stromal cell proliferation and differentiation, neovascularisation, and extracellular matrix synthesis, which were markedly suppressed in postinfectious LA. Transcriptional observations were confirmed by cytokine profiling, histologic analyses, and clinical correlations. We propose that in patients with postinfectious LA, overexpression of IFNγ in synovium prevents appropriate repair of tissue damaged by B. burgdorferi infection, blocking return to tissue homeostasis long after completion of antibiotic therapy and resolution of active infection.
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microrna expression shows inflammatory dysregulation and tumor like proliferative responses in joints of patients with postinfectious Lyme Arthritis
Arthritis & Rheumatism, 2017Co-Authors: Robert B Lochhead, Sheila L Arvikar, Klemen Strle, John M Aversa, Nancy D Kim, Minna J Kohler, Allen C SteereAbstract:Objective Lyme Arthritis (LA) is caused by infection with Borrelia burgdorferi and usually resolves following spirochetal killing with antibiotics. However, in some patients, Arthritis persists after antibiotic therapy. To provide insights into underlying pathogenic processes associated with antibiotic-refractory LA (postinfectious LA), we analyzed differences in microRNA (miRNA) expression between LA patients with active infection and those with postinfectious LA. Methods MicroRNA expression was assayed in synovial fluid (SF) from LA patients before and after oral and intravenous antibiotic therapy, and in synovial tissue obtained months after antibiotic therapy from patients with postinfectious LA. SF and tissue from patients with other forms of Arthritis, such as rheumatoid Arthritis (RA) and osteoArthritis, were used for comparison. Results SF from LA patients during active infection had marked elevations of white blood cells, particularly polymorphonuclear leukocytes, accompanied by elevated levels of microRNA-223 (miR-223). In contrast, SF from postantibiotic LA patients contained greater percentages of lymphocytes and mononuclear cells. SF from postantibiotic LA patients also exhibited marked inflammatory (miR-146a, miR-155), wound repair (miR-142), and proliferative (miR-17–92) miRNA signatures, and higher levels of these miRNAs correlated with longer Arthritis duration. Levels of miR-146a, miR-155, miR-142, miR-223, and miR-17–92 were also elevated in synovial tissue in late postinfectious LA, and levels of let-7a were reduced, similar to RA. Conclusion During active infection, miRNA expression in SF reflected an immune response associated with bacterial killing, while in postinfectious LA, miRNA expression in SF and synovial tissue reflected chronic inflammation, synovial proliferation, and breakdown of wound repair processes, showing that the nature of the Arthritis was altered after spirochetal killing.
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t helper 17 cell cytokine responses in Lyme disease correlate with borrelia burgdorferi antibodies during early infection and with autoantibodies late in the illness in patients with antibiotic refractory Lyme Arthritis
Clinical Infectious Diseases, 2017Co-Authors: Klemen Strle, Annalisa Pianta, Jameson T Crowley, Sheila L Arvikar, Ruslan I Sadreyev, Katherine B Sulka, Anthony Anselmo, Allen C SteereAbstract:Background Control of Lyme disease is attributed predominantly to innate and adaptive T-helper 1 cell (TH1) immune responses, whereas the role of T-helper 17 cell (TH17) responses is less clear. Here we characterized these inflammatory responses in patients with erythema migrans (EM) or Lyme Arthritis (LA) to elucidate their role early and late in the infection. Methods Levels of 21 cytokines and chemokines, representative of innate, TH1, and TH17 immune responses, were assessed by Luminex in acute and convalescent sera from 91 EM patients, in serum and synovial fluid from 141 LA patients, and in serum from 57 healthy subjects. Antibodies to Borrelia burgdorferi or autoantigens were measured by enzyme-linked immunosorbent assay. Results Compared with healthy subjects, EM patients had significantly higher levels of innate, TH1, and TH17-associated mediators (P ≤ .05) in serum. In these patients, the levels of inflammatory mediators, particularly TH17-associated cytokines, correlated directly with B. burgdorferi immunoglobulin G antibodies (P ≤ .02), suggesting a beneficial role for these responses in control of early infection. Late in the disease, in patients with LA, innate and TH1-associated mediators were often >10-fold higher in synovial fluid than serum. In contrast, the levels of TH17-associated mediators were more variable, but correlated strongly with autoantibodies to endothelial cell growth factor, matrix metalloproteinase 10, and apolipoprotein B-100 in joints of patients with antibiotic-refractory LA, implying a shift in TH17 responses toward an autoimmune phenotype. Conclusions Patients with Lyme disease often develop pronounced TH17 immune responses that may help control early infection. However, late in the disease, excessive TH17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory LA.
Catherine E. Costello - One of the best experts on this subject based on the ideXlab platform.
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immunogenic hla dr presented self peptides identified directly from clinical samples of synovial tissue synovial fluid or peripheral blood in patients with rheumatoid Arthritis or Lyme Arthritis
Journal of Proteome Research, 2017Co-Authors: Qi Wang, Allen C Steere, Elise E Drouin, Chunxiang Yao, Jiyang Zhang, Yu Huang, Deborah R Leon, Catherine E. CostelloAbstract:Human leukocyte antigen–antigen D related (HLA-DR) molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory forms of Arthritis. Here, we used LC-MS/MS to identify HLA-DR-presented self-peptides in cells taken directly from clinical samples: ST, synovial fluid mononuclear cells (SFMC), or peripheral blood mononuclear cells (PBMC) from five patients with rheumatoid Arthritis (RA) and eight with Lyme Arthritis (LA). We identified 1593 non-redundant HLA-DR-presented peptides, derived from 870 source proteins. A total of 67% of the peptides identified in SFMC and 55% of those found in PBMC were found in ST, but analysis of SFMC/PBMC also revealed new antigen-presented peptides. Peptides were synthesized and examined for reactivity with the patients’ PBMC. To date, three autoantigens in RA and four novel autoantigens in LA, presented in ST and/or PBMC, were shown to be targets of T- and B-cell responses in these diseases; ongoing analyses may add to this ...
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matrix metalloproteinase 10 is a target of t and b cell responses that correlate with synovial pathology in patients with antibiotic refractory Lyme Arthritis
Journal of Autoimmunity, 2016Co-Authors: Jameson T Crowley, Catherine E. Costello, Elise E Drouin, Annalisa Pianta, Sheila L Arvikar, Klemen Strle, Qi Wang, Allen C SteereAbstract:Infection-induced autoimmunity is thought to be a contributing factor in antibiotic-refractory Lyme Arthritis, but studies of autoimmunity have been hindered by difficulty in identifying relevant autoantigens. We developed a novel approach that begins with the identification of T cell epitopes in synovial tissue using tandem mass spectrometry. Herein, we identified an immunogenic HLA-DR-presented peptide (T cell epitope) derived from the source protein matrix metalloproteinase-10 (MMP-10) from the synovium of a patient with antibiotic-refractory Arthritis. This finding provided a bridge for the identification of autoantibody responses to MMP-10, the "first autoimmune hit" in a subgroup of patients with erythema migrans, the initial skin lesion of the infection. Months later, after priming of the immune response to MMP-10 in early infection, a subset of patients with antibiotic-responsive or antibiotic-refractory Arthritis had MMP-10 autoantibodies, but only patients with antibiotic-refractory Arthritis had both T and B cell responses to the protein, providing evidence for a "second autoimmune hit". Further support for a biologically relevant autoimmune event was observed by the positive correlation of anti-MMP-10 autoantibodies with distinct synovial pathology. This experience demonstrates the power of new, discovery-based methods to identify relevant autoimmune responses in chronic inflammatory forms of Arthritis.
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Immunogenic HLA-DR-Presented Self-Peptides Identified Directly from Clinical Samples of Synovial Tissue, Synovial Fluid, or Peripheral Blood in Patients with Rheumatoid Arthritis or Lyme Arthritis
2016Co-Authors: Qi Wang, Allen C Steere, Chunxiang Yao, Jiyang Zhang, Yu Huang, Elise E. Drouin, Deborah R. Leon, Catherine E. CostelloAbstract:Human leukocyte antigen–antigen D related (HLA-DR) molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory forms of Arthritis. Here, we used LC-MS/MS to identify HLA-DR-presented self-peptides in cells taken directly from clinical samples: ST, synovial fluid mononuclear cells (SFMC), or peripheral blood mononuclear cells (PBMC) from five patients with rheumatoid Arthritis (RA) and eight with Lyme Arthritis (LA). We identified 1593 non-redundant HLA-DR-presented peptides, derived from 870 source proteins. A total of 67% of the peptides identified in SFMC and 55% of those found in PBMC were found in ST, but analysis of SFMC/PBMC also revealed new antigen-presented peptides. Peptides were synthesized and examined for reactivity with the patients’ PBMC. To date, three autoantigens in RA and four novel autoantigens in LA, presented in ST and/or PBMC, were shown to be targets of T- and B-cell responses in these diseases; ongoing analyses may add to this list. Thus, immunoprecipitation and LC-MS/MS can now identify hundreds of HLA-DR-presented self-peptides from individual patients’ tissues or fluids with mixed cell populations. Importantly, identification of HLA-DR-presented peptides from SFMC or PBMC allows testing of more patients, including those early in the disease. Direct analysis of clinical samples facilitates identification of novel immunogenic T-cell epitopes
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annexin a2 is a target of autoimmune t and b cell responses associated with synovial fibroblast proliferation in patients with antibiotic refractory Lyme Arthritis
Clinical Immunology, 2015Co-Authors: Annalisa Pianta, Catherine E. Costello, Elise E Drouin, Jameson T Crowley, Sheila L Arvikar, Klemen Strle, Allen C SteereAbstract:In this study, autoantibody responses to annexin A2 were found in 11–15% of 278 patients with Lyme disease, including in those with erythema migrans (EM), an early sign of the illness, and in those with antibiotic-responsive or antibiotic-refractory Lyme Arthritis (LA), a late disease manifestation. In contrast, robust T cell reactivity to annexin A2 peptides was found only in patients with responsive or refractory LA. In LA patients, annexin A2 protein levels, which were higher in the refractory group, correlated with annexin A2 antibody levels in sera and synovial fluid. In addition, in patients with antibiotic-refractory LA who had anti-annexin A2 antibodies, synovial tissue had intense staining for annexin A2 protein, greater synovial fibroblast proliferation and more tissue fibrosis. Thus, a subset of LA patients had T and B cell responses to annexin A2, and in the refractory group, annexin A2 autoantibodies were associated with specific pathologic findings.
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a novel human autoantigen endothelial cell growth factor is a target of t and b cell responses in patients with Lyme disease
Arthritis & Rheumatism, 2013Co-Authors: Elise E Drouin, Robert J Seward, Gail Mchugh, Catherine E. Costello, Klemen Strle, Diana Londono, Kianoosh Katchar, Allen C SteereAbstract:Presentation of autoantigens by HLA-DR molecules to CD4+ T cells is thought to be a central component of many autoimmune diseases (1), but in most instances, disease-relevant autoantigens have remained elusive. The problem is compounded by the fact that human autoimmune diseases are generally thought to be multifactorial, involving both genetic and environmental factors such as infection (2). Furthermore, in autoimmune diseases such as rheumatoid Arthritis (RA) or lupus, multiple autoantigens are thought to be involved, and autoantibodies are often present months or years before the onset of clinical disease (3, 4), suggesting that additional critical factors are required to trigger tissue pathology (3). Even so, recognition of self-antigens is an essential component in the development of disease pathology. Lyme Arthritis, a late manifestation of infection with the tick-borne spirochete, Borrelia burgdorferi (Bb) (5, 6), provides an important human model to study questions surrounding infection-induced autoimmunity. Lyme Arthritis can usually be treated successfully with 1–2 months of oral or intravenous (IV) antibiotics, called antibiotic-responsive Arthritis (7). However, in a small percentage of patients, proliferative synovitis persists for months or several years after apparent spirochetal killing with ≥3 months of oral and IV antibiotics, referred to as antibiotic-refractory Arthritis (8). This disease course has been postulated to result from either persistent infection, retained spirochetal antigens, or infection-induced autoimmunity (9, 10). Against the persistent infection hypothesis, PCR and culture results of synovectomy specimens obtained in the post-antibiotic period have been uniformly negative (11), and relapse of infection has not been observed with the use of disease modifying anti-rheumatic drugs (DMARDs) after antibiotic therapy (8). Contrary to what might be expected with retained spirochetal antigens, T and B cell responses to Bb decline similarly in patients with refractory or responsive Arthritis (12, 13), whereas inflammatory mediators in synovial fluid (SF), particularly IFN-γ, remain high or even increase in the refractory group during the post-antibiotic period (14). In support of the autoimmunity hypothesis, specific HLA-DR alleles, particularly the DRB1*0101 or 0401 alleles, are the greatest known genetic risk factor for antibiotic-refractory Arthritis (15). As in other chronic inflammatory arthritides, HLA-DR molecules in antibiotic-refractory Lyme Arthritis are intensely expressed in inflamed synovium (16). In a search for molecular mimicry between spirochetal and host proteins, partial sequence homology was found between the human peptides, LFA-1αL332-340 (17) and MAWD-BP280-288 (18), and an epitope of Bb outer-surface protein A (OspA163-175) (19), which binds refractory Arthritis-associated HLA-DR molecules (15). However, only a minority of patients had low-level T cell reactivity with these self peptides, and none had autoantibody responses to these self proteins (18, 20). Later, Ghosh et al., identified human cytokeratin 10 as a cross-reactive target ligand recognized by anti-OspA antibodies in a small group of patients with refractory Arthritis (3 of 15), but not in those with responsive Arthritis (0 of 5) (21). Finally, several neural proteins have been reported to induce T or B cell responses in patients with neuroborreliosis (22–24) or post-Lyme syndrome (25). However, responses against neural proteins would be unlikely to explain antibiotic-refractory Arthritis. In this study, we utilized discovery-based proteomics and translational research in an effort to identify autoantigens in synovial tissue, the target tissue of the immune attack in antibiotic-refractory Lyme Arthritis. Based on this approach, we report here the identification of a novel autoantigen, endothelial cell growth factor (ECGF), which is a target of T and B cell responses in a subset of patients with Lyme disease, thereby providing the first direct evidence for autoimmune T and B cell responses in this illness.
Lisa J Glickstein - One of the best experts on this subject based on the ideXlab platform.
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association of a toll like receptor 1 polymorphism with heightened th1 inflammatory responses and antibiotic refractory Lyme Arthritis
Arthritis & Rheumatism, 2012Co-Authors: Klemen Strle, Lisa J Glickstein, Junghee J Shin, Allen C SteereAbstract:Objective Single-nucleotide polymorphisms (SNPs) that alter immune function, inflammatory responses, and disease susceptibility have been identified in several genes encoding Toll-like receptors (TLRs). The TLR SNPs with the best evidence of an effect on immune function are those in TLR1 (1805GG), TLR2 (2258GA), and TLR5 (1174CT). This study was undertaken to assess the frequency and functional outcomes of these polymorphisms in patients with Lyme disease. Methods SNP frequencies and functional outcomes were assessed in 248 patients with Lyme disease. Cytokine and chemokine levels were determined using multiplex assays in the serum of patients with erythema migrans (EM), joint fluid of patients with Lyme Arthritis, and supernatants of Borrelia burgdorferi–stimulated peripheral blood mononuclear cells (PBMCs) from patients with Lyme Arthritis. Results The frequency of the TLR1-1805GG polymorphism was greater in patients with antibiotic-refractory Arthritis compared with patients with EM or those with antibiotic-responsive Arthritis. Early in the illness, patients with EM carrying 1805GG, primarily those infected with B burgdorferi 16S–23S ribosomal spacer RNA intergenic type 1 (RST1) strains, had higher serum levels of interferon-γ (IFNγ), CXCL9, and CXCL10 and had more severe infection than EM patients carrying the 1805TG/TT polymorphism. These inflammatory responses were amplified in patients with Lyme Arthritis, and the highest responses were observed in patients with 1805GG in the antibiotic-refractory group who had been infected with RST1 strains. When PBMCs from patients with Lyme Arthritis were stimulated with a B burgdorferi RST1 strain, the 1805GG group had a significantly larger fold increase in the levels of IFNγ, CCL2, CXCL9, and CXCL10 compared to the 1805TG/TT group. In contrast, the TLR2 and TLR5 polymorphisms did not vary in frequency or function among the groups. Conclusion The TLR1-1805GG polymorphism in B burgdorferi RST1–infected patients was associated with stronger Th1-like inflammatory responses, an environment that may set the stage for antibiotic-refractory Arthritis.
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burden and viability of borrelia burgdorferi in skin and joints of patients with erythema migrans or Lyme Arthritis
Arthritis & Rheumatism, 2011Co-Authors: Gail Mchugh, Lisa J Glickstein, Nitin Damle, Vijay K Sikand, Allen C SteereAbstract:Objective To determine the burden and viability of Borrelia burgdorferi in the skin and joints of patients with Lyme disease. Methods Standard and quantitative poLymerase chain reaction (PCR) techniques were used to detect B burgdorferi DNA in skin samples from 90 patients with erythema migrans (EM) and in synovial fluid (SF) from 63 patients with Lyme Arthritis (LA) and in synovial tissue from 9 patients. Quantitative PCR determinations of B burgdorferi DNA, messenger RNA (mRNA), and ribosomal RNA (rRNA) were made in 10 skin samples from EM patients and 11 SF samples from LA patients. Results Skin lesions in most patients with EM had positive PCR results for B burgdorferi DNA. In the majority of patients with LA, a late disease manifestation, PCR results in pretreatment SF samples were positive. In patients with antibiotic-refractory Arthritis, positive PCR results persisted for as long as 11 months, but positive results in samples taken during the postantibiotic period did not correlate with relapse or with the subsequent duration of Arthritis, and at synovectomy, all results of PCR of synovial tissue were negative. B burgdorferi mRNA, a marker of spirochetal viability, was detected in 8 of 10 skin samples from EM patients, but in none of 11 SF samples from LA patients, even when obtained prior to antibiotic administration. Moreover, the median ratio of spirochetal rRNA to DNA, a measure of ribosomal activity, was 160 in the 10 EM skin samples, but only 0.15 in the 3 LA SF samples with positive results. Conclusion B burgdorferi in the skin lesions of EM patients were active and viable, whereas those in the SF of LA patients were moribund or dead at any time point. Thus, detection of B burgdorferi DNA in SF is not a reliable test of active joint infection in Lyme disease.
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relationship between immunity to borrelia burgdorferi outer surface protein a ospa and Lyme Arthritis
Clinical Infectious Diseases, 2011Co-Authors: Allen C Steere, Elise E Drouin, Lisa J GlicksteinAbstract:Antibiotic-refractory Lyme Arthritis may result from Borrelia burgdorferi–induced autoimmunity in affected joints. Such patients usually have certain HLA-DRB1 molecules that bind an epitope of B. burgdorferi outer-surface protein A (OspA163–175), and cellular and humoral immune responses to OspA are greater in patients with antibiotic-refractory Arthritis than in those with antibiotic-responsive Arthritis. Recent work in a mouse model suggests that, during B. burgdorferi infection, OspA in genetically susceptible individuals stimulates a particularly strong TH1 response, which may be one of several factors that can help set the stage for a putative autoimmune response in affected joints. However, vaccination with OspA did not induce Arthritis in this mouse model, and case and control comparisons in human vaccine trials did not show an increased frequency of Arthritis among OspA-vaccinated individuals. Thus, a vaccine-induced immune response to OspA does not replicate the sequence of events needed in the natural infection to induce antibiotic-refractory Lyme Arthritis.
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borrelia burgdorferi stimulation of chemokine secretion by cells of monocyte lineage in patients with Lyme Arthritis
Arthritis Research & Therapy, 2010Co-Authors: Junghee J Shin, Lisa J Glickstein, Klemen Strle, Andrew D Luster, Allen C SteereAbstract:Joint fluid in patients with Lyme Arthritis often contains high levels of CCL4 and CCL2, which are chemoattractants for monocytes and some T cells, and CXCL9 and CXCL10, which are chemoattractants for CD4+ and CD8+ T effector cells. These chemokines are produced primarily by cells of monocyte lineage in TH1-type immune responses. Our goal was to begin to learn how infection with Borrelia burgdorferi leads to the secretion of these chemokines, using patient cell samples. We hypothesized that B. burgdorferi stimulates chemokine secretion from monocytes/macrophages in multiple ways, thereby linking innate and adaptive immune responses. Peripheral blood mononuclear cells (PBMC) from 24 Lyme Arthritis patients were stimulated with B. burgdorferi, interferon (IFN)-γ, or both, and the levels of CCL4, CCL2, CXCL9 and CXCL10 were measured in culture supernatants. CD14+ monocytes/macrophages from PBMC and synovial fluid mononuclear cells (SFMC) were stimulated in the same way, using available samples. CXCR3, the receptor for CXCL9 and CXCL10, and CCR5, the receptor for CCL4, were assessed on T cells from PBMC and SFMC. In patients with Lyme Arthritis, B. burgdorferi but not IFN-γ induced PBMC to secrete CCL4 and CCL2, and B. burgdorferi and IFN-γ each stimulated the production of CXCL9 and CXCL10. However, with the CD14+ cell fraction, B. burgdorferi alone stimulated the secretion of CCL4; B. burgdorferi and IFN-γ together induced CCL2 secretion, and IFN-γ alone stimulated the secretion of CXCL9 and CXCL10. The percentage of T cells expressing CXCR3 or CCR5 was significantly greater in SFMC than PBMC, confirming that TH1 effector cells were recruited to inflamed joints. However, when stimulated with B. burgdorferi or IFN-γ, SFMC and PBMC responded similarly. B. burgdorferi stimulates PBMC or CD14+ monocytes/macrophages directly to secrete CCL4, but spirochetal stimulation of other intermediate cells, which are present in PBMC, is required to induce CD14+ cells to secrete CCL2, CXCL9 and CXCL10. We conclude that B. burgdorferi stimulates monocytes/macrophages directly and indirectly to guide innate and adaptive immune responses in patients with Lyme Arthritis.
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strong igg antibody responses to borrelia burgdorferi glycolipids in patients with Lyme Arthritis a late manifestation of the infection
Clinical Immunology, 2009Co-Authors: Kathryn L Jones, Robert J Seward, Catherine E. Costello, Lisa J Glickstein, Gil Benmenachem, Allen C SteereAbstract:In this study, the membrane lipids of B. burgdorferi were separated into 16 fractions; the components in each fraction were identified, and the immunogenicity of each fraction was determined by ELISA using sera from Lyme disease patients. Only the 2 glycolipids, acylated cholesteryl galactoside (ACG, BbGL-I) and monogalactosyl diacylglycerol (MgalD, BbGL-II), were immunogenic. Early in the infection, 24 of 84 patients (29%) who were convalescent from erythema migrans and 19 of the 35 patients (54%) with neuroborreliosis had weak IgG responses to purified MgalD, and a smaller percentage of patients had early responses to synthetic ACG. However, almost all of 75 patients with Lyme Arthritis, a late disease manifestation, had strong IgG reactivity with both glycolipids. Thus, almost all patients with Lyme Arthritis have strong IgG antibody responses to B. burgdorferi glycolipid antigens.
