bluuebunny/crossref_metadata_2025_split huggingface dataset:
A role for γ/δ T cells in a mouse model of fracture healing
Authors: Colburn Nona T. , Zaal Kristien J. M. , Wang Francis , Tuan Rocky S. 
Published: May 2009

AbstractObjectiveFractures can initiate an immune response that disturbs osteoblastic and osteoclastic cellular homeostasis through cytokine production and release. The aim of our study was to investigate γ/δ T cells, innate lymphocytes known to be involved in tissue repair, as potential cellular components of the osteoimmune system's response to an in vivo model of bone injury. The absence of such cells or their effector cytokines influences the fate of other responder cells in proliferation, differentiation, matrix production, and ultimate callus formation.MethodsTibia fractures were created in 60 γ/δ T cell–deficient mice (also called δ T cell receptor [TCR]–knockout mice) and 60 control C57BL/6 mice. Analysis included radiographs, basic histology, mechanical testing, flow cytometry, and immunohistochemical localization of γ/δ TCR–positive subsets from control animals and of CD44 expression from both groups, as well as enzyme‐linked immunosorbent assay for the effector cytokines interleukin‐2 (IL‐2), interferon‐γ (IFNγ), and IL‐6.ResultsAnimals deficient in γ/δ T cells demonstrated more mature histologic elements and quantitative increases in the expression of major bone (bone sialoprotein) and cartilage (type II collagen) matrix proteins and in the expression of bone morphogenetic protein 2 at a critical reparative phase. Moreover, only γ/δ T cell–deficient animals had a decrease in the osteoprogenitor antiproliferative cytokines IL‐6 and IFNγ at the reparative phase. The result was improved stability at the repair site and an overall superior biomechanical strength in γ/δ T cell–deficient mice compared with controls.ConclusionThe evidence for a role of γ/δ T cells in the context of skeletal injury demonstrates the importance of the immune system's effect on bone biology, which is relevant to the field of osteoimmunology, and offers a potential molecular platform from which to develop essential therapeutic strategies.
NOD2‐Associated pediatric granulomatous arthritis, an expanding phenotype: Study of an international registry and a national cohort in spain
Authors: Rosé Carlos D. , Aróstegui Juan I. , Martin Tammy M. , Espada Graciela , Scalzi Lisabeth , Yagüe Jordi , Rosenbaum James T. , Modesto Consuelo , Cristina Arnal Maria , Merino Rosa , García‐Consuegra Julia , Carballo Silva María Antonia , Wouters Carine H. 
Published: May 2009

AbstractObjectiveTo study the phenotype characteristics of the largest to date cohort of patients with pediatric granulomatous arthritis (PGA) and documented mutations in the NOD2 gene.MethodsWe analyzed merged data from 2 prospective cohorts of PGA patients, the International PGA Registry and a Spanish cohort. A systematic review of the medical records of interest was performed to identify phenotype characteristics.ResultsForty‐five patients with PGA (23 sporadic cases and 22 from familial pedigrees) and documented NOD2 mutations were identified and formed the basis of the study. Of these 45 patients, 18 had the R334W‐encoding mutation, 18 had R334Q, 4 had E383K, 3 had R587C, 1 had C495Y, and 1 had W490L. The majority of patients manifested the typical triad of dermatitis, uveitis, and arthritis. In contrast, in 13 patients, the following “atypical” manifestations were noted: fever, sialadenitis, lymphadenopathy, erythema nodosum, leukocytoclastic vasculitis, transient neuropathy, granulomatous glomerular and interstitial nephritis, interstitial lung disease, arterial hypertension, hypertrophic cardiomyopathy, pericarditis, pulmonary embolism, hepatic granulomatous infiltration, splenic involvement, and chronic renal failure. In addition, 4 individuals who were asymptomatic carriers of a disease‐causing mutation were documented.ConclusionNOD2‐associated PGA can be a multisystem disorder with significant visceral involvement. Treating physicians should be aware of the systemic nature of this condition, since some of these manifestations may entail long‐term morbidity.
Remnants of secondarily necrotic cells fuel inflammation in systemic lupus erythematosus
Authors: Muñoz Luis E. , Janko Christina , Grossmayer Gerhard E. , Frey Benjamin , Voll Reinhard E. , Kern Peter , Kalden Joachim R. , Schett Georg , Fietkau Rainer , Herrmann Martin , Gaipl Udo S. 
Published: May 2009

AbstractObjectivePatients with systemic lupus erythematosus (SLE) are often characterized by cellular as well as humoral deficiencies in the recognition and phagocytosis of dead and dying cells. The aim of this study was to investigate whether the remnants of apoptotic cells are involved in the induction of inflammatory cytokines in blood‐borne phagocytes.MethodsWe used ex vivo phagocytosis assays comprising cellular and humoral components and phagocytosis assays with isolated granulocytes and monocytes to study the phagocytosis of secondarily necrotic cell–derived material (SNEC). Cytokines were measured by multiplex bead array technology.ResultsWe confirmed the impaired uptake of various particulate targets, including immunoglobulin‐opsonized beads, by granulocytes and monocytes from patients with SLE compared with healthy control subjects. Surprisingly, blood‐borne phagocytes from two‐thirds of the patients with SLE took up SNEC, which was rarely phagocytosed by phagocytes from healthy control subjects or patients with rheumatoid arthritis. Supplementation of healthy donor blood with IgG fractions derived from patients with SLE transferred the capability to take up SNEC to the phagocytes of healthy donors. Phagocytosis‐promoting immune globulins also induced secretion of huge amounts of cytokines by blood‐borne phagocytes following uptake of SNEC.ConclusionOpsonization of SNEC by autoantibodies from patients with SLE fosters its uptake by blood‐borne monocytes and granulocytes. Autoantibody‐mediated phagocytosis of SNEC is accompanied by secretion of inflammatory cytokines, fueling the inflammation that contributes to the perpetuation of autoimmunity in SLE.
Autoantibodies to a 140‐kd protein in juvenile dermatomyositis are associated with calcinosis
Authors: Gunawardena H. , Wedderburn L. R. , Chinoy H. , Betteridge Z. E. , North J. , Ollier W. E. R. , Cooper R. G. , Oddis C. V. , Ramanan A. V. , Davidson J. E. , McHugh N. J. 
Published: May 2009

AbstractObjectiveThe identification of novel autoantibodies in juvenile dermatomyositis (DM) may have etiologic and clinical implications. The aim of this study was to describe autoantibodies to a 140‐kd protein in children recruited to the Juvenile DM National Registry and Repository for UK and Ireland.MethodsClinical data and sera were collected from children with juvenile myositis. Sera that recognized a 140‐kd protein by immunoprecipitation were identified. The identity of the p140 autoantigen was investigated by immunoprecipitation/immunodepletion, using commercial monoclonal antibodies to NXP‐2, reference anti‐p140, and anti‐p155/140, the other autoantibody recently described in juvenile DM. DNA samples from 100 Caucasian children with myositis were genotyped for HLA class II haplotype associations and compared with those from 864 randomly selected UK Caucasian control subjects.ResultsSera from 37 (23%) of 162 patients with juvenile myositis were positive for anti‐p140 autoantibodies, which were detected exclusively in patients with juvenile DM and not in patients with juvenile DM–overlap syndrome or control subjects. No anti‐p140 antibody–positive patients were positive for other recognized autoantibodies. Immunodepletion suggested that the identity of p140 was consistent with NXP‐2 (the previously identified MJ autoantigen). In children with anti‐p140 antibodies, the association with calcinosis was significant compared with the rest of the cohort (corrected P < 0.005, odds ratio 7.0, 95% confidence interval 3.0–16.1). The clinical features of patients with anti‐p140 autoantibodies were different from those of children with anti‐p155/140 autoantibodies. The presence of HLA–DRB1*08 was a possible risk factor for anti‐p140 autoantibody positivity.ConclusionThis study has established that anti‐p140 autoantibodies represent a major autoantibody subset in juvenile DM. This specificity may identify a further immunogenetic and clinical phenotype within the juvenile myositis spectrum that includes an association with calcinosis.
Decrease in glomerulonephritis and Th1‐associated autoantibody production after progesterone treatment in NZB/NZW mice
Authors: Hughes Grant C. , Martin David , Zhang Kang , Hudkins Kelly L. , Alpers Charles E. , Clark Edward A. , Elkon Keith B. 
Published: May 2009

AbstractObjectiveWhile estrogen treatment exacerbates disease in models of systemic lupus erythematosus (SLE), the effects of progesterone are unclear. This study was undertaken to assess the effects of continuous progesterone treatment on autoantibody production and spontaneous glomerulonephritis (GN) in a mouse model of SLE.MethodsFemale (NZB × NZW)F1 (NZB/NZW) mice were treated with vehicle, 2 mg of depot medroxyprogesterone acetate (DMPA), or 10 mg of DMPA every 6 weeks. Survival, proteinuria, and serum anti–double‐stranded DNA (anti‐dsDNA) levels were monitored. At 39 weeks of age, kidneys were analyzed for abnormalities and glomerular accumulation of IgG subclasses and C3. Spleen leukocyte subsets were also analyzed.ResultsDMPA treatment reduced mortality in a dose‐dependent manner in association with reduced proteinuria and glomerular damage. High‐dose DMPA treatment resulted in a reduction of total serum IgG and IgG2a anti‐dsDNA antibody levels, whereas IgG1 anti‐dsDNA antibody levels were modestly increased. High‐dose DMPA reduced glomerular accumulation of IgG1, IgG2a, IgG3, and complement, while low‐dose DMPA decreased glomerular IgG2a and IgG3 levels compared with vehicle treatment.ConclusionOur findings indicate that treatment of premorbid female NZB/NZW mice with DMPA reduces mortality and attenuates spontaneous GN, likely through multiple mechanisms, including altered ratios of protective Th2‐related IgG antibodies versus nephritogenic Th1‐related IgG autoantibodies. Thus, estrogen and progesterone may have disparate effects on lupus autoimmunity, lending new significance to observed hormonal imbalances in patients with SLE. These data also suggest that treatment of SLE patients with DMPA may have therapeutic benefit.
HLA–B27–restricted antigen presentation by human chondrocytes to CD8+ T cells: Potential contribution to local immunopathologic processes in ankylosing spondylitis
Authors: Kuhne Maren , Erben Ulrike , Schulze‐Tanzil Gundula , Köhler Dorothee , Wu Peihua , Richter F. Jan , John Thilo , Radbruch Andreas , Sieper Joachim , Appel Heiner 
Published: May 2009

AbstractObjectiveAnalysis of the histopathologic features of hip arthritis in patients with ankylosing spondylitis (AS) has revealed accumulation of infiltrating mononuclear cells in the bone end plate and presence of hyaline articular cartilage that is not found in areas of total cartilage destruction. This study was undertaken to assess whether chondrocytes attract lymphocytes and whether cartilage chondrocytes from patients with AS have the potential to directly stimulate T cells in an HLA‐restricted manner.MethodsHuman HLA–B27+ T cell lines, specific for the Epstein‐Barr virus–derived peptide EBNA258–266, and autologous chondrocytes, serving as nonprofessional antigen‐presenting cells (APCs), were available for use in a model system to study chondrocyte functions in femoral head joint cartilage of patients with AS. Peptide functionality of cytotoxic T cells was assessed by flow cytometry, and cellular interactions were detected by fluorescence confocal microscopy.ResultsWhen maintained in an alginate matrix, chondrocytes isolated from the femoral heads of patients with AS constitutively expressed type II collagen and CD80. When pulsed with the EBNA258–266 peptide, autologous chondrocytes functioned as APCs and, specifically, induced interferon‐γ production in CD8+ T cells. In mixed chondrocyte–T cell cultures, cell–cell contacts were dependent on the presence of the EBNA258–266 peptide. T cells adjacent to chondrocytes produced perforin and granzyme B; both molecules were found in focal aggregates, a prerequisite for antigen‐specific lysis of target cells.ConclusionAntigen presentation through human chondrocytes allows the stimulation of peptide‐specific CD8+ T cells. These results indicate that human chondrocytes can act as nonprofessional APCs, and suggest that there is an interferon‐γ–triggered autocrine loop of immune cell–mediated chondrocyte activation in the already inflamed environment. Thus, local HLA‐dependent activation of peptide‐specific cytotoxic CD8+ T cells by chondrocytes might contribute to inflammatory processes in the spondylarthritides.
Intervention of an inflammation amplifier, triggering receptor expressed on myeloid cells 1, for treatment of autoimmune arthritis
Authors: Murakami Yousuke , Akahoshi Tohru , Aoki Naoko , Toyomoto Masayasu , Miyasaka Nobuyuki , Kohsaka Hitoshi 
Published: May 2009

AbstractObjectiveTriggering receptor expressed on myeloid cells 1 (TREM‐1) is inducible on monocyte/macrophages and neutrophils and accelerates tissue destruction by propagating inflammatory responses in disease related to bacterial infections. Its blockade rescues the hosts in murine models of sepsis, to clear the bacteria without impairing the host defense. The aim of this study was to investigate the involvement of TREM‐1 in an autoimmune, noninfectious disease.MethodsSynovial tissue specimens from the joints of patients with rheumatoid arthritis (RA) and the joints of mice with collagen‐induced arthritis (CIA) were examined for TREM‐1 expression, using flow cytometric analysis. Expression of TREM‐1 on macrophages was induced by lipopolysaccharide, with or without a cyclooxygenase inhibitor. Rheumatoid synovial cells were stimulated with agonistic anti–TREM‐1 antibodies. Recombinant adenovirus encoding the extracellular domain of TREM‐1 fused with IgG‐Fc (AxCATREM‐1 Ig) or synthetic TREM‐1 antagonistic peptides were injected to treat CIA, and the clinical manifestations of the antigen‐specific T cell and B cell responses were evaluated.ResultsTREM‐1 was expressed on CD14+ cells in rheumatoid synovial tissue and synovial macrophages from mice with CIA. Unlike murine macrophages, human monocyte/macrophages did not depend on prostaglandin E2 for up‐regulation of TREM‐1. Agonistic anti–TREM‐1 antibodies promoted tumor necrosis factor α production from rheumatoid synovial cells. Blockade of TREM‐1 using AxCATREM‐1 Ig and antagonistic peptides ameliorated CIA without affecting the serum levels of anti–type II collagen antibodies or the proliferative responses of splenocytes to type II collagen.ConclusionTREM‐1 ligation contributes to the pathology of autoimmune arthritis. The results of this study implied that blockade of TREM‐1 could be a new approach to rheumatic diseases that is safer than the presently available immunosuppressive treatments.
Impaired differentiation and cytotoxicity of natural killer cells in systemic lupus erythematosus
Authors: Park Yong‐Wook , Kee Seung‐Jung , Cho Young‐Nan , Lee Eun‐Hee , Lee Hwa‐Youn , Kim Eun‐Mi , Shin Min‐Ho , Park Jeong‐Jin , Kim Tae‐Jong , Lee Shin‐Seok , Yoo Dae‐Hyun , Kang Hyung‐Sik 
Published: May 2009

AbstractObjectiveTo determine the cytotoxicity of natural killer (NK) cells and the level of differentiation of hematopoietic stem cells (HSCs) into NK cells in systemic lupus erythematosus (SLE).MethodsPatients with SLE (n = 108), rheumatoid arthritis (RA; n = 90), Behçet's disease (n = 39), or ankylosing spondylitis (n = 41) and healthy control subjects (n = 173) were enrolled in the study. NK cell levels, NK cell cytotoxicities, and lymphokine‐activated killer (LAK) activities against K562 cells were measured by flow cytometry. Gene expression was assessed by reverse transcription–polymerase chain reaction. NK cells were differentiated from peripheral blood and bone marrow HSCs in vitro.ResultsPercentages and absolute numbers of NK cells, cytotoxicities, and LAK activities were significantly lower in the peripheral blood of SLE and RA patients than in that of healthy controls. In particular, this NK cell deficiency was more prominent in patients with lupus nephritis and those with thrombocytopenia. Notably, purified NK cells derived from SLE patients, but not RA patients, were found to have lower cytotoxicities and LAK activities than those from healthy controls. This defect of NK cells in SLE patients was found to be related to lower numbers of NK precursors and to the down‐regulation of perforin and granzyme in NK cells. The proliferative capacity of HSCs, the percentages of NK cells differentiated from HSCs, and NK cell cytotoxicities were significantly lower in SLE patients.ConclusionIn SLE patients, circulating levels of NK cells were diminished and their cytotoxicities were impaired. Furthermore, the differentiation of HSCs into NK cells was found to be defective. These abnormalities possibly contribute to immune system dysregulation in SLE.
Normalizing memory recall in fibromyalgia with rehearsal: A distraction‐counteracting effect
Authors: Leavitt Frank , Katz Robert S. 
Published: May 2009

AbstractObjectiveTo examine the impact of distraction on the retention of rehearsed information in patients with fibromyalgia syndrome (FMS).MethodsData refer to the neurocognitive examination of 134 patients (91 with FMS and 43 control subjects) presenting with memory loss. Four neurocognitive measures free of distraction, along with 2 measures with added distraction, were completed. Differences in the retention of rehearsed and unrehearsed information with a source of distraction present were calculated.ResultsPatients with FMS showed normal cognitive functioning on verbal memory tests free of distraction. Adding a source of distraction caused unrefreshed information to be lost at a disproportionate rate in patients with FMS. Over 87% of patients with FMS scored in the impaired range on a task of unrehearsed verbal memory. Adding a source of distraction to well‐rehearsed information produced a normal rate of recall in FMS.ConclusionRehearsal mechanisms are intact in patients with FMS and play beneficial roles in managing interference from a source of distraction. In the absence of rehearsal, a source of distraction added to unrefreshed information signals a remarkable level of cognitive deficit in FMS that goes undetected by conventionally relied‐upon neurocognitive measures. We present a theory to promote understanding of the cognitive deficit of people with FMS based on reduced speed of lexical activation and poor recall after distraction.
Role of CTA1R7K‐COL‐DD as a novel therapeutic mucosal tolerance–inducing vector for treatment of collagen‐induced arthritis
Authors: Hasselberg Annemarie , Schön Karin , Tarkowski Andrej , Lycke Nils 
Published: May 2009

AbstractObjectiveTo determine whether a cholera toxin–derived, novel immunomodulating fusion protein, CTA1R7K‐COL‐DD, carrying the class II major histocompatibility complex H‐2q–restricted type II collagen peptide aa 259–274, can induce therapeutic tolerance and prevent collagen‐induced arthritis (CIA) when administered intranasally in DBA/1 mice, and to assess whether ADP‐ribosylation at the mucosal membranes exerts a regulatory function such that the outcome of tolerance or immune enhancement can be controlled.MethodsDBA/1 mice with CIA were treated intranasally with CTA1R7K‐COL‐DD. The therapeutic effect was monitored for 46 days after the onset of disease. Clinical scoring of disease, histologic examination of inflammation, and bone erosion were assessed, and cytokine levels were determined in the serum or supernatants from splenocytes stimulated with recall antigen.ResultsThe protective effect of CTA1R7K‐COL‐DD resulted in roughly 60% of the mice having no clinical signs or histologic evidence of disease after treatment, and those with CIA had significantly milder disease with less bone erosion. The protective status was associated with lower serum titers of IgG1, IgG2a, IgG2b, and IgG3 anticollagen and a substantial decrease in the production of interleukin‐6 (IL‐6), IL‐17, and interferon‐γ, while levels of IL‐10 were markedly up‐regulated both in the serum and at the T cell level.ConclusionThe enzymatically inactive mutant fusion protein CTA1R7K‐COL‐DD provided substantial therapeutic protection against CIA following intranasal administration. The mechanism behind the effect appears to be mediated by peptide‐specific regulatory T cells induced by mucosal exposure to the peptide containing CTA1R7K‐COL‐DD vector. In addition, ADP‐ribosylation at the mucosal membranes acts as a key regulator controlling mucosal tolerance or immunity.
Induction of complete and sustained remission of rheumatoid pachymeningitis by rituximab
Authors: Schmid L. , Müller M. , Treumann T. , Arnold W. , Möller B. , Aeberli D. , Villiger P. M. 
Published: May 2009

AbstractAseptic pachymeningitis is a rare and serious complication of rheumatoid arthritis (RA). Herein, we describe a patient with rheumatoid factor–positive and anti–cyclic citrullinated peptide–positive RA who experienced a focal seizure, with aphasia and convulsions of the right side of the body. The findings of magnetic resonance imaging and histologic analysis led to a diagnosis of rheumatoid pachymeningitis. Because the patient had a large number of CD20‐expressing B lymphocytes, therapy with rituximab was started and has resulted in complete and sustained remission of both the pachymeningitis and the RA for >2 years. Despite a decrease in immunoglobulins, the patient has remained free of infections, which illustrates the favorable outcome that can result from therapeutic B cell depletion in this potentially lethal manifestation of RA.
Dramatic efficacy of infliximab in cauda equina syndrome complicating ankylosing spondylitis
Authors: Cornec Divi , Pensec Valérie Devauchelle , Joulin Sandrine Jousse , Saraux Alain 
Published: May 2009

AbstractCauda equina syndrome is an uncommon complication of ankylosing spondylitis (AS) characterized by the slow and insidious development of severe neurologic impairment. Imaging studies usually show a wide lumbar canal with dural ectasia. No medical or surgical treatment has been proven effective. We managed the care of a 66‐year‐old man who had longstanding AS and clinical features of cauda equina syndrome, including anal incontinence and buttock hypoesthesia. Magnetic resonance imaging demonstrated no cause for these symptoms other than AS. The patient was treated with infliximab, a monoclonal antibody to tumor necrosis factor α that is used for the treatment of active AS. After 3 infliximab infusions, sphincter control and sensation were normal. The treatment was continued, and he was still doing well 1 year later. This is the first report of an effective treatment for cauda equina syndrome complicating AS. Our case report strongly supports an inflammatory mechanism to this condition.