102,897 research outputs found
T cell subsets and disease mechanisms in inflammatory myopathies
No full textThe idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of chronic muscle disorders, typically displaying infiltrating T cells in skeletal muscle tissue and classified into polymyositis, dermatomyositis and sporadic inclusion body myositis. Several studies involving both humans and animal models point towards a role for T cells in the pathogenesis of IIMs, however, the precise phenotype, functionality and specificity of pathogenic T cells remain elusive. Increased frequencies of a subset of T cells, known as CD28null T cells, in peripheral blood and affected organs in various chronic inflammatory disorders, are reported by several studies. Such CD28null T cells are highly differentiated T cells lacking the co-stimulatory molecule CD28, which acquire expression of other receptors commonly associated with natural killer cells, and display proinflammatory, cytotoxic and apoptosis resistant features. In contrast to CD28null T cells, regulatory T cells are T cell subset critical for maintaining immune tolerance and also described to assist in the muscle repair process.The aims of this thesis were to investigate CD28null T cell subsets in both muscle tissue and peripheral blood of patients with IIMs, by evaluating frequencies, phenotype, function and clinical relevance of these cells. The cytotoxic mechanisms of CD28null T cells towards autologous muscle cells were investigated using in vitro T cell - muscle cell co-cultures. Muscle tissues of patients were investigated for the effects of conventional immunosuppressive therapies on CD28null and regulatory T cell subsets. Glucocorticoid and regulatory T cells mediated immunosuppressive effects on circulating CD28nulls T cells were evaluated using in vitro assays.We demonstrate that muscle-infiltrating T cells are predominantly CD4+CD28null and CD8+CD28null T cells in patients with polymyositis and dermatomyositis. Also in sporadic inclusion body myositis, where the role of immune system is controversial, T cell infiltrates in muscle tissue are dominated by CD28null T cells. Circulating CD28null T cell subsets of both CD4 and CD8 lineage were more common in patients compared to healthy controls, and were associated with human cytomegalovirus infection. These cells displayed oligoclonal expansions, proinflammatory cytokine secretion and degranulation potential, and also contained perforin. Using autologous in vitro co-cultures, we showed that the cytotoxic effects of CD28null T cells towards muscle cells are mediated largely via perforin-dependent mechanisms and regulated by IFNγ-induced HLA expression on muscle cells. Interestingly, poor clinical response in patients following immunosuppressive therapy was linked to persistence of CD28null T cells in muscle tissue. CD4+CD28null T cells were also found to be resistant towards glucocorticoid and regulatory T cell mediated immunosuppression in in vitro assays.These findings imply that CD28null T cells represent clinically important effector cells in IIMs, capable of attacking muscle fibers and inducing chronic inflammation mediated pathogenesis. Ineffectiveness of current immunosuppressive therapies appears to be linked with persistent CD28null T cells in muscle tissue as well as their immunosuppression resistant properties; therefore, these cells represent potential target candidates for future therapies.List of scientific papersI. Andreas E. R. Fasth, Maryam Dastmalchi, Afsar Rahbar, Stina Salomonsson, Jayesh M. Pandya, Eva Lindroos, Inger Nennesmo, Karl-Johan Malmberg, Cecilia Söderberg-Nauclér, Christina Trollmo, Ingrid E. Lundberg and Vivianne Malmström. T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells. Journal of Immunology. 2009, Oct 1;183(7):4792-9. https://doi.org/10.4049/jimmunol.0803688 II. Jayesh M. Pandya, Andreas E. R. Fasth, Mei Zong, Snjolaug Arnardottir, Lara Dani, Eva Lindroos, Vivianne Malmström and Ingrid E. Lundberg. Expanded TCR-Vβ Restricted T cells from Sporadic Inclusion Body Myositis Patients are Proinflammatory and Cytotoxic CD28null T cells. Arthritis & Rheumatism. 2010 Nov; 62(11): 3457-66. https://doi.org/10.1002/art.27665 III. Jayesh M. Pandya, Paulius Venalis, Lubna Al-Khalili, Mohammad Shahadat Hossain, Vanessa Stache, Ingrid E. Lundberg, Vivianne Malmström, Andreas E.R. Fasth. CD28null T Cells from Polymyositis Patients are Cytotoxic to Autologous Muscle Cells In Vitro via Perforin-Dependent Mechanisms. [Manuscript]IV. Jayesh M. Pandya, Ingela Loell, Mohammad Shahadat Hossain, Mei Zong, Helene Alexanderson, Sukanya Raghavan, Ingrid E. Lundberg and Vivianne Malmström. Muscle Persistent and Immunosuppression Resistant CD28null T cells in Patients with Polymyositis and Dermatomyositis. [Manuscript]</p
Interaction of human heat shock protein 70 with tumor-associated peptides
No full textMolecular chaperones of the heat shock protein 70 (Hsp70) family play a crucial role in the presentation of exogenous antigenic peptides by antigen-presenting cells (APCs). In a combined biochemical and immunological approach, we characterize the biochemical interaction of tumor-associated peptides with human Hsp70 and show that the strength of this interaction determines the efficacy of immunological cross-presentation of the antigenic sequences by APCs. A fluorescein-labeled cytosolic mammalian Hsc70 binding peptide is shown to interact with human Hsp70 molecules with high affinity (K(d)=0.58 mu M at 25 degrees C). Competition experiments demonstrate weaker binding by Hsp70 of antigenic peptides derived from the tumor-associated proteins tyrosinase (K(d)=32 mu M) and melanoma antigen recognized by T cells (MART-1) (K(d)=2.4 mu M). Adding a peptide sequence (pep70) with high Hsp70 binding affinity (K(d)=0.04 mu M) to the tumor-associated peptides enables them to strongly interact with Hsp70. Presentation of tumor-associated peptides by B cells resulting in T cell activation in vitro is enhanced by Hsp70 when the tumor-associated peptides contain the Hsp70 binding sequence. This observation has relevance for vaccine design, as augmented transfer of tumor-associated antigens to APCs is closely linked to the vaccine's efficacy of T cell stimulation
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
AB0142 Immunosuppressive effects of glucocorticoids and regulatory t cells on cd28null t cells in vitro
No full textBackground CD28null T cells are terminally differentiated T cells lacking CD28 co-receptor. These cells display properties of proinflammatory killer cells1, 2 and are suggested to be resistant to apoptosis in vivo 3. Frequencies of CD28null T cells are increased in various chronic, inflammatory diseases. CD28null T cells dominate both in the affected muscle and peripheral blood of patients with idiopathic inflammatory myopathies2, 4 (myositis), suggesting a role these cells in disease mechanism and muscle pathology. Recently, it was found in our lab that after conventional glucocorticoid treatment, the relative number of regulatory T cells (Tregs) was unchanged or decreased, while the CD28null T cell proportion was mainly increased in muscle tissue of myositis patients (unpublished data). This leads to our working hypothesis that CD28null T cells are resistant to immunosuppression mediated by glucocorticoids in the setting of myositis. Such resistance could also be against Tregs mediated immunosuppression due to distinct phenotype of CD28null T cells. Objectives The aim of this study was to evaluate the immunosuppressive effects of glucocorticoids and Tregs on CD28null T cells in an in vitro system. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from 3 healthy individuals using Ficoll separation. CD3+CD4+CD25++(high) cells were sorted as Tregs by flow cytometry. For glucocorticoid or Tregs mediated T cell suppression assays, PBMCs were stimulated with plate bound α-CD3 antibody in presence of 4uM glucocorticoid (methyl prednisolone sodium succinate) or optimal proportion of Tregs. Up-regulation of the early activation marker CD69 was measured by flow cytometry. Suppression was estimated based on % reduction in CD69 mean fluorescent intensity compared to stimulated control cells. Results CD4+CD28null T cells (median % suppression: 40.1%) displayed lower sensitivity towards glucocorticoid-mediated suppression compared to CD28+ counterparts (median: 54.7%), seen in all individuals tested. Similarly, CD4+CD28null T cells (median: 17.5%) were less sensitive towards Tregs mediated suppression compared to CD28+ counterparts (median: 34.4%) in all individuals. No clear trend could be observed in CD8 compartment so far. Conclusions Although, more individuals need to be tested, the above in vitro data support our in vivo findings that CD28null T cells are relatively resistant to glucocorticoid and Tregs mediated immunosuppression. Lower sensitivity of CD28null T cells towards glucocorticoid and Tregs mediated suppression support their treatment resistance nature in myositis and a role in chronic inflammation and autoimmunity. References 1. Fasth, A. E. et al. Arthritis Res Ther (2007), 9, R87, 2286. 2. Pandya, J. M. et al. Arthritis Rheum (2010). 62, 3457-3466. 3. Schirmer, M. et al. J Immunol (1998) 161, 1018-1025. 4. Fasth AE, et al. J Immunol. (2009) Oct 1;183(7):4792-9. Disclosure of Interest None Declare
Handwritten biographical information on Paulina T. McClung Merritt
No full textA handwritten biography of Paulina T. McClung Merritt by an unknown author, 1892.
Heterogeneous and tissue-specific regulation of effector T cell responses by IFN-gamma during Plasmodium berghei ANKA infection.
No full textIFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN-γ(-/-) mice during P. berghei ANKA infection. The expansion of splenic CD4(+) and CD8(+) T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ, but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ(-/-) mice; however, the migration to, and accumulation of, effector CD4(+) and CD8(+) T cells in the lung, liver, and brain was altered in IFN-γ(-/-) mice. Interestingly, activation and accumulation of T cells in various nonlymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN-γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended on active IFN-γ-dependent environmental signals--leading to T cell apoptosis--rather than upon intrinsic alterations in T cell programming. To our knowledge, this is the first study to fully investigate the role of IFN-γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Labour analgesia: Recent advances
No full textAdvances in the field of labour analgesia have tread a long journey from the days of ether and chloroform in 1847 to the present day practice of comprehensive programme of labour pain management using evidence-based medicine. Newer advances include introduction of newer techniques like combined spinal epidurals, low-dose epidurals facilitating ambulation, pharmacological advances like introduction of remifentanil for patient-controlled intravenous analgesia, introduction of newer local anaesthetics and adjuvants like ropivacaine, levobupivacaine, sufentanil, clonidine and neostigmine, use of inhalational agents like sevoflourane for patient-controlled inhalational analgesia using special vaporizers, all have revolutionized the practice of pain management in labouring parturients. Technological advances like use of ultrasound to localize epidural space in difficult cases minimizes failed epidurals and introduction of novel drug delivery modalities like patient-controlled epidural analgesia (PCEA) pumps and computer-integrated drug delivery pumps have improved the overall maternal satisfaction rate and have enabled us to customize a suitable analgesic regimen for each parturient. Recent randomized controlled trials and Cochrane studies have concluded that the association of epidurals with increased caesarean section and long-term backache remains only a myth. Studies have also shown that the newer, low-dose regimes do not have a statistically significant impact on the duration of labour and breast feeding and also that these reduce the instrumental delivery rates thus improving maternal and foetal safety. Advances in medical technology like use of ultrasound for localizing epidural space have helped the clinicians to minimize the failure rates, and many novel drug delivery modalities like PCEA and computer-integrated PCEA have contributed to the overall maternal satisfaction and safety
Pelevin’s Trinity in the novel “t”: author – protagonist – reader
No full textThe article attempts to interpret Pelevin's artistic strategy in the novel "T" by exploring its subject organization and addressing the key problems of the author, the protagonist, and the reader as they are seen by the researcher. The article analyzes the peculiarities of constructing the narrative reality in the novel "T", and goes on to discuss Pelevin's philosophic models of the development of the humankind, and the emergence of his new anthropology
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