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3. Ligand Specificity and Repertoire Development of Murine TCRγδ Cells

Author

Bluestone, J. A., Cron, R. Q., Rellahan, B., Matis, L. A., Compans, R. W., editor, Cooper, M., editor, Koprowski, H., editor, McConnell, I., editor, Melchers, F., editor, Nussenzweig, V., editor, Oldstone, M., editor, Olsnes, S., editor, Potter, M., editor, Saedler, H., editor, Vogt, P. K., editor, Wagner, H., editor, Wilson, I., editor, Pfeffer, Klaus, editor, Heeg, Klaus, editor, Wagner, Hermann, editor, and Riethmüller, Gert, editor

Published
1991
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21. Octamer proteins inhibit IL-4 gene transcription in normal human CD4 T cells.

Author

Cron, R Q, Zhou, B, Brunvand, M W, and Lewis, D B

Subjects
*GENETIC transcription, *INTERLEUKIN-4, *T cells
Abstract

The balance of Th1 (eg, interleukin-2 (IL-2)) and Th2 (eg, IL-4) cytokines produced by CD4 T cells markedly influences the outcome of the adaptive immune response. Although octamer transcription factor proteins increase IL-2 transcription in T cells, their role in IL-4 gene transcription remains controversial We have previously shown and now confirm that the proximal octamer binding site of the human IL-4 promoter, which separates the two most proximal NFAT binding sites, is bound prior to, but not after, activation in vivo. Since these two NFAT sites are essential for optimal IL-4 promoter activity, this suggested that prior engagement by octamer proteins might prevent adjacent NFAT binding and inhibit IL-4 gene transcription. In support of this hypothesis, here we show that NFAT proteins are unable to bind to a combined octamer/NFAT site unless the octamer proteins are competed away. Moreover, activity of an IL-4 reporter gene mutated in the proximal octamer binding site is increased compared to the wild-type promoter in human peripheral blood CD4 T cells. In addition, over-expression of either Oct-1 or Oct-2 decreased wild-type IL-4 promoter activity, while increasing IL-2 promoter activity. No decrease in promoter activity was seen when Oct-1 or Oct-2 was over-expressed with the octamermutant IL-4 reporter gene. Thus, octamer proteins are candidates to promote a Th1 rather than Th2 pattern of cytokine gene expression by activated CD4 T cells. [ABSTRACT FROM AUTHOR]

Published
2001
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22. The human gp39 promoter. Two distinct nuclear factors of activated T cell protein-binding elements contribute independently to transcriptional activation.

Author

Schubert, L A, King, G, Cron, R Q, Lewis, D B, Aruffo, A, and Hollenbaugh, D

Abstract

gp39, a cytokine expressed on the surface of activated T cells, is essential for T cell-dependent antibody responses in vivo. We cloned and sequenced 1.2 kilobases of the 5' flank region of the human gp39 gene promoter and determined its transcription start site. When used in reporter gene assays, this DNA segment conferred promoter activity in response to T cell activation. gp39 promoter function in transfectants was inhibited by cyclosporin A, as is expression of the endogenous gp39 gene in T-lineage cells. At least 0.5 kilobase of the 5' flank region was required for promoter activity. Two putative binding sites for the NF-AT family of transcriptional activator proteins were identified at -259 to -265 and -62 to -69 with respect to the transcription start site. Both sites contributed significantly and independently to promoter activity in response to T cell activation. Additionally, when incubated in vitro with nuclear protein purified from activated human CD4 T cells, both of these sites preferentially bound the NF-AT family member, NF-ATp. These results suggest that NF-ATp, via binding to at least two cis-elements, is essential for the induction of gp39 gene expression in response to T cell activation.

Published
1995

23. Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4-, CD8- T lymphocytes.

Author

Bluestone, J A, Cron, R Q, Cotterman, M, Houlden, B A, and Matis, L A

Abstract

Analyses of TCR-bearing murine and human T cells have defined a unique subpopulation of T cells that express the TCR-gamma/delta proteins. The specificity of TCR-gamma/delta T cells and their role in the immune response have not yet been elucidated. Here we examine alloreactive TCR-gamma/delta T cell lines and clones that recognize MHC-encoded antigens. A BALB/c nu/nu (H-2d)-derived H-2k specific T cell line and derived clones were both cytolytic and released lymphokines after recognition of a non-classical H-2 antigen encoded in the TL region of the MHC. These cells expressed the V gamma 2/C gamma 1 protein in association with a TCR-delta gene product encoded by a Va gene segment rearranged to two D delta and one J delta variable elements. A second MHC-specific B10 nu/nu (H-2b) TCR-gamma/delta T cell line appeared to recognize a classical H-2D-encoded MHC molecule and expressed a distinct V gamma/C gamma 4-encoded protein. These data suggest that many TCR-gamma/delta-expressing T cells may recognize MHC-linked antigens encoded within distinct subregions of the MHC. The role of MHC-specific TCR-gamma/delta cells in immune responses and their immunological significance are discussed.

Published
1988
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36. Standardizing Terminology and Assessment for Orofacial Conditions in Juvenile Idiopathic Arthritis: International, Multidisciplinary Consensus-based Recommendations

Author

Troels Herlin, Peter Stoustrup, Randy Q. Cron, Patrizia Defabianis, Kasper Kristensen, Mathew L. Stoll, Annelise Küseler, Giuliana Caserta, Sven Erik Nørholt, Lynn Spiegel, Linda Z. Arvidsson, Zachary S. Peacock, Sarah Ringold, Ambra Michelotti, Iveta Jankovska, Shelly Abramowicz, Thomas Klit Pedersen, Carlalberta Verna, Per Alstergren, Paula Frid, Timo Peltomäki, Josefine Halbig, Melissa A. Lerman, Cory M. Resnick, Ellen Nordal, Mia Glerup, Christian J. Kellenberger, Marinka Twilt, University of Zurich, Stoustrup, Peter, Stoustrup, P., Resnick, C. M., Pedersen, T. K., Abramowicz, S., Michelotti, A., Kuseler, A., Verna, C., Kellenberger, C. J., Nordal, E. B., Caserta, G., Jankovska, I., Halbig, J. M., Kristensen, K. D., Arvidsson, L. Z., Spiegel, L., Stoll, M. L., Lerman, M., Glerup, M., Defabianis, P., Frid, P., Alstergren, P., Cron, R. Q., Ringold, S., Norholt, S. E., Peltomaki, T., Herlin, T., Peacock, Z. S., and Twilt, M.

Subjects
Male, 2745 Rheumatology, CHILDHOOD, Arthritis, CHILDREN, Comorbidity, Severity of Illness Index, Temporomandibular joint, Terminology, Childhood, Juvenile Idiopathic Arthritis, 0302 clinical medicine, Multidisciplinary approach, Prevalence, Immunology and Allergy, Child, JUVENILE IDIOPATHIC ARTHRITIS, Incidence, Reference Standards, Temporomandibular Joint Disorders, Prognosis, TEMPOROMANDIBULAR-JOINT ARTHRITIS, Maxillofacial Abnormalities, Treatment Outcome, Practice Guidelines as Topic, 2723 Immunology and Allergy, Female, medicine.medical_specialty, Consensus, Adolescent, Immunology, TEMPOROMANDIBULAR JOINT, 610 Medicine & health, Risk Assessment, 03 medical and health sciences, Rheumatology, stomatognathic system, Internal medicine, Terminology as Topic, medicine, Juvenile, Humans, VDP::Medisinske Fag: 700, 030203 arthritis & rheumatology, Juvenile Idiopathic Arthriti, 2403 Immunology, business.industry, 030206 dentistry, medicine.disease, Arthritis, Juvenile, VDP::Medical disciplines: 700, stomatognathic diseases, 10036 Medical Clinic, Family medicine, business
Abstract

This is a pre-copyediting, author-produced PDF of an article accepted for publication in The Journal of Rheumatology following peer review. The definitive publisher-authenticated version Stoustrup, P., Resnick, C.M., Pedersen, T.K., Abramowicz, S., Michelotti, A., Küseler, A. ...Twilt, M. (2019). Standardizing Terminology and Assessment for Orofacial Conditions in Juvenile Idiopathic Arthritis: International, Multidisciplinary Consensus-based Recommendations. The Journal of Rheumatology, 46(5), is available online at: https://doi.org/10.3899/jrheum.180785. Objective - To propose multidisciplinary, consensus-based, standardization of operational terminology and method of assessment for temporomandibular joint (TMJ) involvement in juvenile idiopathic arthritis (JIA). Methods - Using a sequential expert group–defined terminology and methods-of-assessment approach by (1) establishment of task force, (2) item generation, (3) working group consensus, (4) external expert content validity testing, and (5) multidisciplinary group of experts final Delphi survey consensus. Results - Seven standardized operational terms were defined: TMJ arthritis, TMJ involvement, TMJ arthritis management, dentofacial deformity, TMJ deformity, TMJ symptoms, and TMJ dysfunction. Conclusion - Definition of 7 operational standardized terms provides an optimal platform for communication across healthcare providers involved in JIA-TMJ arthritis management.

Published
2019

37. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome

Author

Francesca Minoia, Francesca Bovis, Sergio Davì, Antonella Insalaco, Kai Lehmberg, Susan Shenoi, Sheila Weitzman, Graciela Espada, Yi-Jin Gao, Jordi Anton, Toshiyuki Kitoh, Ozgur Kasapcopur, Helga Sanner, Rosa Merino, Itziar Astigarraga, Maria Alessio, Michael Jeng, Vyacheslav Chasnyk, Kim E. Nichols, Zeng Huasong, Caifeng Li, Concetta Micalizzi, Nicolino Ruperto, Alberto Martini, Randy Q. Cron, Angelo Ravelli, AnnaCarin Horne, Mario Abinun, Amita Aggarwal, Jonathan Akikusa, Sulaiman Al-Mayouf, Maria Teresa Apaz, Tadej Avcin, Nuray Aktay Ayaz, Patrizia Barone, Bianca Bica, Isabel Bolt, Luciana Breda, Rolando Cimaz, Fabrizia Corona, Ruben Cuttica, Zane Davidsone, Carmen De Cunto, Jaime De Inocencio, Erkan Demirkaya, Eli M. Eisenstein, Sandra Enciso, Michel Fischbach, Michael Frosch, Romina Gallizzi, Maria Luz Gamir, Thomas Griffin, Alexei Grom, Soad Hashad, Teresa Hennon, Jan-Inge Henter, Gerd Horneff, Adam Huber, Norman Ilowite, Maka Ioseliani, Agneza Marija Kapović, Raju Khubchandani, Isabelle Koné-Paut, Sheila Knupp Feitosa de Oliveira, Bianca Lattanzi, Loredana Lepore, Jeffrey M. Lipton, Silvia Magni-Manzoni, Despoina Maritsi, Deborah McCurdy, Paivi Miettunen, Velma Mulaosmanovic, Susan Nielsen, Seza Ozen, Priyankar Pal, Sampath Prahalad, Donato Rigante, Ingrida Rumba-Rozenfelde, Ricardo Russo, Claudia Saad Magalhães, Wafaa Mohamed Saad Sewairi, Clovis Artur Silva, Valda Stanevicha, Gary Sterba, Kimo C. Stine, Gordana Susic, Flavio Sztajnbok, Syuji Takei, Ralf Trauzeddel, Elena Tsitsami, Erbil Unsal, Yosef Uziel, Olga Vougiouka, Carol A. Wallace, Lehn Weaver, Jennifer E. Weiss, Carine Wouters, Nico Wulffraat, Mabruka Zletni, Maurizio Arico, R. Maarten Egeler, Alexandra H. Filipovich, Helmut Gadner, Shinsaku Imashuku, Gritta Janka, Stephan Ladisch, Ken L. McClain, David Webb, Minoia, F., Bovis, F., Davi, S., Insalaco, A., Lehmberg, K., Shenoi, S., Weitzman, S., Espada, G., Gao, Y. -J., Anton, J., Kitoh, T., Kasapcopur, O., Sanner, H., Merino, R., Astigarraga, I., Alessio, M., Jeng, M., Chasnyk, V., Nichols, K. E., Huasong, Z., Li, C., Micalizzi, C., Ruperto, N., Martini, A., Cron, R. Q., Ravelli, A., Horne, A., Abinun, M., Aggarwal, A., Akikusa, J., Al-Mayouf, S., Apaz, M. T., Avcin, T., Ayaz, N. A., Barone, P., Bica, B., Bolt, I., Breda, L., Cimaz, R., Corona, F., Cuttica, R., Davidsone, Z., De Cunto, C., De Inocencio, J., Demirkaya, E., Eisenstein, E. M., Enciso, S., Fischbach, M., Frosch, M., Gallizzi, R., Gamir, M. L., Griffin, T., Grom, A., Hashad, S., Hennon, T., Henter, J. -I., Horneff, G., Huber, A., Ilowite, N., Ioseliani, M., Kapovic, A. M., Khubchandani, R., Kone-Paut, I., de Oliveira, S. K. F., Lattanzi, B., Lepore, L., Lipton, J. M., Magni-Manzoni, S., Maritsi, D., Mccurdy, D., Miettunen, P., Mulaosmanovic, V., Nielsen, S., Ozen, S., Pal, P., Prahalad, S., Rigante, D., Rumba-Rozenfelde, I., Russo, R., Magalhaes, C. S., Sewairi, W. M. S., Artur Silva, C., Stanevicha, V., Sterba, G., Stine, K. C., Susic, G., Sztajnbok, F., Takei, S., Trauzeddel, R., Tsitsami, E., Unsal, E., Uziel, Y., Vougiouka, O., Wallace, C. A., Weaver, L., E. Weiss, J., Wouters, C., Wulffraat, N., Zletni, M., Arico, M., Egeler, R. M., Filipovich, A. H., Gadner, H., Imashuku, S., Janka, G., Ladisch, S., Mcclain, K. L., and Webb, D.

Subjects
Male, 0301 basic medicine, Hemophagocytic, Logistic regression, Pediatrics, hemophagocytic syndrome, 0302 clinical medicine, diagnostic score, Diagnosis, Medicine, Cutoff, Child, primary hemophagocytic lymphohistiocytosi, Lymphohistiocytosis, education.field_of_study, primary hemophagocytic lymphohistiocytosis, Perinatology and Child Health, Quartile, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Macrophage activation syndrome, Child, Preschool, macrophage activation syndrome, Absolute neutrophil count, Female, Human, medicine.medical_specialty, Adolescent, Population, Lymphohistiocytosis, Hemophagocytic, Diagnosis, Differential, 03 medical and health sciences, Internal medicine, Humans, Preschool, education, 030203 arthritis & rheumatology, Receiver operating characteristic, business.industry, Infant, Reproducibility of Results, medicine.disease, Surgery, 030104 developmental biology, Macrophage Activation Syndrome, Pediatrics, Perinatology and Child Health, Differential, Differential diagnosis, business
Abstract

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of =123. A cutoff value of =60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

Published
2017

38. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Author

Ravelli, A, Minoia, F, Davì, S, Horne, A, Bovis, F, Pistorio, A, Aricò, M, Avcin, T, Behrens, Em, De Benedetti, F, Filipovic, A, Grom, Aa, Henter, J-i, Ilowite, Nte, Jordan, Mb, Khubchandani, R, Kitoh, T, Lehmberg, K, Lovell, Dj, Miettunen, P, Nichols, Ke, Ozen, S, Schmid, Jp, Ramanan, Av, Russo, R, Schneider, R, Sterba, G, Uziel, Y, Wallace, C, Wouters, C, Wulffraat, N, Demirkaya, E, Brunner, Hi, Martini, A, Ruperto, N, Cron, Rq, Angioloni, S, Pallotti, C, Pesce, M, Rinaldi, M, Villa, L, Abinun, M, Aggarwal, A, Akikusa, J, Al-mayouf, Sm, Alessio, M, Anton, J, Apaz, Mt, Astigarraga, I, Ayaz, Na, Barone, P, Bica, B, Bolt, I, Breda, L, Chasnyk, V, Cimaz, R, Corona, F, Cuttica, R, D'Angelo, G, Davidsone, Z, De Cunto, C, De Inocencio, J, Eisenstein, E, Enciso, S, Espada, G, Fischbach, M, Frosch, M, Gallizzi, R, Gamir, Ml, Gao, Y-j, Griffin, T, Hashad, S, Hennon, T, Horneff, G, Huasong, Z, Huber, A, Insalaco, A, Ioseliani, M, Jelusic-drazic, M, Jeng, M, Kapovic, A, Kasapcopur, O, Kone-paut, I, De Oliveira Skf, Lattanzi, B, Lepore, L, Li, C, Lipton, Jm, Magni-manzoni, S, Maritsi, D, Mccurdy, D, Merino, R, Mulaosmanovic, V, Nielsen, S, Pal, P, Prahalad, S, Rigante, Donato, Rumba-rozenfelde, I, Magalhaes, Cs, Sanner, H, Sawhney, S, Sewairi, Wm, Shakoory, B, Shenoi, S, Clovis, As, Stanevicha, V, Stine, Kc, Susic, G, Sztajnbok, F, Takei, S, Tezer, H, Trauzeddel, R, Tsitsami, E, Unsal, E, Vougiouka, O, Weaver, Lk, Weiss, J, Weitzman, S, On Behalf Of The Pediatric Rheumatology International Trials Organization, Zletni M., The Childhood Arthritis & Rheumatology Research Alliance, The Pediatric Rheumatology Collaborative Study Group And The Histiocyte Society, Ravelli, A., Minoia, F., Davi, S., Horne, A., Bovis, F., Pistorio, A., Arico, M., Avcin, T., Behrens, E. M., De Benedetti, F., Filipovic, A., Grom, A. A., Henter, J. -I., Ilowite, N. T., Jordan, M. B., Khubchandani, R., Kitoh, T., Lehmberg, K., Lovell, D. J., Miettunen, P., Nichols, K. E., Ozen, S., Schmid, J. P., Ramanan, A. V., Russo, R., Schneider, R., Sterba, G., Uziel, Y., Wallace, C., Wouters, C., Wulffraat, N., Demirkaya, E., Brunner, H. I., Martini, A., Ruperto, N., Cron, R. Q., Angioloni, S., Pallotti, C., Pesce, M., Rinaldi, M., Villa, L., Abinun, M., Aggarwal, A., Akikusa, J., Al-Mayouf, S. M., Alessio, M., Anton, J., Apaz, M. T., Astigarraga, I., Ayaz, N. A., Barone, P., Bica, B., Bolt, I., Breda, L., Chasnyk, V., Cimaz, R., Corona, F., Cuttica, R., D'Angelo, G., Davidsone, Z., De Cunto, C., De Inocencio, J., Eisenstein, E., Enciso, S., Espada, G., Fischbach, M., Frosch, M., Gallizzi, R., Gamir, M. L., Gao, Y. -J., Griffin, T., Hashad, S., Hennon, T., Horneff, G., Huasong, Z., Huber, A., Insalaco, A., Ioseliani, M., Jelusic-Drazic, M., Jeng, M., Kapovic, A., Kasapcopur, O., Kone-Paut, I., De Oliveira, S. K. F., Lattanzi, B., Lepore, L., Li, C., Lipton, J. M., Magni-Manzoni, S., Maritsi, D., Mccurdy, D., Merino, R., Mulaosmanovic, V., Nielsen, S., Pal, P., Prahalad, S., Rigante, D., Rumba-Rozenfelde, I., Magalhaes, C. S., Sanner, H., Sawhney, S., Sewairi, W. M., Shakoory, B., Shenoi, S., Clovis, A. S., Stanevicha, V., Stine, K. C., Susic, G., Sztajnbok, F., Takei, S., Tezer, H., Trauzeddel, R., Tsitsami, E., Unsal, E., Vougiouka, O., Weaver, L. K., Weiss, J., Weitzman, S., Zletni, M., and Çocuk Sağlığı ve Hastalıkları

Subjects
medicine.medical_specialty, systemic juvenile idiopathic arthritis, Epidemiology, Immunology, Arthritis, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Journal Article, Immunology and Allergy, 030212 general & internal medicine, Juvenile Idiopathic Arthritis, Prospective cohort study, 030203 arthritis & rheumatology, medicine.diagnostic_test, business.industry, Paediatric Rheumatology, medicine.disease, Outcomes research, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Macrophage activation syndrome, Erythrocyte sedimentation rate, Absolute neutrophil count, sense organs, business
Abstract

OBJECTIVE: To identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA).METHODS: A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the 5 laboratory tests in which change was most important for the diagnosis of MAS and to rank the 5 selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at a consensus conference.RESULTS: Platelet count was the most frequently selected test, followed by ferritin level, aspartate aminotransferase (AST), white cell count, neutrophil count, and fibrinogen and erythrocyte sedimentation rate. Ferritin was most frequently assigned the highest score. At the end of the process, platelet count, ferritin level and AST were the laboratory tests in which the experts found change over time to be most important.CONCLUSIONS: We identified the laboratory tests in which change over time is most valuable for the early diagnosis of MAS in sJIA. The dynamics of laboratory values during the course of MAS should be further scrutinised in a prospective study in order to establish the optimal cut-off values for their variation.

Published
2016

39. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients

Author

Minoia, F, Davì, S, Horne, A, Demirkaya, E, Bovis, Francesca, Li, C, Lehmberg, K, Weitzman, S, Insalaco, A, Wouters, C, Shenoi, S, Espada, G, Ozen, S, Anton, J, Khubchandani, R, Russo, R, Pal, P, Kasapcopur, O, Miettunen, P, Maritsi, D, Merino, R, Shakoory, B, Alessio, M, Chasnyk, V, Sanner, H, Gao, Yj, Huasong, Z, Kitoh, T, Avcin, T, Fischbach, M, Frosch, M, Grom, A, Huber, A, Jelusic, M, Sawhney, S, Uziel, Y, Ruperto, N, Martini, Alberto, Cron, Rq, Ravelli, Angelo, Minoia, F., Davi, S., Horne, A., Demirkaya, E., Bovis, F., Li, C., Lehmberg, K., Weitzman, S., Insalaco, A., Wouters, C., Shenoi, S., Espada, G., Ozen, S., Anton, J., Khubchandani, R., Russo, R., Pal, P., Kasapcopur, O., Miettunen, P., Maritsi, D., Merino, R., Shakoory, B., Alessio, M., Chasnyk, V., Sanner, H., Gao, Y. -J., Huasong, Z., Kitoh, T., Avcin, T., Fischbach, M., Frosch, M., Grom, A., Huber, A., Jelusic, M., Sawhney, S., Uziel, Y., Ruperto, N., Martini, A., Cron, R. Q., and Ravelli, A.

Subjects
musculoskeletal diseases, Male, Biological Products, Fever, International Cooperation, Macrophage Activation Syndrome, Arthritis, Juvenile, Cohort Studies, Survival Rate, Intensive Care Units, Treatment Outcome, Adrenal Cortex Hormones, Child, Preschool, Splenomegaly, Cyclosporine, Prevalence, Humans, Female, Child, Etoposide, Hepatomegaly, Retrospective Studies
Abstract

Objective To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). Methods In this multinational, multicenter study, pediatric rheumatologists and hemato-oncologists entered patient data collected retrospectively into a web-based database. Results A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d-dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre-MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one-third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%. Conclusion This study provides information on the clinical spectrum and current management of systemic JIA-associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.

Published
2014

40. NFAT transcription factors--new players in the pathogenesis of inflammatory arthropathies?

Author

Pessler F, Dai L, Cron RQ, and Schumacher HR

Subjects
Antirheumatic Agents therapeutic use, Arthritis drug therapy, Arthritis etiology, Cyclosporine therapeutic use, Cytokines metabolism, Fibroblasts metabolism, Humans, Leukocytes metabolism, Lymphocyte Activation immunology, Macrophages metabolism, Models, Biological, NFATC Transcription Factors antagonists & inhibitors, Arthritis metabolism, NFATC Transcription Factors metabolism
Abstract

Inflammatory arthropathies are characterized by major changes in gene expression, which-ultimately-result from differential activities of intracellular signaling pathways and their associated inducible transcription factors. The nuclear factor of activated T cells' (NFAT) family of transcription factors plays diverse roles in a variety of processes in the immune system and other tissues. Preliminary evidence has recently emerged implicating NFAT family members directly in the pathogenesis of inflammatory arthropathies. Specific anti-NFAT drug therapy may add to the pharmacologic armamentarium against rheumatoid arthritis, other inflammatory arthropathies, and related autoimmune disorders.

Published
2006
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42. Methotrexate used as a steroid-sparing agent in non-renal chronic Henoch-Schönlein purpura.

Author

Rettig P and Cron RQ

Subjects
Adrenal Cortex Hormones therapeutic use, Child, Chronic Disease, Dose-Response Relationship, Drug, Drug Administration Schedule, Follow-Up Studies, Humans, IgA Vasculitis diagnosis, Injections, Subcutaneous, Long-Term Care, Male, Risk Assessment, Severity of Illness Index, Treatment Outcome, Adrenal Cortex Hormones adverse effects, IgA Vasculitis drug therapy, Methotrexate administration & dosage
Abstract

Henoch-Schönlein purpura (HSP) is the most common form of systemic vasculitis in childhood and a small percentage of children develop a chronic form of the disease that often requires prolonged corticosteroid therapy. A detailed case description of a child with non-renal chronic HSP treated with methotrexate to allow for tapering of corticosteroids is presented. This represents the first report of methotrexate use in the treatment of chronic HSP.

Published
2003

43. HIV-1, NFAT, and cyclosporin: immunosuppression for the immunosuppressed?

Author

Cron RQ

Subjects
Binding Sites, CD4-Positive T-Lymphocytes virology, Cells, Cultured, Gene Expression, HIV Long Terminal Repeat physiology, HIV-1 drug effects, Humans, Immunosuppression Therapy, Lymphocyte Activation drug effects, NFATC Transcription Factors, Tacrolimus pharmacology, Virus Replication drug effects, Cyclosporine pharmacology, DNA-Binding Proteins metabolism, HIV-1 physiology, Immunosuppressive Agents pharmacology, Nuclear Proteins, Transcription Factors metabolism
Abstract

The human immunodeficiency virus-1 (HIV-1), the cause of AIDS, remains a significant cause of morbidity and mortality throughout the planet. Although reverse transcriptase and protease inhibitors have substantially slowed the virus, viral resistance complicates therapy. Because HIV-1 relies on its host's transcriptional machinery for its own replication, strategies for targeting activation-dependent transcription factors in CD4 T cells are being considered for adjunctive therapy in HIV-1-infected individuals. The nuclear factor of activated T cells (NFAT) family of transcription factors is one such target. On T-cell stimulation, NFAT proteins translocate to the nucleus, where they activate a large number of early response genes, including cytokines such as interleukin-2. Activation and nuclear translocation of NFAT proteins are abrogated by the powerful immunosuppressants cyclosporin A (CsA) and FK506. Over the last several years, various investigators have demonstrated that NFAT proteins bind to the HIV-1 LTR promoter and increase viral transcription. In this report, further evidence supporting a role for NFAT proteins in augmenting HIV-1 transcription is presented. In addition, other mechanisms of HIV-1 inhibition by CsA are reviewed, and the rationale for the use of CsA to treat AIDS is discussed.

Published
2001
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45. Nabumetone induced pseudoporphyria in childhood.

Author

Cron RQ and Finkel TH

Subjects
Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Arthritis, Psoriatic drug therapy, Butanones administration & dosage, Child, Female, Humans, Nabumetone, Photosensitivity Disorders chemically induced, Photosensitivity Disorders diagnosis, Porphyrias diagnosis, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Butanones adverse effects, Porphyrias chemically induced
Published
2000

46. NFAT1 enhances HIV-1 gene expression in primary human CD4 T cells.

Author

Cron RQ, Bartz SR, Clausell A, Bort SJ, Klebanoff SJ, and Lewis DB

Subjects
Binding Sites, CD4-Positive T-Lymphocytes virology, Cyclosporine pharmacology, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins metabolism, Gene Expression drug effects, HIV Core Protein p24 genetics, HIV Long Terminal Repeat drug effects, Humans, NF-kappa B metabolism, NFATC Transcription Factors, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism, CD4-Positive T-Lymphocytes metabolism, DNA-Binding Proteins pharmacology, HIV-1 genetics, Nuclear Proteins, Transcription Factors pharmacology
Abstract

Cyclosporin A (CsA) is a potent inhibitor of the NFAT family of transcription factors that enhance T cell activation. The observation that human immunodeficiency virus type 1 (HIV-1)-positive transplant recipients have a reduced HIV-1 viral burden during treatment with CsA suggested that NFAT may play a direct role in enhancing transcription of the HIV-1 viral genome. Two sets of NFAT binding sites were identified in the HIV-1 long terminal repeat (LTR) promoter by in vitro footprinting with full-length recombinant NFAT protein, and gel shift analysis of nuclear protein from polyclonally activated primary CD4 T cells revealed specific binding of NFAT1 to the NFkappaB binding sites of the HIV-1 LTR. Activation of primary CD4 T cells transiently transfected with a HIV-1 LTR luciferase reporter plasmid, lacking the NFAT binding sites in the upstream putative negative regulatory element but maintaining the NFkappaB/NFAT sites, demonstrated increased HIV-1 gene expression when cotransfected with a NFAT1 expression vector. Moreover, CsA, FK506, and a dominant-negative NFAT1 protein independently inhibited HIV-1 LTR promoter activity in CD4 T cells stimulated with phorbol ester and calcium ionophore. In primary human CD4 T cells, CsA also inhibited promoter activity directed by multimers of binding sites for NFAT, while having no effect on NFkappaB multimer-driven promoter activity. Increasing NFAT1 levels in CD4 T cells transiently transfected with a HIV-1 provirus also increased p24 protein expression. Thus, NFAT may be a target for prevention of HIV-1 LTR-directed gene expression in human CD4 T cells., (Copyright 2000 Academic Press.)

Published
2000
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47. Current treatment by United States and Canadian pediatric rheumatologists.

Author

Cron RQ, Sharma S, and Sherry DD

Subjects
Adolescent, Adrenal Cortex Hormones therapeutic use, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Canada, Child, Child, Preschool, Clinical Competence, Female, Health Surveys, Humans, Male, Methotrexate therapeutic use, Pediatrics standards, Pediatrics trends, Sulfasalazine therapeutic use, Surveys and Questionnaires, United States, Arthritis, Juvenile drug therapy, Practice Patterns, Physicians' statistics & numerical data
Abstract

Objective: To determine current treatment practices for 11 selected pediatric rheumatic diseases., Methods: A questionnaire was mailed to 224 US and Canadian physicians who were listed in membership directories that included pediatric rheumatologists., Results: One hundred seventy-four questionnaires (78%) were returned. Board certified pediatricians accounted for 86% of respondents. Nonsteroidal antiinflammatory drugs were the most commonly used medicines for all forms of juvenile rheumatoid arthritis (JRA), seronegative enthesopathy and arthropathy syndrome (SEA), and Henoch-Schönlein purpura, whereas oral corticosteroids were most frequently used for systemic lupus erythematosus (SLE), juvenile dermatomyositis, polyarteritis nodosa, and sarcoidosis. Intraarticular corticosteroid injection was the second most common therapy for pauciarticular JRA, but methotrexate (MTX) was second for polyarticular and systemic onset forms of JRA, and sulfasalazine was second for SEA. For all diseases, MTX was administered orally roughly twice as often as subcutaneously. In treating SLE, cyclophosphamide was used more frequently than azathioprine, cyclosporin A, or intravenous immunoglobulin., Conclusion: The results from this survey should allow individual practitioners to compare their treatment patterns to pediatric rheumatologists in the US and Canada as a whole.

Published
1999

48. T cell priming enhances IL-4 gene expression by increasing nuclear factor of activated T cells.

Author

Cron RQ, Bort SJ, Wang Y, Brunvand MW, and Lewis DB

Subjects
5' Untranslated Regions immunology, Adult, Amino Acid Sequence, CD4-Positive T-Lymphocytes metabolism, Cell Nucleus immunology, DNA-Binding Proteins metabolism, DNA-Binding Proteins physiology, Humans, Interleukin-4 biosynthesis, Interphase immunology, Molecular Sequence Data, NFATC Transcription Factors, Promoter Regions, Genetic immunology, Transcription Factors metabolism, Transcription Factors physiology, Transcription, Genetic immunology, CD4-Positive T-Lymphocytes immunology, DNA-Binding Proteins biosynthesis, Gene Expression Regulation immunology, Interleukin-4 genetics, Lymphocyte Activation genetics, Nuclear Proteins, Transcription Factors biosynthesis
Abstract

The repetitive activation of T cells (priming) enhances the expression of many cytokines, such as IL-4, but not others, such as IL-2. Molecular mechanisms underlying selective expression of cytokines by T cells remain poorly understood. Here we show that priming of CD4 T cells selectively enhances IL-4 expression relative to IL-2 expression by a transcriptional mechanism involving nuclear factor of activated T cells (NFAT) proteins. As detected by in vivo footprinting, priming markedly increases the activation-dependent engagement of the P0 and P1 NFAT-binding elements of the IL-4 promoter. Moreover, each proximal P element is essential for optimal IL-4 promoter activity. Activated primed CD4 T cells contain more NFAT1 and support greater NFAT-directed transcription than unprimed CD4 T cells, while activator protein 1 binding and activator protein 1-mediated transcription by both cell types is similar. Increased expression of wild-type NFAT1 substantially increases IL-4 promoter activity in unprimed CD4 T cells, suggesting NFAT1 may be limiting for IL-4 gene expression in this cell type. Furthermore, a truncated form of NFAT1 acts as a dominant-negative, reducing IL-4 promoter activity in primed CD4 T cells and confirming the importance of endogenous NFAT to increased IL-4 gene expression by effector T cells. NFAT1 appears to be the major NFAT family member responsible for the initial increased expression of IL-4 by primed CD4 T cells.

Published
1999

49. Methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis.

Author

Cron RQ, Sherry DD, and Wallace CA

Subjects
Child, Female, Humans, Alveolitis, Extrinsic Allergic chemically induced, Antirheumatic Agents adverse effects, Arthritis, Juvenile drug therapy, Methotrexate adverse effects
Abstract

Low-dose methotrexate, widely used for juvenile rheumatoid arthritis, has been reported to cause pneumonitis in adults. We report on methotrexate-induced hypersensitivity pneumonitis in a child with juvenile rheumatoid arthritis. Physicians should be aware of this rare complication.

Published
1998
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