title: Variations in T cell transcription factor gene structure and expression associated with the two disease forms of sheep paratuberculosis.
abstract: Two different forms of clinical paratuberculosis in sheep are recognised, related to the level of bacterial colonization. Paucibacillary lesions are largely composed of lymphocytes with few bacteria, and multibacillary pathology is characterized by heavily-infected macrophages. Analysis of cytokine transcripts has shown that inflammatory Th1/Th17 T cells are associated with development of paucibacillary pathology and Th2 cytokines are correlated with multibacillary disease. The master regulator T cell transcription factors TBX21, GATA3, RORC2 and RORA are critical for the development of these T cell subsets. Sequence variations of the transcription factors have also been implicated in the distinct disease forms of human mycobacterial and gastrointestinal inflammatory diseases. Relative RT-qPCR was used to compare expression levels of each transcript variant of the master regulators in the ileo-caecal lymph nodes of uninfected controls and sheep with defined paucibacillary and multibacillary pathology. Low levels of GATA3 in multibacillary sheep failed to confirm that multibacillary paratuberculosis is caused simply by a Th2 immune response. However, high levels of TBX21, RORC2 and RORC2v1 highlights the role of Th1 and Th17 activation in paucibacillary disease. Increased RORAv1 levels in paucibacillary tissue suggests a role for RORα in Th17 development in sheep; while elevated levels of RORAv4 hints that this variant might inhibit RORα function and depress Th17 development in multibacillary sheep.
authors.affiliation: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Nicol
authors.affiliation: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Wilkie
authors.affiliation: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.
authors.forename: Anton
authors.initials: A
authors.lastname: Gossner
authors.affiliation: Moredun Research Institute, International Research Centre, Pentlands Science Park, Penicuik, Midlothian, EH26 0PZ, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Watkins
authors.affiliation: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Dalziel
authors.affiliation: The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK. john.hopkins@ed.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Hopkins
mesh_terms: D000818:Animals; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism; D010283:Paratuberculosis / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction / Q000662:veterinary; D012756:Sheep; D012757:Sheep Diseases / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D020825:T-Box Domain Proteins / Q000378:metabolism; D051820:TCF Transcription Factors / Q000235:genetics* / Q000502:physiology
chemical_list: D050990:GATA3 Transcription Factor; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D020825:T-Box Domain Proteins; D051820:TCF Transcription Factors