Investigating differential T cell polarization in the two pathological forms of sheep paratuberculosis
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Date
02/07/2016Author
Nicol, Louise Maureen Marie
Metadata
Abstract
Paratuberculosis is a chronic enteropathy of ruminants that presents as two
distinct disease forms in sheep; paucibacillary (or tuberculoid) and
multibacillary (or lepromatous) disease. The immunopathology of
paucibacillary and multibacillary sheep paratuberculosis has been linked to
inflammatory Th1/Th17 cell and Th2/macrophage responses respectively.
IL23 and IL25 are key to the development of these responses by interaction
with their complex receptors, IL23R/IL12RB1 and IL17RA/IL17RB.
Furthermore, the polarization of T cells and the development of appropriate
immune responses is controlled by the master regulator transcription factor;
T-bet, GATA3, RORγt and RORα. In humans, variations in the structure,
sequence and/or expression of the genes encoding these proteins have been
implicated in the different pathological forms of tuberculosis and leprosy, and
gastrointestinal inflammatory disorders such as Crohn’s disease. In the
current study, sequencing has identified multiple transcript variants of sheep
IL23R, IL12RB1 and IL17RB and a single IL17RA transcript. RT-qPCR
assays were developed for the cytokine receptor variants identified in this
study and known transcript variants of the transcription factor genes.
Expression levels were compared in the ileo cecal lymph node of
paucibacillary or multibacillary paratuberculosis diseased sheep. Of the
cytokine receptors; the IL12RB1v3 variant, which lacks the receptor
activation motif, was differentially expressed and was significantly increased
in multibacillary disease; this may contribute to high Th2 responses. Full
length IL17RB was differentially expressed and was significantly increased in
multibacillary pathology, which may also contribute to Th2 polarization.
IL17RA was significantly increased in paucibacillary disease. The contrast
between the IL17RA and IL17RB results may indicate that, in addition to Th1
cells, Th17 T cells are also involved in paucibacillary pathology. Of the
transcription factor transcripts; full length TBX21 (T-bet) was differentially
expressed and was significantly increased in paucibacillary disease; this may
explain increased Th1 responses in these sheep. Full length GATA3 was
significantly increased in paucibacillary compared to multibacillary sheep,
suggesting a loss of Th2 responses in late-stage multibacillary pathology.
RORAv1 variant was differentially expressed and was significantly increased
in paucibacillary pathology, indicating a role of Th17 T cells in paucibacillary
pathology.
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