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Reducing immunopathology in patients with primary Sjogrenís syndrome

Tuesday 7 April 2015

Reducing immunopathology in patients with primary Sjogrenís syndrome by targeting CCR9 Tfh-like cells

Background/Research objectives
In primary Sjögrenís syndrome (pSS) B cell activation and autoantibody secretion are hallmark immunopathological features. Specific lymphoid organization (including germinal centers) is associated with increased risk for development of extraglandular manifestations and lymphoma. Thus, better understanding of the cellular and molecular pathways that underlie formation of ectopic lymphoid structures is of pivotal importance. TFH cells, expressing CXCR5, ICOS, PD-1 and cytokines like IL-21 play a critical role in the formation of lymphoid structures and in the activation of B cells. Recently, a novel subset of CD4+ T cells with TFH-like characteristics was found to be specifically attracted to mucosal sites by TECK (thymus expressed chemokine, CCL25), the ligand for CCR9.
Our results suggest that enhanced expression of TECK in the labial salivary gland might promote elevation of CCR9-expressing TFH-like cells at the site of inflammation. Preliminary IHC data point towards enhanced CCR9 cells in pSS salivary glands. Considering the expression of ICOS and the capacity of TECK to induce proinflammatory cytokine secretion we hypothesize that the CCL25/CCR9-axis plays a role in the immunopathology of pSS driving B cell activation, thus representing a novel therapeutic target in this disease.
To test this hypothesis we would like to address the following research questions:
1) In what way do CCR9 effector T cells from pSS patients regulate B cell activity in the absence or presence monocytes/macrophages and dendritic cells?
2) To what extent do CCR9 effector T cells molecularly* differ from classical Tfh cells in Sjögren patients and how does this differ from healthy individuals?
3) Can specific targeting of CCR9 T cells prevent inflammatory responses and tissue destructive processes in vitro?

MACS cell sorting to isolate classical (CXCR5) Tfh cells and CCR9 (vs double positives and negatives), CD19 B cells, CD14 monocytes/macrophages and CD1c myeloid dendritic cells; co-culture of T cells en APCs; *quantitative HT-PCR analysing (micro)RNA, *cell phenotyping by FACS analysis; *intra-cellular cytokine staining; *cytokine assessment by ELISA/Luminex; *proliferation assays.

Duration: 6/9 months

J.vanRoon@umcutrecht.nl, 088-755 4009
Prof. Tim Radstake
T.R.D.J.Radstake@umcutrecht.nl, 088-755 7357

Laboratory of Translational Immunology and Dept of Rheumatology & Clinical Immunology