Abstract
Infections are implicated in autoimmunity. Autoantibodies are produced in lymphoid tissue where lymph node stromal cells (LNSCs) regulate lymphocyte function. Infections can alter the interaction between LNSCs and lymphocytes resulting in defective immune responses. In rheumatoid arthritis (RA) autoantibody production precedes clinical disease allowing identification of at risk individuals. We investigated the ability of human LNSCs derived from RA, RA-risk and healthy individuals to sense and respond to pathogens. Human LNSCs cultured directly from freshly collected lymph node biopsies expressed TLR1-9 with exception of TLR7. In all donors TLR3 triggering induced expression of ISGs, IL-6 and adhesion molecules like VCAM-1 and ICAM-1. Strikingly, T cell guiding chemokines CCL19 and IL-8 as well as the antiviral gene MxA were less induced upon TLR3 triggering in autoimmune LNSCs. This observed decrease, found already in LNSCs of RA-risk individuals, may lead to incorrect positioning of lymphocytes and aberrant immune responses during viral infections.
Highlights
Autoimmunity develops when tolerance mechanisms fail and self-reactive lymphocytes get activated in the periphery
We chose to trigger TLR3 with poly(I:C), which can be sensed by all donors, to simulate a viral infection in lymph node stromal cells (LNSCs) after which we compared the response between healthy, rheumatoid arthritis (RA)-risk and RA donors
We measured the induction of genes downstream of TLR3 signaling to evaluate the functional responsiveness of TLR3 in cultured LNSCs from healthy, RA-risk and RA donors
Summary
Autoimmunity develops when tolerance mechanisms fail and self-reactive lymphocytes get activated in the periphery. We developed an experimental model to investigate the response of human LNSCs to viral infection during very early stages of systemic autoimmunity. We use rheumatoid arthritis (RA) as a model autoimmune disease since the production of the RA-specific autoantibodies IgM rheumatoid factor (IgM-RF) and anti-citrullinated protein antibodies (ACPAs) can be detected years before clinical onset of disease[30]. This allows for the selection of individuals at risk for developing RA (RA-risk individuals) and to study the earliest phases of systemic autoimmunity without the interference of an inflammatory clinical disease[31]. We show that the TLR3 induced production of T cell guiding chemokines by human LNSCs is diminished at a very early stage of systemic autoimmunity
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