The Lymphotoxin Network: Orchestrating a Type I Interferon Response to Optimize Adaptive Immunity

Cytokine & growth factor reviews (Impact Factor: 6.49). 04/2014; DOI: 10.1016/j.cytogfr.2014.02.002

ABSTRACT The Lymphotoxin (LT) pathway is best known for its role in orchestrating the development and homeostasis lymph nodes and Peyer's patch through the regulation of homeostatic chemokines. More recently an appreciation of the LTβR pathway in the production of Type I interferons (IFN-I) during homeostasis and infection has emerged. LTβR signaling is essential in differentiating stromal cells and macrophages in lymphoid organs to rapidly produce IFN-I in response to virus infections independently of the conventional TLR signaling systems. In addition, LTβR signaling is required to produce homeostatic levels of IFN-I from dendritic cells in order to effectively cross-prime a CD8+ T cell response to protein antigen. Importantly, pharmacological inhibition of LTβR signaling in mice has a profound positive impact on a number of autoimmune disease models, although it remains unclear if this efficacy is linked to IFN-I production during chronic inflammation. In this review, we will provide a brief overview of how the “Lymphotoxin Network” is linked to the IFN-I response and its impact on the immune system.

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    ABSTRACT: A subset of patients with autoimmune diseases including rheumatoid arthritis (RA) and lupus appear to be exposed continually to interferon (IFN) as evidenced by elevated expression of IFN induced genes in blood cells. In lupus, detection of endogenous chromatin complexes by the innate sensing machinery is the suspected driver for the IFN, but the actual mechanisms remain unknown in all of these diseases. We investigated in two randomized clinical trials the effects on RA patients of baminercept, a lymphotoxin-beta receptor-immunoglobulin fusion protein that blocks the lymphotoxin-αβ/LIGHT axis. Administration of baminercept led to a reduced RNA IFN signature in the blood of patients with elevated baseline signatures. Both RA and SLE patients with a high IFN signature were lymphopenic and lymphocyte counts increased following baminercept treatment of RA patients. These data demonstrate a coupling between the lymphotoxin-LIGHT system and IFN production in rheumatoid arthritis. IFN induced retention of lymphocytes within lymphoid tissues is a likely component of the lymphopenia observed in many autoimmune diseases. NCT00664716.
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