The Leukocyte Immunoglobulin-like Receptors (LILRs) are a family of receptors that is broadly expressed on all leukocytes and have the ability to regulate their function. A substantial amount of evidence suggests that LILRs may be involved in immune homeostasis but also immune dysregulation. We therefore studied the role of LILRs in relation to the autoimmune disease, rheumatoid arthritis (RA). RA is a chronic and systemic inflammatory disease involving inflammation of the joints affecting the synovial membrane, cartilage and bone. Much of the tissue damage is a result of an inappropriate immune response within the joint space caused by the unwarranted activation of leukocytes. Here were report that LILRA2 (an activating receptor) that has been previously shown to be highly expressed in the rheumatoid synovium, induces the production of pro-inflammatory cytokines TNF-α, IL-1, IL-6, IFN-γ and IL-10 in primary monocytes. These cytokines are known to have an important role in the pathogenesis of RA indicating a pathway by which LILRA2 exacerbates RA. Co-ligation of LILRB4 (an inhibitory receptor) with LILRA2 abolishes cytokine production suggesting that LILRB4 is able to suppress the function of LILRA2. Expression of both LILRA2 and LILRB4 are regulated by inflammatory cytokines and LPS, indicative of a feedback mechanism. There is also cross-talk between LILRs and TLR4 as co-stimulation with LPS and either LILRA2 or LILRB4 inhibits cytokine production. A differential expression of LILRs has also been identified on lymphocytes of patients with RA whereby an increase of LILRA1 (activating) and LILRB1 (inhibitory) expressing circulating lymphocytes is present in RA patients when compared to healthy control subjects. From these studies, we propose that LILRs have a functional role in RA by regulating local and systemic inflammation. The presence of LILRA2 in the RA joint is detrimental since its potent ability to induce inflammatory cytokines, particularly TNF-α, can initiate leukocyte recruitment and activation of proteases. Along with TLR4, LILRA2 and LILRB4 have the potential to moderate the innate immune system via regulation of cytokine production. Furthermore, suppression of LILRA2 function may serve as a therapeutic tool in many inflammatory diseases.
| Identifer | oai:union.ndltd.org:ADTP/234872 |
| Date | January 2008 |
| Creators | Huynh, Owen Anthony, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Publisher:University of New South Wales. Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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