Regulation and Effector function of Th1 and Th17 cells in psoriatic arthritis
Final Report Abstract
The proinflammatory cytokine IL-17A is considered a crucial player in rheumatoid arthritis (RA) pathogenesis. In experimental models of autoimmune arthritis, it has been suggested that the cellular source of IL-17A are CD4+ T cells (Th17 cells). However, little is known about the source of IL-17 in human inflamed RA tissue. I explored the cellular sources of IL-17A in human RA synovium. Surprisingly, only a small proportion of IL-17–expressing cells were T cells, and these were CCR6 negative. Unexpectedly, the majority of IL-17A expression colocalized within mast cells. Furthermore, we demonstrated in vitro that mast cells produced RORC-dependent IL-17A upon stimulation with TNF-a, IgG complexes, C5a, and LPS. These data are consistent with a crucial role for IL-17A in RA pathogenesis but suggest that in addition to T cells innate immune pathways particularly mediated via mast cells may be an important component of the effector IL-17A response. The novel cytokine IL-33 is released upon cell death, acts as an alarmin and might account for initiation and maintenance of psoriatic lesions as well as psoriatic arthritis in which occurrence has been described to be linked to “mechanically stressful” events such as accidents or moving houses. I addressed the role of IL-33 in psoriasis to understand initiation processes in psoriatic arthritis and explored that IL-33 induces psoriasis like dermatitis by recruitment of macrophages but mainly neutrophils. This will be further investigated in psoriatic arthritis models.
Publications
- Immune regulation in psoriasis and psoriatic arthritis – recent developments Immunol Lett. 2007 Dec 15;114(2):59-65
Hueber AJ and McInnes IB
- Pathogenesis in RA – Cytokines. Rheumatoid Arthritis, Hochberg, et al. 11 Dec 2008, Mosby, 0323054757
Hueber AJ and McInnes IB
- Imaging inflammation in real time – future use of nanoparticles. Autoimmunity. 2009 May;42(4):368-72
Hueber AJ, Stevenson R, Stokes RJ, Graham D, Garside P, McInnes IB
- Liver X agonism promotes articular inflammation in murine collagen-induced arthritis. Arthritis Rheum. 2009 Sep;60(9):2655-65
Asquith DL, Miller AM, Hueber AJ, McKinnon HJ, Sattar N, Graham GJ, McInnes IB
- Embracing novel cytokines in RA – Complexity grows as does opportunity! Best Pract Res Clin Rheumatol. 2010 Aug;24(4):479-87
Hueber AJ, Asquith DL, McInnes IB, Miller AM
- IL-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ Res. 2010, Sep 3; 107(5):650-8
Miller AM, Asquith DL, Hueber AJ, Holmes WM, McKenzie A, Xu D, Packard CJ, Sattar N, McInnes IB, Liew FY
- Inflammation is present in early human tendinopathy. Am J Sports Med. 2010 Oct; 38(10):2085-91
Miller NL, Hueber AJ, Reilly JH, Xu Y, Fazzi UG, Murrell GAC, McInnes IB
- Mast cells express IL-17A in rheumatoid arthritis synovium. J. Immunol Cutting Edge 2010 Apr 1;184(7):3336-40
Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, Melendez AJ, McInnes IB
