Hueber, Axel Johannes
The role of the cytokines IL-17A and IL-33 in inflammatory arthritis and psoriasis.
PhD thesis, University of Glasgow.
Full text available as:
The inflammatory autoimmune diseases rheumatoid arthritis, psoriatic arthritis and psoriasis have seen a break through in therapy by targeting cytokines in the last decade. Interleukin-17A, a potential new target, is considered as a crucial player in rheumatoid arthritis, and has been suggested to be produced by CD4+ T cells (Th17 cells). I explored the cellular sources of IL-17A in human established
RA synovium. Surprisingly, only a small proportion of IL-17 positive cells were T cells without expression of a Th17 marker CCR6. Unexpectedly, the majority of IL-17A expression colocalized within mast cells. These data do not contradict a crucial role for IL-17A in RA pathogenesis, however, suggest that in addition to Th17 cells, cells of the innate immune system, particularly mast cells, may be an
important component of the effector IL-17A response. Psoriasis is a common chronic autoimmune disease of the skin characterized by hyperplasia of epidermal keratinocytes with associated inflammation. IL-33 is a new member of the IL-1 superfamily that signals through the ST2 receptor and was originally defined as an inducer of T helper 2 (Th2) cytokines. Recently broader immune potential has been discovered for IL-33 particularly via mast cell activation. With its expression at body barrier surfaces it is assumed to act as an alarmin. In this thesis I demonstrate that IL-33 expression is up-regulated in the epidermis of psoriatic lesions, compared to healthy skin, thus indicating that IL-33 may be a mediator regulating crosstalk between keratinocytes and infiltrating immune cells in psoriatic plaques. In a phorbol ester-induced model
of skin inflammation ST2-/- mice exhibited reduced cutaneous inflammatory responses compared to WT mice. Furthermore, consecutive injections of IL-33 into the ears of mice induced a psoriasis-like inflammatory lesion. This was partially mast cell dependent and cellular analysis demonstrated recruitment of neutrophils to the ear. This concludes that IL-33, via activation of mast cells and
recruitment of neutrophils, may play a role in psoriasis plaque inflammation.
In the last part of the thesis I tested if nanoparticles can be utilized to image cytokine driven inflammation. Bio-linkages with protein-nanoparticles have been established and in vivo detection of nanoparticles performed. This final
interdisciplinary outlook demonstrates a still to be established/finalized method with great potential.
Actions (login required)