A Case of Right Cytokine, Wrong Cell!

2010-03-10T05:51:00.000-08:00

Significant strides have been taken in understanding the pathogenesis of rheumatoid arthritis (RA) in recent years with beneficial translation into clinically effective treatments. The past 20 years has seen the greatest therapeutic leap in RA with the advent of TNF blockading biologics. TNF blockade has produced significant clinical improvement in the majority of RA patients; in particular the development of erosive changes seems to be specifically delayed and very early treatment with infliximab and methotrexate reduces magnetic resonance imaging evidence of synovitis and damage. Nevertheless, up to 40% of patients fail to respond adequately to anti-TNF therapy for poorly understood reasons.

Recently, targeting the proinflammatory cytokine, IL-17 has begun to receive attention as a new therapeutic strategy. Its elevated expression in RA synovium and synovial fluid was first detected in 1999. Animal models of arthritis have since identified this proinflammatory cytokine to be a key player in the disease process. Attempts to identify the cellular source of IL-17 have been the focus of several research groups worldwide. Many reports identified T cells as the predominant producer of IL-17, coining this population of cells as Th17s. However, identification of these cells in the synovium or synovial fluid of RA patients has proven difficult with a paucity of these cells evident.

Hueber et al, reporting in their Cutting Edge Journal of Immunology article, may have found the solution [1]. They identify that mast cells as opposed to T cells are the predominant source of IL-17 in inflamed RA joint tissue. Examination of synovial tissue sections from established RA patients identified that less than 4% of cells staining positive for IL-17 colocalized with CD3. In fact, nearly 10% of IL-17+ cells were also positive for the macrophage marker, CD68. However, the frequency of both of these cell subsets paled in significance compared with over 90% of IL-17+ cells co-staining for MCT (mast cell tryptase), the cell marker for mast cells.

The authors also found that mast cells could be induced to make IL-17 through stimulation with either TNF, immune complexes, complement or LPS. IL-17 production could be blocked by transfecting mast cells with the short interfering RNA against the RORC gene, a known transcription factor (RORgammaT) specific for IL-17.

This study is a critical advance in identifying the primary source of IL-17 in RA and helps to clarify the paradox created by the evidence for high levels of IL-17 in the RA joint but very few Th17 cells. However, it is still unclear as to the role of IL-17-producing mast cells at different stages of the disease process. Despite this, we cannot discount that Th17 cells may still have a significant role to play. It is unclear in the early stages of arthritis for which higher detectable levels of IL-17 have been reported compared with established RA as to which cell type is driving its production. This will likely be the active focus of research to come.

1. Cutting Edge: Mast Cells Express IL-17A in Rheumatoid Arthritis Synovium. Axel J Hueber, Darren L. Asquith, Ashley M. Miller, Jim Reilly, Shauna Kerr, Jan Leipe, Alirio J. Melendez, Iain B. McInnes. J Immunol. 2010, 184:000-000 ahead of print.

Launch date: December 1st

2009-11-04T08:45:00.000-08:00

Hello,
The main purpose of this blog is to provide each month a review of 'published' cutting edge research primarily into rheumatoid arthritis, but undoubtedly will dip a toe into other arthritidies and relevant Immunological advances.

A theme will be chosen for each blog posting, which will include subjects such as therapeutic advances, T cell biology in RA, Inflammatory cascades, etc.

The theme chosen will be determined by the recent published literature and also my own selfish interests. However, if readers feel they would like a particular topic discussed I will welcome suggestions, and openly encourage interaction.

The search criteria for the monthly reviews will be focused on English language rheumatological journals including:
Annals of Rheumatic diseases
Arthritis and Rheumatism
Arthritis Research and Therapy
Nature Clinical Practice Rheumatology
Journal of Rheumatology
Rheumatology

However, the search will not be restricted to these publications.

I hope that the Blog will serve to highlight stimulating research that will be relevant to Rheumatologists, researchers and patients.

See you in December

kind regards

Leigh

Rheumatology Review

A Case of Right Cytokine, Wrong Cell!

Launch date: December 1st