RESEARCH - What does TNF excess do to the immune system long term?

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Ann Rheum Dis. 2005 Nov;64 Suppl 4:iv70-6.

What does tumour necrosis factor excess do to the immune system long term?

J, Vagenas P, Panesar M, Cope AP.

Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial

College, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK.

Members of the tumour necrosis factor (TNF)/TNF-receptor (TNF-R) superfamily

coordinate the immune response at multiple levels. For example, TNF,

LTalpha, LTbeta and RANKL provide signals required for lymphoid neogenesis,

CD27, OX-40, 4-1BB and CD30 deliver costimulatory signals to augment immune

responses, while pro-apoptotic members such as TNF, CD95L and TRAIL may

contribute to the termination of the response. Biological identity of

individual family members has been revealed through studies of gain of

function or gene deficient mutants. Most notable are the development of

spontaneous inflammatory polyarthritis in human TNF-globin transgenic mice,

the auto-inflammatory syndromes resulting from mutations in the 55-kDa

TNF-R, and, in particular, the obligatory role for the RANKL/RANK axis in

osteoclastogenesis and bone remodelling. A growing appreciation of the

molecular basis of signalling pathways transduced by TNF-R has provided a

framework for better understanding the biology of this expanding family. For

while the rapid and robust activation of NF-kappaB and MAPK pathways is

typical of acute TNF-R engagement, the molecular basis of sustained receptor

signalling remains a mystery, in spite of its relevance to chronic

inflammatory and immune responses. Focusing on T cells, this report

describes some of the molecular footprints of sustained TNF-R engagement and

illustrates how these may influence immune function. A common theme arising

is that prolonged TNF stimulation alters signalling thresholds over time.

The authors propose that one major outcome of long term exposure to TNF is a

state of localised IL-2 deficiency at sites of inflammation. The

implications of this deficiency are discussed.

PMID: 16239393

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

6239393 & dopt=Abstract

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