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To the Editor:

We thank Todd et al for their interest in our report. It may be very important that they have also found similar levels of TNF-stimulated IL-6 production in cells from TRAPS patients and normal controls. C-reactive protein and serum amyloid A, surrogate markers for serum IL-6, are elevated in patients with TRAPS (1). Thus, it appears that IL-6 may be important to the pathology of the disease, and so targeting IL-6 may be an effective therapeutic approach.

We agree that each mutation may have a number of effects accounting for the heterogeneity in the clinical manifestations of TRAPS. One of the key advances from our study is the observation of reduced NF-κB activation, which suggests a signaling defect. However, our findings also suggest that elucidating the question of whether TRAPS mutants can signal normally may depend on what signal is being measured, because we see reduced NF-κB activation and TNF-induced apoptosis while IL-6 induction is normal. The observation that fibroblasts from patients with the C33Y mutation did not consistently show decreased TNF-induced cell death suggests that the response to apoptosis may vary for different mutations. While this is consistent with data from transfected cells (2), Todd et al state that exogenous expression of large amounts of TNFRSF1A may cause misfolding (3) and drive signaling in ways that are not driven in vivo (4). Thus, analysis of signaling in cells from patients with other TRAPS mutations will hopefully resolve this issue in the future.

The key objective of our study was to investigate signaling in patients. Our findings add an alternative dimension to the previous work done in this area. We hope that complementary research at a number of centers will drive knowledge forward to quickly resolve the question of how TRAPS occurs and to optimize the treatment of patients with this disorder.

  • 1
    McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 1999; 97: 13344.
  • 2
    Todd I, Radford PM, Draper-Morgan KA, McIntosh R, Bainbridge S, Dickinson P, et al. Mutant forms of tumour necrosis factor receptor I that occur in TNF-receptor-associated periodic syndrome retain signalling functions but show abnormal behaviour. Immunology 2004; 113: 6579.
  • 3
    Sanders CR, Nagy JK. Misfolding of membrane proteins in health and disease: the lady or the tiger? Curr Opin Struct Biol 2000; 10: 43842.
  • 4
    Boldin MP, Mett IL, Varfolomeev EE, Chumakov I, Shemer-Avni Y, Camonis JH, et al. Self-association of the “death domains” of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects. J Biol Chem 1995; 270: 38791.

Stefan Siebert MBBCh, MRCP*, Bryan D. Williams FRCP, FRCPath*, Paul Brennan PhD*, * Cardiff University, Cardiff, UK.