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LETTERS TO THE EDITOR |
Department of Pediatrics, Institute of Experimental Dermatology Interdisciplinary Center of Clinical Research University of Muenster Muenster, Germany
In the May issue of The Journal of Immunology, Abe et al. reported that S100A8, S100A9, and S100A12 are among the genes most profoundly up-regulated during acute Kawasaki disease (1), supporting previously published data (2, 3, 4). The authors found profoundly differing serum concentrations using different ELISA kits. They explain these differences with the presence of monomers and complex forms of S100A8 and S100A9. However, there is clear evidence proving that the S100A8/S100A9 complex is the relevant form in vivo (5, 6, 7). In our opinion, differing concentrations reported in this article can be simply explained by the use of various Abs detecting different epitopes with different affinities. Especially, quantitative comparison with data generated using the mAb 27E10, which detects a specific epitope formed exclusively by the S100A8/S100A9 complex, is critical. Lack of formation of this unique epitope by the protein standard may explain high concentrations of S100A8/S100A9 reported in this article. We use S100A9-specific Abs and calibrate our ELISA with a protein standard that was extensively characterized by independent methods to ensure correct determination of S100A8/S100A9 concentrations (8, 9). Exact characterization of the gold standard is a crucial step mandatory for any assay before measuring S100A8/S100A9 serum levels for diagnostic purposes.
Proinflammatory S100 proteins are differentially expressed in Kawasaki disease, may contribute to vasculitis, and may serve as biomarkers for monitoring inflammation. However, there are serious pitfalls associated with the detection of these proteins in patient samples. Therefore, both the methodology of detection assays and the interpretation of data have to be validated thoroughly.
References
* Department of Allergy and Immunology National Research Institute for Child Health and Development Tokyo, Japan
Graduate School of Medicine Chiba University Chiba, Japan
We appreciate the comments by Drs. Foell and Roth. We reported that plasma S100A8/A9 heterocomplex levels were significantly higher in preintravenous infusion of high-dose IG (IVIG) Kawasaki disease (KD) patients (25.3 ± 1.5 µg/ml) than in post-IVIG patients (18.4 ± 1.7 µg/ml) and febrile controls (10.7 ± 1.0 µg/ml) (R1 ). In the paper, we used an MRP8/14 ELISA kit (Buhlmann Laboratories) that does not cross-react with S100A8 or S100A9 monomer (R2 ). Although we did not measure healthy controls by this kit, the manufacturer’s proposed serum cut-off titer in healthy adults was 12.4 µg/ml. In addition, we obtained similar results after we measured the same samples with our ELISA using the mAb 27E10 and the recombinant S100A8 and S100A9 proteins as protein standard (r = 0.852, p < 0.0001, our unpublished data). Thus, we believe the different S100A8/A9 plasma levels observed between the pre- and post-IVIG patients reflect exact changes brought on by IVIG therapy and were not caused by using various Abs detecting different epitopes with different affinities as Drs. Foell and Roth suggested.
With regard to the plasma S100A9 levels, we reported much lower values compared with S100A8/A9 levels for both pre-IVIG patients (12.8 ± 2.6 ng/ml) and febrile controls (12.5 ± 5.8 ng/ml) by using a MRP14 ELISA kit (Chemicon International) (R1 ). The kit contains two mAbs that detect different epitopes of S100A9 and do not cross-react with S100A8/A9 heterocomplex. These results indicate that S100A9 is mainly present as heterocomplex with S100A8 in human plasma. In this respect, we agree with Drs. Foell and Roth that the S100A8/A9 heterocomplex is the relevant form in vivo (R3 R4 ).
Finally, our oligonucleotide microarray analysis suggests that suppression of an array of immune activation genes underlies the effect of IVIG therapy in KD patients. S100A8/A9 is one of those most significantly down-regulated genes after IVIG. It is important to determine whether plasma S100A8/A9 levels are reliable markers for the responsiveness of patients to the therapy and to elucidate the role of S100A8/A9 in the pathogenesis of KD as well as other autoimmune diseases (R5 ).
References
This article has been cited by other articles:
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  T Kaiser, J Langhorst, H Wittkowski, K Becker, A W Friedrich, A Rueffer, G J Dobos, J Roth, and D Foell Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome Gut, December 1, 2007; 56(12): 1706 - 1713. [Abstract] [Full Text] [PDF]
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