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Neuropsychiatric systemic lupus erythematosus
  1. DAVID ISENBERG
  1. Centre for Rheumatology, UCLH, London
  2. Department of Molecular Pathology, UCLMS
  3. Department of Molecular Pathology, UCLMS
    1. ESTHER CRAWLEY
    1. Centre for Rheumatology, UCLH, London
    2. Department of Molecular Pathology, UCLMS
    3. Department of Molecular Pathology, UCLMS
      1. PAT WOO
      1. Centre for Rheumatology, UCLH, London
      2. Department of Molecular Pathology, UCLMS
      3. Department of Molecular Pathology, UCLMS
        1. M J ROOD,
        2. T W J HUIZINGA
        1. Leiden University Medical Centre, Department of Rheumatology, Building 1, C4-R, PO Box 9600, 2300 RC Leiden, the Netherlands

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          The considerable difficulties in making sense of the literature on patients with lupus involving the central nervous system are re-emphasised in the paper by Rood et al.1 The authors, who to be fair take a sensibly cautious approach to their results, nevertheless seek to persuade us that the IL10 locus is associated with neuropsychiatric lupus on the basis of a historical case notes review of 42 lupus patients with neuropsychiatric disease, compared with 50 who lack such involvement.

          Their conclusion needs to be treated with caution. Does it make sense to lump together 42 highly diverse patients and make the kind of claim they have made? The authors suggest that CNS lupus is attributable to either antiphospholipid antibody related thrombotic events, or “immune mediated” disease. This division is artificial. There is a considerable literature on CNS lupus that proposes that a wide variety of immunopathogenic mechanisms may be responsible in individual cases. These mechanisms include thrombotic effects, which may be linked to antiphospholipid antibodies, a true vasculitis, a cross reaction between antibodies that recognise the lymphocyte surface targets and neurological antigens, and antibodies to a wide variety of neurological targets. A considerably larger number of patients will have to be studied before any claims of links to an IL10 promoter haplotype can be truly convincing.

          We agree with the authors that patients with SLE have a higher innate production of IL10 than controls. However, as there is no significant difference in the frequency of the IL10 promoter single nucleotide polymorphisms (SNP)s in SLE patients when compared with controls in their study, we suspect that the difference in IL10 production is not attributable to functional difference between patients with SLE and controls in terms of the IL10 SNP alleles frequencies.2-4Differences have been described with respect to microsatellites5 and one awaits confirmation from other populations or family studies. To our knowledge, a difference in IL10 production between patients with neuropsychiatric disease SLE and non-neuropsychiatric disease SLE has not been described. The described associations would be biologically meaningless if IL10 production is similar between these two groups.

          The authors suggest that the -1082A allele is associated with a higher innate IL10 production, however, they appear to ignore the only published study to date that showed that the A allele was associated with lower IL10 production.6 In addition we have confirmed that the A allele is associated with lower IL10 production in transient transfection studies and the ATA/ATA genotype is associated with lower IL10 production in whole blood culture.4 The increase in the A allele is mainly accounted for by an increase in the ATA haplotype in their neuropsychiatric disease patients and therefore they are describing an association with a low IL10 producing haplotype, not a high IL10 producing haplotype. One interpretation of this would be that patients with neuropsychiatric disease symptoms are unable to adequately control inflammation from a variety of different pathological mechanisms because of low IL10 production.

          References

          Authors’ reply

          We thank Drs Isenberg, Crawley and Woo for their interest in our paper.1-1

          They argued that the dichotomy of the pathogenesis of CNS lupus in “immune mediated” and tromboembolic disease is too rigid, because a wide variety of immunopathogenetic mechanisms can be deemed responsible for CNS lupus. As the hallmark of SLE is the production of autoantibodies, it seems to be justified to assume that the pathogenesis underlying CNS lupus is B cell mediated. Based upon this assumption we clustered the individual neuropsychiatric disease SLE patients and tested the hypothesis that a genetic marker in the promoter of the IL10 gene is associated with the phenotype of CNS-SLE.

          In general, a positive result in a genetic association study is only possible after a correct definition of the phenotype. After all, if the phenotype is inadequately defined, the magnitude and statistical significance of the association will be less or lost because of the random distribution of the genetic marker in the misclassified patients. If misclassification occurred in the sense that CNS lupus patients were attributed to the non-neuropsychiatric disease SLE population, the fact that we still found a positive result strengthens our conclusions instead of weakens it.

          It might be argued that thromboembolic events do not fit in the pathogenetic model of B cell mediated CNS lupus. But, as stated clearly in the article, even after exclusion of these ambiguous patients, the distribution of the frequencies in the neuropsychiatric disease SLE and non-neuropsychiatric disease SLE patients remains the same.

          Of course we agree with the notion that our findings must be repeated in another group of patients. Interestingly, the increased prevalence of ATA in neuropsychiatric disease SLE patients has already been reported by Mok in a group of Chinese SLE patients.1-2Currently we are investigating the distribution of the IL10 promoter haplotypes of neuropsychiatric disease SLE patients in an ethnically different population.

          In our article we have elaborated on two possible explanations of our findings. Firstly, the increased frequency of the ATA haplotype might be associated with an increased production of IL10. We made this assumption in the light of previous studies stating that SLE as a whole is characterised by an increased innate IL10 production.1-3 1-4 It is wrong to extrapolate these conclusions to our population. Because of the retrospective character of our study, we were not able to measure IL10 production in our populations and therefore cannot say whether or not IL10 production in our SLE patients as a whole was similar to or different from the control population. It might well be that differences in IL10 production would only emerge after stratifying into neuropsychiatric disease SLE and non-neuropsychiatric disease SLE patients. Furthermore, it might be that in the populations mentioned before, there was an excess of patients with neuropsychiatric disease SLE.

          The second explanation for the skewing found in IL10 promoter polymorphisms might be that the increased susceptibility to neuropsychiatric disease SLE in the ATA patients is not conferred via an increased IL10 production at all, but that it is merely a marker for the real neuropsychiatric disease SLE susceptibility allele.

          It is not clear whether or not IL10 promoter SNPs are associated with low or high IL10 production, because of the ambiguous reports in the literature. In our laboratory, the -1082 A allele has been found to be associated with high IL10 production.1-5 In this light we have speculated about the possible link of high IL10 production and the pathogenesis of neuropsychiatric disease SLE. Isenberget al have referred to another group stating that -1082 A is associated with a low ex vivo IL10 production and they interpret our results with this finding in mind.1-6 In conclusion, we do not know the relevance of the IL10 promoter in the in vivo regulation of IL10 production and therefore both explanations are equally speculative.

          References

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