FULL PAPER Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen C Timmann 1 , S Fuchs 1,2 , C Thoma 1,3 , B Lepping 1 , NW Brattig 1 , J Sievertsen 1 , T Thye 1 , B Mu ¨ ller-Myhsok 1,4 and RD Horstmann 1 1 Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany Since interleukin (IL)-10 is a key mediator of immunosuppression, and immunosuppression is considered an important element of helminth infection, we studied variants of the putative IL-10 gene promoter in 337 individuals from 130 families heavily exposed to infection by the tissue nematode Onchocerca volvulus. As shown by transmission disequilibrium tests, variants of the IL-10 promoter at positions –1082(G/A), –819(C/T), and –592(C/A) in the haplotype of ATA were significantly associated with high peripheral blood cell (PBC) proliferative responses to O. volvulus antigen (OvAg). No associations were observed using phytohemagglutinin-induced PBC proliferation or with qualitative or quantitative phenotypes of onchocerciasis or onchocerciasis-related skin disease. The findings are compatible with the hypothesis that the ATA haplotype causes a decrease in IL-10 production by OvAg-reactive type-1 regulatory T-lymphocytes, thereby alleviating the suppression of other T cells. To our knowledge, this is the first time that an influence of IL-10 promoter variants is shown on the adaptive immune response. Genes and Immunity (2004) 5, 256–260. doi:10.1038/sj.gene.6364094 Published online 6 May 2004 Keywords: onchocerciasis; filariasis; immune tolerance; TDT; QTDT Introduction Interleukin (IL)-10 is considered a key mediator of immunosuppression and tolerance. 1 It appears to be primarily produced by monocytes and T regulatory (Tr)1-lymphocytes and to act on a number of cells, including monocytes, helper and cytotoxic T cells as well as B cells. IL-10 was shown to play a role in a broad variety of tumors, autoimmune and infectious diseases. 1 Evidence for its immunosuppressive activity has been based on the observations that (i) increased production of IL-10 ex vivo and in animal models was associated with states of immunosuppression, 2,3 (ii) neutralizing antibodies to IL- 10 reversed hyporesponsiveness of T cells ex vivo, 4,5 and (iii) deletion of the IL-10 gene rendered mice more resistant to tumors or infection and more susceptible to infection pathology or autoimmune disease. 6–9 Substantial interindividual variability has been noted in several studies with humans, and heritability of high or low IL-10 secretion was observed. 10,11 Polymorphisms in the putative promoter region of the human IL-10 gene were identified and correlated to high or low IL-10 production of peripheral blood cells (PBCs) upon in vitro stimulation with lipopolysacharide (LPS) or concanavalin A (ConA). 12,13 Variants at positions –2849 (G/A), –1082(G/A), –819(C/T), and –592(C/A) were found to be involved, whereby the variants at positions – 1082, –819, and –592 occurred in haplotypes of ATA and GCC. 12–15 A number of studies have been presented providing evidence for associations between these IL-10 promoter variants and infectious or autoimmune diseases, includ- ing meningococcal infection, fatal septicemia, systemic lupus erythematodes, reactive arthritis, psoriasis, Sjog- ren ´ s syndrome, and multiple sclerosis. 10,12,16–20 So far, it has not been studied, however, whether IL-10 promoter variants influence lymphocyte proliferation upon anti- gen stimulation, a major regulatory function attributed to IL-10. Infections with the tissue nematode Onchocerca volvu- lus cause a spectrum of clinical manifestations ranging from poles of immunosuppression to immunopathol- ogy. 21 Immunosuppression is marked by high numbers of the larval microfilariae without significant immune reactions, whereas immunopathology is characterized by various forms of immunoreactive dermatitis. 22 A role of Received 25 November 2003; revised 01 March 2004; accepted 15 March 2004; published online 6 May 2004 Correspondence: Dr. med. C Timmann, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, Hamburg 20359, Germany. E-mail: timmann@bni.uni-hamburg.de 2 Current address: Institute for Human Genetics, Universita ¨tsklini- kum Hamburg-Eppendorf, Hamburg, Germany 3 Current address: Bundeswehrzentralkrankenhaus, Koblenz, Germany 4 Current address: Computational Genetics Group, Max-Planck- Institute of Psychiatry, Munich, Germany Genes and Immunity (2004) 5, 256–260 & 2004 Nature Publishing Group All rights reserved 1466-4879/04 $30.00 www.nature.com/gene