Interleukin-10 (IL-10) has a critical role in the regulation of immune responses. The relative contribution of genetic and environmental factors to IL-10 production is under debate. We performed a twin study in 246 monozygotic and dizygotic twins to assess the heritability of IL-10 production after LPS stimulation in whole blood. In addition, the influence of promoter single nucleotide polymorphisms (À1082, À819 and À592) on transcriptional activity and their binding to nuclear factors was studied in luciferase reporter gene and electrophoretic mobility shift assays. IL-10 production showed a genetic determination with a heritability of 0.5. Decreasing body mass index (BMI), smoking and female gender lead to decreased IL-10 production. In monocytes, the À1082A allele showed higher binding affinity to the transcription factor PU.1 resulting in decreased transcriptional activity of À1082A promoter haplotypes. Genetic determination of IL-10 secretion is probably lower than that previously reported. Fifty percent of the observed variability explained by genetic factors. Female individuals produce less IL-10 than male subjects. Environmental factors like smoking and decreasing BMI exert suppressing effects on IL-10 production. Although the À1082A allele shows higher binding affinity to the PU.1 transcription factor and lower transcriptional activity, this polymorphism probably explains only a small fraction of the observed heritability.

Genes encoded on chromosome 6 within the major histocompatibility complex region are thought to play an important role in the pathogenesis of psoriasis. A potential candidate gene is tumor necrosis factor alpha. The tumor necrosis factor alpha promoter contains several polymorphisms including two G-->A transitions at position -308 and -238, which are the most common in Caucasian populations. The TNF238.2 (-238A) allele has been strongly associated with psoriasis. We have investigated the effect of the -238 and -308 variants on transcription of the tumor necrosis factor alpha gene in luciferase reporter gene assays. In addition, peripheral blood mononuclear cells of 47 patients with psoriasis and 43 controls were stimulated with different antigens and mitogens (streptococcal sonicate and superantigen, lipopolysaccharide, phorbol-12-myristate, phytohemagglutinin, CD3 antibodies) and tumor necrosis factor alpha production was measured in supernatants by enzyme-linked immunosorbent assay. The psoriasis-associated tumor necrosis factor alpha promoter allele TNF238.2 showed a significantly decreased transcriptional activity. Peripheral blood mononuclear cells carrying this allele produced significantly less tumor necrosis factor alpha after stimulation with T cell mitogens and streptococcal antigens in comparison to controls. The promoter allele TNF238.2 seems to influence tumor necrosis factor alpha production; a possible role in the pathogenesis of psoriasis has to be further evaluated.

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H epatitis B virus (HBV) vaccination is highly effective in the primary prevention of acute and chronic HBV. Nationwide vaccination programs have succeeded in reducing HBV related morbidity and mortality considerably. Hepatitis B vaccine responsiveness shows large interindividual variability. Results of a twin study have shown a strong genetic determination of the HBsAg specific immune response with 60% of the observed variability explained by genetic factors. Although there is a strong contribution of genes encoded within the major histocompatibility complex (MHC) most of the genetic effect originates from genes outside the MHC. 1 Possible candidates for immunoregulatory functions are cytokine genes and proteins involved in intracellular signaling pathways in lymphocytes.Interleukin (IL-10) is an important immunoregulatory cytokine that is produced by monocytes and lymphocytes. 2 It inhibits formation of proinflammatory cytokines like TNF-␣ in T cells and monocytes 3 and downregulates MHC class II expression in monocytes. 4 Contrary to its inhibitory function in T cells and macrophages, in B cells IL-10 stimulates the production of immunoglobulins and the expression of MHC class II antigens. 5 We and others have recently shown that approximately 50% of the observed interindividual variability in IL-10 production can be explained by genetic factors. 6,7 Some of the observed variability in IL-10 production is determined by polymorphisms in the 5Ј-flanking region of the IL-10 gene on chromosome 1 (1q31). The proximal promoter contains three biallelic single nucleotide polymorphisms (SNPs) at positions Ϫ1082 (G/ A), Ϫ819 (C/T) and Ϫ592 (C/A) bp from the transcription start site. These SNPs are closely linked and

Objective: To investigate the potential association of tumour necrosis factor α (TNFα) microsatellite and promoter alleles with psoriatic arthritis (PsA). Methods: DNA from 89 white patients with PsA, 65 patients with psoriasis, and 99 healthy white controls was investigated for two TNFα promoter (-238 and -308) and three microsatellite polymorphisms (TNFa, c, and d). Patients had previously been studied by serology for HLA class I antigens and by sequence-specific polymerase chain reaction for DRB1* alleles. In addition, TNFα production of Ficoll separated peripheral blood mononuclear cells (PBMC) into culture supernatants after stimulation with lipopolysaccharide, αCD3 antibodies, phytohaemagglutinin, and streptococcal superantigen C was determined.Results: A significant, HLA class I independent increase of the TNFa6c1d3 haplotype was found in the group with PsA but not among patients with psoriasis (32% v 8%, pc<0.008; relative risk (RR)=5.3). In addition, patients with PsA showed a marked decrease of the TNF308A promoter allele (6% v 18%; pc<0.008; RR=3.5) compared with healthy controls, which was independent of the increased frequency of the -238A polymorphism in this group. PBMC from patients with PsA secreted significantly less TNFα than cells from patients without arthritis. In particular, the TNFa6 microsatellite was associated with decreased TNFα production. Conclusion: These data indicate that allelic variations at the TNFα locus influence susceptibility to PsA. Decreased production of TNFα is at least in part genetically determined and might be related to the development of arthritis. However, the association of the TNF308G allele with the disease also points to other disease related haplotypes with still unknown susceptibility genes.