Differential effect of IL10 and TNFα genotypes on determining susceptibility to discoid and systemic lupus erythematosus

Objective: To ascertain the possible involvement of functional interleukin 10 (IL10) and tumour necrosis a (TNF alpha) cytokine promoter polymorphisms on the susceptibility to discoid and systemic lupus erythematosus (DLE, SLE), and their associations with immunological features. Methods: Single nucleotide polymorphisms of the IL10 (21082, 2819, and 2592) and TNF alpha (2308) genes were determined using allele specific probes in 248 lupus patients and 343 matched controls. To assess functional significance of genotypes, basal mRNA cytokine levels were quantified in 106 genotyped healthy controls by real time RT-PCR. Specific autoantibodies and cutaneous manifestations were analysed in SLE patients and associated with functional genotypes. Results: After analysing the distribution of IL10 and TNF alpha transcript levels according to promoter genotypes in healthy individuals, patients and controls were classified into functional single and combined genotypes according to the expected high or low constitutive cytokine production. High TNF alpha genotypes (-308AA or AG) were associated with SLE independently of IL10 alleles, whereas the risk of developing DLE and the prevalence of discoid lesion in SLE were higher in the high IL10/low TNF alpha producer group (-1082GG/-308GG). Cytokine interaction also influences the appearance of autoantibodies. Antibodies against Sm are prevalent among low producer patients for both cytokines, a genotype not associated with lupus incidence, whereas low IL10/high TNF alpha patients have the highest frequency of antibodies to SSa and SSb. Conclusions: IL10/TNF alpha interaction influences susceptibility to DLE and the appearance of specific autoantibodies in SLE patients, whereas high TNFa producer genotypes represent a significant risk factor for SLE.