Search

We analysed a polymorphism of the interleukin (IL)-1 receptor antagonist (IL1RN) gene in 93 Japanese patients with palmoplantar pustulosis (PPP). None of the IL1RN alleles was significantly increased in the patients compared with controls. Because PPP has been reported to be associated with the tumour necrosis factor (TNF) region, we examined the association between the TNF and IL1RN genes. There was a difference in IL1RN*2 positivity between patients with and without the AA genotype of the TNF gene. In contrast, such a difference was not found in controls. These data indicate a possible epistatic effect between TNF and IL1RN linked genes for susceptibility to the pathogenesis of PPP.

We investigated the allelic distributions of single nucleotide polymorphisms (SNPs) of the TNFA, TNFB and IKBL genes, 3 microsatellites within the tumor necrosis factor (TNF) region of HLA locus, and the HLA phenotypes as well as the TLR4 gene in Chromosome 9 in 26 healthy Caucasian volunteers. These individuals were also assessed as ultraviolet B (UVB)-susceptible (S) or UVB-resistant (R). Our results identified 12 UVB-S and 14 UVB-R individuals. Attempts to correlate particular HLA-A, -B, -C, and -DR antigens with the UVB phenotypes failed. Similarly, attempts to correlate SNP at the NcoI-RFLP within intron 1 of the TNFB, IKBL and TLR4 gene with UVB phenotypes also failed. However, microsatellite analyses of TNFa, TNFc, and TNFd markers revealed a significant increase in the frequencies of TNFa2 in UVB-S individuals (P=0.00032) and of TNFd3 in UVB-R individuals (P=0.012). Moreover, DNA sequencing analyses of 5 SNPs of the TNFA promoter region revealed a significant increase in the frequency of the allele B of the TNFA gene (TNFApB) representing the nucleotide A at position -863 and C at position -1031 (P=0.015). Since it is known that TNFa2 and TNFApB is a high TNF-alpha responder, whereas TNFd3 is a TNF-alpha low responder, we propose that the TNF region of HLA contains polymorphic genes that confer susceptibility and resistance to the deleterious effects of UVB radiation on the induction of contact hypersensitivity. This proposal is consistent with previous reports that a unique microsatellite region of the Tnfa gene in mice contains alleles that dictate the UVB-dependent phenotypes in mice, and implicate TNF-alpha as the primary mediator of the immune-damaging effects of UVB radiation.

Polymorphisms of the 5′-flanking promoter/enhancer region of the TNFA gene were determined in 80 Japanese patients with pulmoplantar pustulosis (PPP). The 5′-flanking region of the TNFA gene from –1107 to –66 was amplified by polymerase chain reaction (PCR) method. Nucleotide sequencing data from the PCR products revealed that 5 single nucleotide polymorphisms at position –1031, –863, –857, –307 and –237. None of the nucleotide substitutions were significantly increased in PPP patients when compared with those in controls. To clarify the linkage among the neighboring genetic marker, we analyzed the association between the polymorphisms in the TNFA promoter region and the NcoI polymorphism in the first intron of the TNFB gene as well as HLA-DR9. The genotype at –1031C is strongly associated with TNFB1 and negatively associated with TNFB2 which is reported to be associated with PPP. These data indicate that TNFA gene centromeric to TNFB is not associated with PPP and the susceptible gene of PPP is located between TNFB and HLA-B.

The role of antigen-presenting cells (APC) in the induction of antigen-specific unresponsiveness was examined, using two functionally distinct murine macrophage hybridomas, #59 and #63 cells. Derivatized with the hapten (dinitrofluorobenzene; DNFB), #59 cells induced contact hypersensitivity (CH) in mice. Hapten-derivatized #63 cells failed to induce CH. Instead, they prevented recipients from acquiring CH when exposed subsequently to a sensitizing dose of the hapten. Similarly, hapten-derivatized #59 cells, pretreated in vitro with transforming growth factor-beta2 (TGF-beta2) lost their capacity to evoke CH, and induced tolerance. Hapten-derivatized #63 cells and TGF-beta2-treated #59 cells eliminated CH in mice sensitized to hapten. Reverse transcription-polymerase chain reaction analysis of mRNAs for various accessory molecules important in T-cell activation revealed that #63 and TGF-beta2-treated #59 cells differed only in their expression of tumour necrosis factor-alpha (TNF-alpha) mRNA. The latter expressed higher levels of TNF-alpha mRNA than did untreated #59 cells. As a consequence, #63 and TGF-beta2-treated #59 cells, both of which induce tolerance, secrete TNF-alpha protein unlike untreated #59 cells, which do not induce tolerance to hapten. Since neutralizing anti-TNF-alpha antibodies abrogated the tolerogenic potential of #63 cells in vivo, we conclude that TGF-beta2 equips hapten-bearing APC with the capacity to evoke systemic immune deviation in which CH is selectively silenced. We speculate that one effect of TGF-beta2 is to cause APC to up-regulate TNF-alpha production. In turn, this cytokine biases the functional property of responding hapten-specific T cells in a direction that not only interferes with acquisition, but suppresses induction of CH.

We investigated the allele and genotype distribution of a polymorphism of the tumor necrosis factor (TNF) B gene and the frequency of HLA-DR9 in 49 patients with Palmoplantar pustulosis (PPP) and 51 healthy controls. We found that the frequency of TNFB2 in the PPP patients was significantly higher than that in the controls. Furthermore, the DR9-TNFB2 haplotype was significantly more frequent in the PPP patients (P=0.0045). These results suggest that TNFB2 may confer susceptibility to PPP.