Background/Aims: It is known that allelic variants of the gene encoding the vitamin-D receptor (VDR) detected by BsmI increase the risk of some advanced malignant tumors, suggesting that such variants may cause functional differences in 1,25(OH)₂ vitamin D₃. We examined the VDR genes of Japanese systemic lupus erythematosus (SLE) patients, to determine whether different genotypes are correlated with SLE or its criteria. Methods: VDR genotyping of 58 unrelated Japanese SLE patients was performed based on polymerase chain reaction-restriction fragment length polymorphism (RFLP). Following amplification, products were digested with BsmI. The RFLPs were coded as Bb, where the uppercase letter signifies the absence of the digested site and the lowercase letter signifies the presence of the site. Results: The frequency of the VDR BB genotype was significantly higher in SLE patients (15.5%, n = 9/58, p < 0.0001) than in controls (5.7%, n = 5/87). Furthermore, a larger proportion of bb individuals was observed among patients with nephrotic syndrome (61.5%, n = 8/13) than among SLE patients without renal dysfunction (35.7%, n = 10/28). There was a significant tendency for the population of patients with the bb genotype to be correlated with that of patients with renal dysfunction (p = 0.0304). Conclusion: These findings suggest that the BB genotype might trigger the development of SLE, and that the bb genotype is associated with lupus nephritis.

We assessed the role of platelet activation markers (PMPs, Annexin V and CD62P on activated platelets), cytokines (IL-1 beta, IL-4, IL-6, IFN- gamma, GM-CSF, and TNF alpha ), and soluble factors (sIL-2R, TM, sHLA-1, beta(2) -m, sVCAM-1, sPECAM-1, sP-selectin and sE-selectin) in vascular damage related to SLE. There were differences in the levels of PMPs and platelet activation markers between the SLE patients and controls (PMPs: 493+/-82 vs. 328+/-36, p<0.05; plt-CD62P; 8.5%+/-1.2 % vs. 4.6%+/-0.7 %, p<0.05; plt-Annexin V: 11.3%+/-2.1 % vs. 4.9%+/-0.6 %, p<0.01). There were no differences in the levels of IFN- gamma between the groups. However, the levels of IL-1 beta, IL-4, IL-6, GM-CSF, TNF alpha, and soluble factors were higher in the SLE patients than in the controls. The levels of IL-4, IL-6, beta2 -m, sIL-2R, sVCAM-1, sP-selectin, and sE-selectin in SLE patients with elevated sTM levels were higher than those in the SLE patients without elevated sTM levels. On the other hand, elevations of sIL-2R, sVCAM-1, and sP-selectin were not found in patients with Behçet disease or rheumatoid arthritis. The levels of platelet CD62P, platelet annexin V, and PMP were significantly elevated in high-sTM patients. These findings suggest the possibility that activated platelets and cytokines participate in the pathogenesis of SLE in patients with elevated sTM levels.

We performed HLA-A, -B, and -C antigen and -DR DNA typing in 111 Japanese patients with idiopathic thrombocytopenic purpura (ITP). DRB1*0410 was significantly increased in ITP patients compared with healthy controls (relative risk = 9.52, P < .05), but the other DRB1*04 alleles showed no significant differences. On HLA-DR serotyping, patients with Vogt-Koyanagi-Harada disease (VKH) had a high frequency of DR4, so we compared the frequencies of DRB1*04 suballeles between ITP and VKH. The high frequency of DRB1*04 was dependent on DRB1*0405 in VKH, but on DRB1*0410 in ITP. Plasma autoantibodies were studied in 111 patients using a microtiter well assay. Thirty-six patients had anti-GPIIb/IIIa autoantibodies, and antibody positivity was associated with HLA-DR4 (29 of 36, 80.6% v 28 of 75, 37.3%) but not with DRB1*0410. When HLA-DR4 and DRB1*0410 were compared between patients with a good or poor response to prednisolone, HLA-DR4 was decreased and DRB1*0410 was significantly decreased (χ2 = 11.455, P < .01) in patients with a good response. In conclusion, this study showed that genetically determined factors influence the course of ITP. However, our findings should be considered preliminary because of possible racial differences in HLA status between Japanese and other ITP patients.

We investigated the levels of various cytokines and soluble factors in ITP patients, in order to determine the influence of these factors on the pathogenesis of ITP. We found increases in IL-2, IL-6, IFN-gamma, and M-CSF levels in ITP patients compared with those in healthy individuals. On lymphocyte phenotype analysis, we found no clear difference in total T cell population (CD2+ CD19- cells) or cytotoxic T cell frequency (CD8+ CD11b- cells) between these two groups. The frequency of helper/inducer T cells (CD4+ CD8- cells) was decreased in ITP patients. There was a significant increase in activated T cells (CD3+ HLA-DR+ cells) in ITP patients. Furthermore, frequencies of NK cells of potent activity (CD16+ CD56+ cells) were significantly elevated in ITP patients. Seventeen of the 54 ITP patients (31.5%) had elevated levels of sFas, and 11 of the 54 patients (20.4%) of sFasL. In addition, a significant increase of sFasL was observed in sFas-positive ITP patients, and in these patients the sFasL level was correlated with that of sFas (r = 0.687, p < 0.01). We found significant increases in IL-2 and sIL-2R levels in sFas-positive ITP patients. For other factors examined, however, there were no differences in level between sFas-positive and -negative ITP patients. Percentages of activated T cells (CD3+ and HLA-DR+ cells) and NK cells (CD16+ and CD56+ cells) were significantly higher in sFas-positive ITP patients than in sFas-negative ITP patients. These findings suggests that the pathogenesis of ITP includes alteration of the Fas/FasL pathway.

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