Beretta L, Cappiello F, Barili M, Scorza R
Referral Centre for Systemic Autoimmune Diseases, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via Pace 9, 20122 Milano, Italy.
Tissue Antigens. 2007 Apr;69(4):305-12. doi: 10.1111/j.1399-0039.2007.00811.x.
Interleukin-10 (IL-10) can favour the development of fibrosis by promoting a relative shift towards T helper 2 responses. Three single base pair substitutions in the 5' flanking region of the IL-10 gene (G/A -1082, C/T -819 and C/A -592) influence the amount of IL-10 secreted in cell cultures: the GCC haplotype is associated with an increased production, while the ACC and the ATA haplotypes are associated with intermediate and decreased production. Accordingly, three phenotypes have been individuated: high producers (GCC+/GCC+), medium producers (GCC+/GCC-) and low producers (GCC-/GCC-). We hypothesised that IL-10 haplotypes and genotypes are differently expressed in patients with systemic sclerosis (SSc) with the limited cutaneous SSc (lcSSc) subset or the diffuse cutaneous SSc (dcSSc) subset. One hundred and sixty-one unrelated Italian patients with SSc and 94 controls have been included. Their DNA was extracted and stored before being analysed by polymerase chain reaction with sequence-specific primers. The GCC haplotype is overrepresented in patients with SSc; subjects with dcSSc were the primary contributors to these results (dcSSc: 52.2% vs controls: 37.2%; chi2= 8.519, 2 d.f., corrected P= 0.04). In Scl70-positive patients, the GCC haplotype increased the likelihood of presenting the dcSSc subset [chi2= 12.56, P < 0.0005; odds ratio (OR) = 3.89, 95% confidence interval (CI(95)) = 1.69-9.08]; these results were confirmed at the phenotypic level (chi2= 11.67, 2 d.f., P= 0.003). In Scl70-positive patients, the high-producing phenotype was associated with poor survival, independently from disease subset and gender (hazard ratio = 9.9, CI(95)= 1.6-61.27, P < 0.05). The IL-10 haplotype and genotype associated with high IL-10 production may alter the susceptibility to SSc and/or its expression, increasing the prognostic value of other well-known markers of disease severity.
白细胞介素-10(IL-10)可通过促进向辅助性T细胞2型反应的相对转变,来推动纤维化的发展。IL-10基因5'侧翼区域的三个单碱基对替换(G/A -1082、C/T -819和C/A -592)会影响细胞培养中IL-10的分泌量:GCC单倍型与产量增加相关,而ACC和ATA单倍型则与产量中等和降低相关。相应地,已确定了三种表型:高产量者(GCC+/GCC+)、中等产量者(GCC+/GCC-)和低产量者(GCC-/GCC-)。我们推测,IL-10单倍型和基因型在局限性皮肤型系统性硬化症(lcSSc)亚组或弥漫性皮肤型系统性硬化症(dcSSc)亚组的系统性硬化症(SSc)患者中表达不同。纳入了161名无亲缘关系的意大利SSc患者和94名对照。在通过序列特异性引物进行聚合酶链反应分析之前,提取并储存了他们的DNA。GCC单倍型在SSc患者中占比过高;dcSSc患者是这些结果的主要贡献者(dcSSc:52.2% vs对照:37.2%;χ2 = 8.519,自由度为2,校正P = 0.04)。在抗Scl70抗体阳性的患者中,GCC单倍型增加了出现dcSSc亚组的可能性[χ2 = 12.56,P < 0.0005;比值比(OR) = 3.89,95%置信区间(CI(95)) = 1.69 - 9.08];这些结果在表型水平得到了证实(χ2 = 11.67,自由度为2,P = 0.003)。在抗Scl70抗体阳性的患者中,高产量表型与生存率低相关,且与疾病亚组和性别无关(风险比 = 9.9,CI(95)= 1.6 - 61.27,P < 0.05)。与高IL-10产量相关的IL-10单倍型和基因型可能会改变对SSc的易感性和/或其表达,提高其他已知疾病严重程度标志物的预后价值。