Frezza D, Giambra V, Mattioli C, Piccoli K, Massoud R, Siracusano A, Di Giannantonio M, Birshtein B K, Rubino I A
Department of Biology, University of Rome, Tor Vergata, Rome, Italy.
Int J Immunopathol Pharmacol. 2009 Jan-Mar;22(1):115-23. doi: 10.1177/039463200902200113.
Infectious and autoimmune pathogenic hypotheses of schizophrenia have been proposed, prompting searches for antibodies against viruses or brain structures, and for altered levels of immunoglobulins. Previous experiments have shown that allele frequencies of the Ig heavy chain 3' enhancer HS1,2A are associated with several autoimmune diseases, suggesting a possible correlation between HS1,2 alleles and Ig production. To test this, we analyzed levels of serum Igs and HS1,2A genotypes in two independent cohorts, one of 88 schizophrenic inpatients (24 women) and a second of 133 healthy subjects (59 women). Both groups were similar in the frequency of individuals with altered serum concentration of Ig classes and IgG subclasses (schizophrenia panel-80 percent; controls-68 percent). With the possible exception of a stabilizing effect of olanzapine, no psychopharmacological drug consumed during the month prior to serum sampling in the schizophrenia group significantly affected Ig levels. In both patient and control cohorts, an increased frequency of the HS1,22A allele corresponded to increased Ig plasma levels, while an increased frequency of the HS1,21A allele corresponded to decreased Ig plasma levels. EMSA analysis with nuclear extracts from human B cells showed that the transcription factor SP1 bound to the polymorphic region of both HS1,21A and HS1,22A while NF-kB bound only to the HS1,2*2A. We predict that differences in transcription factor binding sites in the two allelic variants of the 3' IgH enhancer HS1,2 may provide a mechanism by which differences in Ig expression are affected.
精神分裂症的感染性和自身免疫性致病假说已被提出，这促使人们寻找针对病毒或脑结构的抗体以及免疫球蛋白水平的变化。先前的实验表明，免疫球蛋白重链3'增强子HS1,2A的等位基因频率与几种自身免疫性疾病相关，提示HS1,2等位基因与免疫球蛋白产生之间可能存在关联。为了验证这一点，我们在两个独立队列中分析了血清免疫球蛋白水平和HS1,2A基因型，一个队列有88名精神分裂症住院患者（24名女性），另一个队列有133名健康受试者（59名女性）。两组中免疫球蛋白类别和IgG亚类血清浓度改变的个体频率相似（精神分裂症组为80%；对照组为68%）。除了奥氮平可能具有的稳定作用外，精神分裂症组在血清采样前一个月服用的任何精神药物均未显著影响免疫球蛋白水平。在患者和对照队列中，HS1,22A等位基因频率增加对应着免疫球蛋白血浆水平升高，而HS1,21A等位基因频率增加对应着免疫球蛋白血浆水平降低。用人B细胞核提取物进行的电泳迁移率变动分析表明，转录因子SP1与HS1,21A和HS1,22A的多态性区域结合，而NF-κB仅与HS1,2*2A结合。我们预测，3'免疫球蛋白重链增强子HS1,2的两个等位基因变体中转录因子结合位点的差异可能为免疫球蛋白表达差异受到影响提供一种机制。
