Experimental study of pathogenesis and therapeutic effect for Sjogren's syndrome

我们建立了一种新的人类原发性干燥综合征的动物模型，该模型为常染色体隐性基因携带的NFS/sld突变小鼠，并伴有舌下腺分化阻滞。出生后3天切除胸腺的NFS/sld突变小鼠的唾液腺和泪腺自发发生明显的炎症变化，而其他器官一般未发现炎症病变。这种病理类似原发性干燥综合征，包括腮腺、下颌下唾液腺和泪腺。研究发现，雌性小鼠自身免疫性病变的发生率明显更高，抗唾液管抗体经常在有自身免疫性病变的小鼠血清中检测到，但在对照组小鼠中没有检测到。涎腺、泪腺炎性浸润以CD3^+、CD4^+ T细胞为主，CD8^+ T细胞和B220^+ B细胞比例较小。在这些病变中偶见Mac-1^+细胞。当对免疫病变小鼠炎症浸润中转录和表达的T细胞受体（TCR） Vbeta基因库进行分析时，在疾病过程中，在这些病变中检测到TCR Vbeta基因（vbeta8>Vbeta6）的优先利用。此外，我们成功地通过腹腔注射利用唾液腺炎症细胞将MRL/lpr小鼠干燥综合征过继转移到SCID小鼠。抗cd4和抗vbeta8处理可阻止SCID小鼠的过继转移。我们得出结论，小鼠唾液腺和泪腺的自身免疫性病变明显依赖于t细胞依赖性免疫反应，采用类似方法设计的治疗方法可能用于预防自身免疫性疾病。

We have established a new animal model for human primary Sjogren's syndrome in NFS/sld mutant mice bearing autosomal recessive gene with sublingual gland differentiation arrest. Significant inflammatory changes develop spontaneously in both the salivary and lacrimal glands of NFS/sld mutant mice thymetomized 3 days after birth without later immunization, whereas no inflammatory lesions were found in other organ in general. This pathology resembles primary Sjogren's syndrome involving the parotid, submandibular salivary gland and lacrimal gland. A significantly higher incidence of autoimmune lesions in females was found, and the antisalivary duct anibody was frequently detected in sera from mice with autommune lesions, but not in control mice. The inflammatory infiltrates in the salivary and lacrimal glands consisted mainly of CD3^+, CD4^+ T cells with lesser proportion of CD8^+ T cells, and B220^+ B cells. Mac-1^+ cells were occasionally found within these lesions. When the repertoire of T cell receptor (TCR) Vbeta genes transcribed and expressed within the inflammatory infiltration was analyzed in mice with autommune lesions, a preferential utilization of TCR Vbeta gene (vbeta8>Vbeta6) was detected in these lesions during the course of disease. Moreover, we succeeded in adoptive transfer of Sjogren's syndrome in MRL/lpr mice into SCID mice by intraperioneal injection using the salivary gland inflammatory cells. The treament with anti-CD4 and anti-Vbeta8 prevented the adoptive transfer into SCID mice. We concluded that murine autoimmune lesions developping in the salivary and lacrimal glands are obvious to depend on T-cell dependent immune response, and therapies designed with similar approaches might be used to prevent autoimmune diseases.