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

我们用携带常染色体隐性遗传基因的NFS/sld突变小鼠建立了一种新的人类原发性干燥综合征动物模型。NFS/sld突变小鼠出生后3天胸腺切除后未再免疫，其唾液腺和泪腺均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。这种病理学类似于原发性干燥综合征，累及腮腺、颌下腺和泪腺。雌性小鼠的自身免疫性病变发生率显著增高，在自身免疫性病变小鼠的血清中经常检测到抗唾液腺管抗体，而在对照小鼠中未检测到。涎腺和泪腺中的炎性浸润主要由CD 3 ^+、CD 4 ^+ T细胞组成，少量为CD 8 ^+ T细胞和B220^+ B细胞。Mac-1^+细胞偶尔出现在这些病变中。当在具有自身免疫性病变的小鼠中分析在炎性浸润内转录和表达的T细胞受体（TCR）V β基因的库时，在疾病过程中检测到TCR V β基因在这些病变中的优先利用（V β 8> V β 6）。此外，我们成功地通过腹膜内注射使用唾液腺炎性细胞将MRL/lpr小鼠中的干燥综合征过继转移到SCID小鼠。用抗-CD 4和抗-Vbeta 8处理防止过继转移到SCID小鼠中。我们的结论是，在唾液腺和泪腺中发展的小鼠自身免疫性病变明显依赖于T细胞依赖性免疫应答，并且用类似方法设计的疗法可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.