Manganelli Paolo, Fietta Pieranna
Osteo-Articular Department, Rheumatic Disease and Internal Medicine Unit, Hospital of Parma, Italy.
Semin Arthritis Rheum. 2003 Aug;33(1):49-65. doi: 10.1053/sarh.2003.50019.
To examine the role of apoptosis in the pathogenesis of Sjögren syndrome (SS), a chronic autoimmune disease characterized by the infiltration of mononuclear cells in the salivary and lacrimal glands, leading to the destruction of the parenchymal tissue.
A detailed search via MEDLINE (PubMed) and Biosis, covering the period from January 1994 to July 2002, was accomplished, combining the key terms SS and apoptosis. A qualitative review of the articles was undertaken and the obtained information was summarized.
Apoptosis of the acinar and ductal epithelial cells of the salivary and lacrimal glands has been proposed as a possible mechanism responsible for the impairment of secretory function. Apoptotic cell death may be induced by either cytotoxic T cells through the release of proteases, such as perforin and granzyme B, or the interaction of Fas ligand (FasL/CD95L), expressed by T lymphocytes, with Fas (Apo-1/CD95) on epithelial cells. The increased rate of apoptosis of epithelial cells in SS may result from either the imbalance between the down-regulated apoptosis-inhibitor Bcl-2 and the up-regulated apoptosis-inducer Bax, or the autocrine and/or paracrine Fas/FasL interaction. Lymphocytes infiltrating the salivary glands are blocked in their ability to commit to apoptosis, despite the expression of the apoptosis-inducer Fas. The expression of Bcl-2 in these cells may explain their resistance to apoptosis, resulting in a prolonged production of proinflammatory cytokines and autoantibodies, as well as in their longer survival that may result in the late development of lymphoma in some SS patients. Studies of the SS-like sialoadenitis of nonobese diabetic (NOD) mice with severe combined immunodeficiency (NOD.scid) suggest that the primary defect responsible for the initiation of SS resides in the epithelial cells that undergo apoptosis mediated by the autocrine Fas/FasL interaction. This first not-immune-mediated phase of target cell destruction is followed by a lymphocyte-dependent autoimmune aggression, which leads to extensive tissue damage and subsequent loss of secretory function. Apoptosis of the salivary epithelial cells has been shown in other animal models of SS and in cell lines in vitro. Apoptosis may also play a role in the pathogenesis of some extraglandular manifestations of SS, such as interstitial nephritis and peripheral CD4(+) lymphocytopenia.
The possible role of apoptosis in SS is suggested from the literature review. A better understanding of the mechanisms responsible for the epithelial cell apoptosis may allow the discovery of new therapeutic strategies. By inhibiting programmed cell death, the glandular damage and the subsequent impairment of the secretory function should be reduced.
研究细胞凋亡在干燥综合征（SS）发病机制中的作用。干燥综合征是一种慢性自身免疫性疾病，其特征为唾液腺和泪腺中有单核细胞浸润，导致实质组织破坏。
通过MEDLINE（PubMed）和Biosis进行详细检索，检索时间跨度为1994年1月至2002年7月，结合关键词SS和细胞凋亡。对文章进行定性综述并总结所获信息。
唾液腺和泪腺的腺泡及导管上皮细胞凋亡被认为是导致分泌功能受损的一种可能机制。细胞毒性T细胞通过释放蛋白酶（如穿孔素和颗粒酶B），或T淋巴细胞表达的Fas配体（FasL/CD95L）与上皮细胞上的Fas（Apo-1/CD95）相互作用，均可诱导凋亡性细胞死亡。SS中上皮细胞凋亡率增加可能是由于凋亡抑制因子Bcl-2下调与凋亡诱导因子Bax上调之间的失衡，或自分泌和/或旁分泌Fas/FasL相互作用所致。尽管表达了凋亡诱导因子Fas，但浸润唾液腺的淋巴细胞凋亡能力受阻。这些细胞中Bcl-2的表达可能解释了它们对凋亡的抵抗，导致促炎细胞因子和自身抗体的持续产生，以及它们的更长存活时间，这可能导致一些SS患者后期发生淋巴瘤。对重度联合免疫缺陷（NOD.scid）的非肥胖糖尿病（NOD）小鼠的类SS涎腺炎研究表明，引发SS的主要缺陷存在于通过自分泌Fas/FasL相互作用介导凋亡的上皮细胞中。这种靶细胞破坏的首个非免疫介导阶段之后是淋巴细胞依赖性自身免疫攻击，导致广泛的组织损伤和随后分泌功能丧失。在其他SS动物模型和体外细胞系中也已显示唾液上皮细胞凋亡。细胞凋亡也可能在SS的一些腺外表现（如间质性肾炎和外周CD4(+)淋巴细胞减少）的发病机制中起作用。
文献综述提示细胞凋亡在SS中可能起的作用。更好地理解上皮细胞凋亡的机制可能有助于发现新的治疗策略。通过抑制程序性细胞死亡，应可减少腺体损伤及随后的分泌功能损害。
