New concepts for the development of autoimmune exocrinopathy derived from studies with the NOD mouse model
New concepts for the development of autoimmune exocrinopathy derived from studies with the NOD mouse model
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DOI：
10.1016/s0003-9969(99)90008-0
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发表时间：
1999-05-01
影响因子：
3
通讯作者：
Peck, AB
中科院分区：
文献类型：
--
作者：
Humphreys-Beher, MG;Peck, AB
非肥胖糖尿病（NOD）小鼠现在被认为是研究人类干燥综合征患者普遍存在的自身免疫性外源性疾病的合适模型。随着年龄的增长，NOD小鼠的组织病理变化与人类干燥综合征患者相似，但更重要的是表现出与人类相同的外分泌组织分泌功能下降的临床表现。对nod -酸免疫缺陷小鼠的研究提供了证据，证明几种主要唾液蛋白的表达在时间上缺失，唾液组织中腺泡细胞的存在减少。在T淋巴细胞和b淋巴细胞缺失的情况下，腺泡细胞的减少伴随着与凋亡相关的酶的增加。尽管有这些改变，NOD-scid小鼠与NOD小鼠不同，不会丧失分泌功能。最近对第二种同源NOD菌株NOD的分析。缺乏b淋巴细胞的Igmnull表明，在NOD和NOD-scid小鼠中，外分泌腺的t细胞浸润在组织学上存在，caspace活性增加，并诱导了蛋白质表达的生化改变。点头。Igmnull小鼠也不会丧失分泌功能，但在输注自身免疫性NOD小鼠或干燥综合征患者的IgG组分后，可以通过操纵使分泌反应减少。在缺乏免疫系统适应性臂的情况下，这些观察结果引起了自身免疫性外皮病分两个阶段发展的概念。初始阶段是淋巴细胞独立的，由于外分泌组织稳态或分化功能的先天错误而发生。随后的组织特异性免疫攻击，部分由b细胞自身抗体产生，是导致分泌功能丧失的原因。我们对NOD小鼠和干燥综合征患者的初步观察表明，针对细胞表面毒蕈碱/胆碱能受体的抗体似乎在临床疾病的发病中起重要作用。
The non-obese diabetic (NOD) mouse is now recognized as an appropriate model to study autoimmune exocrinopathy prevalent in human Sjogren's syndrome patients. With increasing age, NOD mice undergo histopathological changes similar to human Sjogren's syndrome patients, but more importantly, exhibit the same clinical manifestation of declining exocrine tissue secretory function. Studies with the immunodeficient NOD-acid mouse have provided evidence for the temporal loss in the expression of several major salivary proteins and a decreased presence of acinar cells in salivary tissues. The diminished presence of acinar cells is accompanied by an increase in the enzymes associated with apoptosis in the absence of T- and B-lymphocytes. Despite these alterations, NOD-scid mice, unlike NOD mice, do not lose secretory function. Recent analyses of a second congenic NOD strain, the NOD.Igmnull, which lacks B-lymphocytes, indicate the histological presence of a T-cell infiltrate of the exocrine glands, increased caspace activity and induction of the biochemical alterations in protein expression observed in NOD and NOD-scid mice. NOD.Igmnull mice also do not lose secretory function, but can be manipulated to generate a reduced secretory response following the infusion of IgG fractions from autoimmune NOD mice or Sjogren's syndrome patients. These observations, in the absence of components of the adaptive arm of the immune system, have given rise to the concept that autoimmune exocrinopathy develops in two phases. The initial phase is lymphocyte independent and occurs as a consequence of an innate error in exocrine tissue homeostasis or differentiated function. The subsequent tissue specific immunological attack, generated in part by B-cell autoantibodies, is responsible for the loss of secretory function. Our preliminary observations in both NOD mice and Sjogren's syndrome patients is that antibody directed against the cell surface muscarinic/cholinergic receptors appears to play an important part in the onset of clinical disease.