Brandtzaeg Per, Carlsen Hege S, Halstensen Trond S
Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, Norway.
Adv Exp Med Biol. 2006;579:149-67. doi: 10.1007/0-387-33778-4_10.
Secretory immunity is the best-defined part ot the mucosal immune system. This adaptive humoral defense mechanism depends on a fine-tuned cooperation between secretory epithelia and local plasma cells. Such mucosal immunocytes produce preferentially dimers and larger polymers of immunoglobulin A (collectively called pIgA), which contain J chain and therefore can bind to the epithelial secretory component (SC). This transmembrane glycoprotein functions as pIg receptor (pIgR) that also translocates pentameric IgM to the epithelial surface. B cells with a high level of J-chain expression and pIg-pIgR interactions at mucosal effector sites are thus necessary for the generation of secretory antibodies (SIgA and SIgM). Secretory antibodies perform immune exclusion in a first-line defense, thereby counteracting microbial colonization and mucosal penetration of soluble antigens. However, local production of pIgA is significantly down-regulated in inflammatory bowel disease (IBD), as revealed by strikingly decreased J-chain expression. Although the total increase of the immunocyte population in IBD lesions probably compensates for the relatively reduced pIgA production, decreased pIgR/SC expression in regenerating and dysplastic epithelium signifies that the SIgA system is topically deficient. There is, moreover, a significant shift from IgA2 to IgA1 production, the latter subclass being less resistant to proteolytic degradation. These changes--together with activation of mucosal macrophages and a dramatic increase of IgG-producing cells--may reflect local establishment of a second defense line which, however, is unsuccessful in its attempt to eliminate antigens derived from the indigenous microbial flora. Such a 'frustrated' local humoral immune system results in altered immunological homeostasis and jeopardized mucosal integrity. Complement activation observed in relation to epithelium-bound IgG1 in ulcerative colitis indicates, moreover, that the surface epithelium is subjected to immunological attack by an autoimmune reaction. These luminal deposits regularly contain terminal cytotoxic complement, and often also C3b as a sign of persistent activation. Comparison of identical twins, discordant with regard to ulcerative colitis, suggests that the markedly skewed local IgG1 response seen in this IBD entity may be genetically determined. The initial event(s) eliciting B-cell driven immunopathology in IBD remains unknown. Abrogation of oral tolerance to certain antigens from commensal bacteria has been suggested as a putative early mechanism, and lymphoid neogenesis and hyperplasia in the lesions most likely signify massive microbial overstimulation of the local B-cell system. Such ectopic lymphoid microcompartments may contribute substantially to the proinflammatory systemic-type of B-cell responses occurring in established IBD lesions.
分泌性免疫是黏膜免疫系统中定义最明确的部分。这种适应性体液防御机制依赖于分泌上皮细胞与局部浆细胞之间的精确协作。此类黏膜免疫细胞优先产生免疫球蛋白A的二聚体和更大的聚合物（统称为多聚免疫球蛋白A），其含有J链，因此能够与上皮分泌成分（SC）结合。这种跨膜糖蛋白作为多聚免疫球蛋白受体（pIgR）发挥作用，它还能将五聚体IgM转运至上皮表面。因此，在黏膜效应部位具有高水平J链表达以及pIg - pIgR相互作用的B细胞对于分泌性抗体（分泌型IgA和分泌型IgM）的产生是必需的。分泌性抗体在一线防御中执行免疫排斥，从而对抗微生物定植以及可溶性抗原的黏膜穿透。然而，炎症性肠病（IBD）中多聚免疫球蛋白A的局部产生显著下调，这通过J链表达的显著降低得以体现。尽管IBD病变中免疫细胞群体的总体增加可能补偿了相对减少的多聚免疫球蛋白A产生，但再生和发育异常上皮中pIgR/SC表达的降低表明分泌型IgA系统在局部存在缺陷。此外，免疫球蛋白A的产生存在从IgA2到IgA1的显著转变，后者亚类对蛋白水解降解的抵抗力较弱。这些变化——连同黏膜巨噬细胞的激活以及产生IgG细胞的急剧增加——可能反映了第二条防御线的局部建立，然而，这条防御线在试图清除源自本地微生物群落的抗原时并未成功。这样一个“受挫”的局部体液免疫系统导致免疫稳态改变以及黏膜完整性受到损害。在溃疡性结肠炎中观察到的与上皮结合的IgG1相关的补体激活还表明，表面上皮受到自身免疫反应的免疫攻击。这些腔内沉积物通常含有终末细胞毒性补体，并且常常也含有C3b，这是持续激活的标志。对同卵双胞胎（其中一方患有溃疡性结肠炎）的比较表明，在这种IBD类型中所见的明显偏向的局部IgG1反应可能是由基因决定的。引发IBD中B细胞驱动的免疫病理的初始事件仍然未知。对来自共生细菌的某些抗原的口服耐受性丧失已被认为是一种假定的早期机制，并且病变中的淋巴样新生和增生很可能意味着局部B细胞系统受到大量微生物过度刺激。这种异位淋巴微区室可能在很大程度上促成了在已确诊的IBD病变中发生的促炎性全身性B细胞反应类型。
