Specific signals are required to recruit plasmablasts to the effector sites, then stimulate their differentiation to mature plasmacytes and support their ongoing function. Plasmablast differentiation typically requires T cell cytokines. Therefore, the effector sites also generate signals for T-cell recruitment. Evidence that different signals may attract T lymphocytes and IgA+ plasmablasts to the common effector sites comes in part from studies of small intestine and of mammary gland during pregnancy and lactation. The mucosal address in cell adhesion molecule MAdCAM-1, expressed by endothelial cells, mediates extravasation of T lymphocytes (57,58). In contrast, extravasation of IgA+ plasma blasts is mediated by CCL25 in salivary glands (59), CCL25, CCL28, and CXCL12 in small intestine, and by CCL28 and CXCL12 in large intestine (60).
Once plasmablasts have extravasated into the effector sites, various signals promote their final maturation to plasma cells and support plasma cell survival and ongoing dIgA secretion. Many of the same signals support expression of pIgR by the overlying epithelium. VIP increases SC secretion by primary cultured lacrimal acinar cells (61). Some signals, e.g., a-MSH, VIP (62-65), and nitric oxide, are released from nerve endings (66). The epithelial cells themselves provide additional critical signals, including IL-6 (67-69), which is an important survival factor for plasma cells, and TGF-^, which supports epithelial function in the mucosal immune system in autocrine fashion, by enhancing epithelial expression of pIgR (70) and IL-6 (71), and in paracrine fashion, by supporting dIgA production (72,73).
It appears that the epithelia at different effector sites may express different spectra of immunomodulatory paracrine mediators in addition to IL-6 and TGF-^. Mammary gland epithelial cells express IL-8 (74) in addition to IL-6 (75,76) and TGF-^1(77). In the liver, parenchymal cells produce IL-5 (78), and duct cells express IL-4 (79). Small intestinal surface epithelial cell lines express IL-8, IL-10, and TNF-a (80,81); they also express receptors for IL-10 (82). Cultured human bronchial epithelial cells express IL-4; during Fas-induced apoptosis they upregu-late IL-4 and TGF-^ and downregulate IL-6 (83). Conjunctival epithelial cells express IL-1a, IL-8, and TNF-a (84). Human salivary epithelial cells express IL1a (85), IL-1j3 (86), IL-2 (87), IL-10 (85,87), TNF-a (85,87), and IFN-y (87). Lacrimal gland ductal cells express TGF-^ and prolactin (19), while acinar cells have been reported to express IL-2 (88), and both neuronal- and inducible-nitric oxide synthases, nNOS (89) and iNOS (90).
Systemic hormones support mucosal immune functions at several different effector sites. Ventral prostate and urethral gland epithelial cells express pIgR, and IgA+ cells populate the underlying tissue spaces, and castration decreases pIgR expression. In the rat, the effect of castration can be reversed by either estradiol or dihydrotestosterone, but neither hormone has a substantial effect on IgA+ cell content (91). In contrast, testosterone prevents the effects of castration on both pIgR expression and IgA+ cell number in the mouse prostate and urethral glands (92). To the extent data on the mouse prostate and urethral glands are available, they resemble the extensive body of data on hormonal influences on pIgR expression and IgA+ cell infiltration in the rodent lacrimal gland that has been published by Sullivan et al. (93,94).
The pattern of systemic hormonal influences on secretory immune functions in the mammary glands differs markedly from the patterns in the lacrimal glands and prostate. Estrogen and progesterone, alone or in combination, have little direct effect on mammary gland epithelial development, pIgR expression, or IgA+ cell accumulation (95-97). However, they can inhibit conversion of TGF-^ from the latent to the active form (98), permitting prolactin to induce epithelial proliferation in some (95), but not all (96,97), species. Prolactin both stimulates accumulation of IgA+ cells and expression of pIgR by epithelial cells in the intact mammary gland. Notably, these actions of prolactin are inhibited by testosterone, which also inhibits the actions of estrogen and progesterone (95).
Prolactin receptors couple to several signaling pathways, including those initiated by activation of Jak2, Fyn, Tec, SHP-2, Vav, and SOCS (99), and prolactin appears to have important influences on B cells. In an early experiment, an 18-70 kDa fraction of a placental extract increased the numbers of IgA+ cells and increased IgA secretion in LPS-stimulated spleen cell cultures, and this activity was abrogated by antibodies to prolactin (100). Prolactin stimulated B-cell expansion in bone marrow cell primary cultures (101). Prolactin counteracted the inhibitory effect of TGF-^ and enhanced the stimulatory effects of IL-4, IL-5, and IL-6 on mouse B-cell hybridoma proliferation (102). When some, but not all, strains of mice transgenic for an anti-DNA antibody heavy chain antibody are treated with prolactin for four weeks, they develop a lupus-like syndrome, with elevated anti-DNA titers, increased numbers of anti-DNA B cells, and an overall shift of B cells from the transitional compartment to the follicular and marginal zone compartments (103). Therefore, it appears that interactions between prolactin and TGF-^ take different forms to support mucosal immune function in different tissues.
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