Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sjögren's syndrome–like autoimmune exocrinopathy

Abstract

Although several autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen defi ciency infl uences autoimmunity remain unclear. Recently, we found that retinoblastoma-associated protein 48 (RbAp48) induces tissuespecifi c apoptosis in the exocrine glands depending on the level of estrogen defi ciency. In this study, we report that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sj ö gren ' s syndrome. CD4 + T cell -mediated autoimmune lesions were aggravated with age, in association with autoantibody productions. Surprisingly, we obtained evidence that salivary and lacrimal epithelial cells can produce interferon-␥ (IFN-␥ ) in addition to interleukin-18, which activates IFN regulatory factor-1 and class II transactivator. Indeed, autoimmune lesions in Rag2 ؊ / ؊ mice were induced by the adoptive transfer of lymph node T cells from RbAp48 -Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-␥ , resulting in loss of local tolerance before developing gender-based autoimmunity.

Regulation of T cell activation in Sjögren's syndrome

“…The breakdown of T cell tolerance via disorders of signaling molecules for T cell activation such as NF-kB may tend to induce autoimmune lesions in salivary and lacrimal glands resembling human SS, suggesting that salivary or lacrimal gland cells are much more sensitive to any cytokines or stimulation factors from autoreactive and pathogenic Tcells. We hypothesize that there may be a unique system ''local immune tolerance'' in salivary and lacrimal glands [30]. With the loss of local immune tolerance by any change of immune homeostasis, the salivary and lacrimal gland cells might become target cells toward autoreactive T cells.…”

“…As for environmental factor such as hormone, autoimmne lesions of salivary glands from aromatase KO mice are observed [29]. Recently, we have established retinoblastoma-associated protein 48 (RbAp48) TG mouse as one of SS models in which transgenic expression of RbAp48 in the salivary glands resulted in the development of autoimmune exocrinopathy resembling SS [30]. These studies using several SS models raise the new findings as to not only the pathogenesis of SS, but also the molecular mechanisms for central or peripheral T cell tolerance in the immune system.…”

“…Therefore, it is possible that NF-kB2-deficient T cells may be hyperreactive to any self-antigen through excessive activation of NF-kB1/RelA [14] MRL/lpr Fas, RA, SLE 1989 [27] HTLV-1 tax TG Human T cell leukemia 1992 [15] NOD Type I DM 1994 [12] NFS/sld thymectomy, a-fodrin 1996 [20] TGF-b1 KO IFN-g 1996 [17] aly/aly NIK 1999 [21] IL-10 TG FasL 2002 [23] AIRE KO autoantigens 2004 [29] Aromatase KO a-fodrin 2004 [25] Id3 KO T cell development 2006 [26] ClassIA PI3K KO SSA, IFN-g, Treg 2006 [22] IL-14a TG Aging, CD5 + B cell 2006 [24] CCR7 KO thymic T cell selection 2006 [28] NZW2328 MCMV 2008 [30] RbAp48 TG estrogen pathway, suggesting that NF-kB2 is one of key molecules for T cell regulation in autoimmunity.…”

Current aspects of pathogenesis in Sjögren’s syndrome

“…In a model of SS (RbAp48-Tg mice), the overexpression of retinoblastoma-associated protein 48 (a gene specific for oestrogen deficiency-dependent apoptosis) in the exocrine glands caused an age-dependent SS-like autoimmune exocrinopathy [Ishimaru et al 2008]. The salivary epithelial cells of these transgenic mice behaved as antigen-presenting cells, upregulating MHC class II, secreting IFN-g and IL-18, leading to CD4 þ T-cell activation and glandular inflammation.…”

Primary Sjögren’s Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances

“…Estrogens play a cardinal role in targeting salivary epithelial cell and stimulating apoptosis through a Fas-mediated mechanism (Ishimaru et al, 1999). Retinoblastomaassociated protein 48 (RbAp48) induces tissue specific apoptosis in salivary glands depending on the level of estrogen deficiency (Ishimaru et al, 2008). More recently, the presence of functional estrogen receptors has been observed in salivary epithelial cells (Tsinti et al, 2009).…”