[1]

Barone F,Colafrancesco S.Sjögren’s syndrome:from pathogenesis to novel therapeutic targets[J]. Clin Exp Rheumatol,2016,34(4 Suppl 98):58-62.Primary Sjgren's syndrome (pSS) is a chronic inflammatory autoimmune disease, characterised by a chronic infiltration of exocrine glands, mainly salivary glands, with the histological features of focal lymphocytic sialoadenitis. Disease spectrum is broad and the occurrence of several extra-glandular manifestations, and in rare cases lymphoma development, is well known. A specific approved treatment for pSS is still lacking and the detection of novel therapeutic biologic target is ongoing. The identification of biological fingerprints seems essential in order to stratify patients both in clinical trials and in real life. Discovery of new components of the inflammatory response will be the key in the future for the identification of novel additional therapeutic options. https://www.ncbi.nlm.nih.gov/pubmed/27586806 http://europepmc.org/abstract/MED/27586806 Cited in this article [1]

[2]	Rischmueller M,Tieu J,Lester S.Primary Sjögren’s syndrome[J]. Best Pract Res Clin Rheumatol,2016,30(1):189-220.

[3]	Pers JO,Saraux A.Future treatments for Sjögren’s syndrome[J]. Presse Med,2016,45(6 Pt 2):e193-e200. Cited in this article [1]

[4]

Kikutani H,Makino S.The murine autoimmune diabetes model:NOD and related strains[J]. Adv Immunol,1992,51:285-322.This chapter summarizes the experimental findings and observations based on the nonobese diabetic (NOD) mouse model and discusses the pathogenesis and the etiology of autoimmune diabetes. To elucidate the etiology of insulin-dependent diabetes mellitus (IDDM), several animal models have been developed, including experimentally induced and spontaneously developing models. One is low-dose streptozocin-induced diabetes. A high dose of streptozocin destroys completely pancreatic cells but not and cells, resulting in acute diabetes. Multiple injections of subdiabetogenic doses of streptozocin can also induce diabetes a few weeks after treatment. In the latter case, mononuclear infiltration in and around pancreatic islets is observed. IDDM in NOD mice is also immunologically mediated. IDDM in BB rats and NOD mice is very similar to the disease in humans. The availability of a large number of data and materials in mouse genetics and immunology has accelerated the use of NOD mice by diabetologists and immunologists who are interested in the pathogenesis of IDDM and the mechanism of autoimmunity. Several important findings obtained from studies on NOD mice have provided new insights into the immunological and genetic control of IDDM. The development of IDDM in NOD mice is divided roughly into two phases: initiation of autoimmune insulitis and promotion of islet destruction and overt diabetes. https://doi.org/10.1016/S0065-2776(08)60490-3 https://www.ncbi.nlm.nih.gov/pubmed/1323922 http://europepmc.org/abstract/MED/1323922 Cited in this article [1]

[5]	Inoue H,Kishimoto A,Ushikoshi-Nakayama R,et al.Resveratrol improves salivary dysfunction in a non-obese diabetic (NOD) mouse model of Sjögren’s syndrome[J]. J Clin Biochem Nutr,2016,59(2):107-112. Cited in this article [2]

[6]	Delaleu N,Immervoll H,Cornelius J,et al.Biomarker profiles in serum and saliva of experimental Sjögren’s syndrome:associations with specific autoimmune manifestations[J]. Arthritis Res Ther,2008,10(1):R22. doi:10.1186/ar2375. Cited in this article [1]

[7]

Li CL,He J,Li ZG,et al.Effects of multi-glycosides of tripterygium wilfordiion in the treatment of Sjögren’s syndrome in the non-obese diabetic mouse model[J]. Chin J Dent Res,2015,18(2):95-101.To investigate the effects of the multi-glycosides of Tripterygium wilfordii (GTW) on Sjgren's syndrome (SS) in the non-obese diabetic (NOD) mouse model.Twenty-seven 8-week-old, female NOD mice were divided into the GTW group, the hydroxychloroquine (HCQ) group, and control (normal saline) group, and received corresponding treatment for 16 weeks. The treatment-induced changes in stimulated total saliva flow rate (STFR), level of serum anti-SSA/SSB, ratio of regulatory T (Treg) cells, histology of the submandibular gland (SMG) and the gene expression profile that is related to inflammation and autoimmunization were evaluated.Compared to the untreated (control) mice, STRF, SMG index and Treg/CD4+ cell ratio were significantly higher, whereas anti-SSA, anti-SSB and lymphoid foci were remarkably lower in GTW-treated mice. HCQ-treated mice showed similar results except SMG index was not different from the untreated mice. NOD mice showed 19.03% altered gene expression with maturation from the age of 8 weeks to 24 weeks. Treatment with HCQ and GTW reduced the change in gene expression to 13.09% and 7.14%, respectively.GTW is as effective as HCQ in the treatment of Sjgren's syndrome in the NOD mouse model. https://www.ncbi.nlm.nih.gov/pubmed/26167547 http://europepmc.org/abstract/MED/26167547 Cited in this article [1]

[8]

Humphreys-Beher MG,Hu Y,Nakagawa Y,et al.Utilization of the nonobese diabetic (NOD) mouse as an animal model for the study of secondary Sjögren’s syndrome[J]. Adv Exp Med Biol,1994,350:631-636.Sj02gren’s syndrome (S.S.) in the human patient population is an autoimmune inflammatory disease presenting clinical symptoms of xerophthalmia and xerostomia 1 . This condition predominantly affects women. Most diagnoses of S.S. is made in association with autoimmune connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus. 2 However, it can also be obseved as an isolated phenomenon, described as primary S.S. https://doi.org/10.1007/978-1-4615-2417-5_105 https://www.ncbi.nlm.nih.gov/pubmed/8030546 http://link.springer.com/10.1007/978-1-4615-2417-5_105

[9]	Gervais EM,Desantis KA,Pagendarm N,et al.Changes in the submandibular salivary gland epithelial cell subpopulations during progression of Sjögren’s syndrome-like disease in the NOD/ShiLtJ mouse model[J]. Anat Rec (Hoboken),2015,298(9):1622-1634. Cited in this article [1]

[10]	Robinson CP,Yamachika S,Bounous DI,et al.A novel NOD-derived murine model of primary Sjögren’s syndrome[J]. Arthritis Rheum,1998,41(1):150-156. Cited in this article [3]

[11]	Kong L,Robinson CP,Peck AB,et al.Inappropriate apoptosis of salivary and lacrimal gland epithelium of immunodeficient NOD-scid mice[J]. Clin Exp Rheumatol,1998,16(6):675-681. Cited in this article [1]

[12]

Fearon DT,Carroll MC.Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex[J]. Annu Rev Immunol,2000,18:393-422.The membrane protein complex CD19/CD21 couples the innate immune recognition of microbial antigens by the complement system to the activation of B cells. CD21 binds the C3d fragment of activated C3 that becomes covalently attached to targets of complement activation, and CD19 co-stimulates signaling through the antigen receptor, membrane immunoglobulin. CD21 is also expressed by follicular dendritic cells and mediates the long-term retention of antigen that is required for the maintenance of memory B cells. Understanding of the biology of this receptor complex has been enriched by analyses of genetically modified mice; these analyses have uncovered roles not only in positive responses to foreign antigens, but also in the development of tolerance to self-antigens. Studies of signal transduction have begun to determine the basis for the coreceptor activities of CD19. The integration of innate and adaptive immune recognition at this molecular site on the B cell guides the appropriate selection of antigen by adaptive immunity and emphasizes the importance of this coreceptor complex. https://doi.org/10.1146/annurev.immunol.18.1.393 https://www.ncbi.nlm.nih.gov/pubmed/10837064 http://www.annualreviews.org/doi/pdf/10.1146/annurev.immunol.18.1.393 Cited in this article [1]

[13]

Mostafa S,Seamon V,Azzarolo AM.Influence of sex hormones and genetic predisposition in Sjögren’s syndrome:a new clue to the immunopathogenesis of dry eye disease[J]. Exp Eye Res,2012,96(1):88-97.Sjgren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration, destruction of lacrimal and salivary glands and the presence of serum autoantibodies. Most women that suffer from SS are post-menopausal however, not all post-menopausal women develop SS, suggesting that other factors, in addition to the decrease in ovarian hormones, are necessary for the development of SS. The purposes of this study were to investigate a) the time course of lymphocytic infiltration and apoptosis in the lacrimal gland after ovariectomy, b) if a predisposed genetic background for SS aggravates the effects of decreasing levels of sex hormones in the lacrimal glands and c) if physiological doses of estrogen or androgen prevent the effects observed after ovariectomy. Six weeks old mice that are genetically predisposed to SS (NOD.B10.H2(b)) and control (C57BL/10) mice were either sham operated, ovariectomized (OVX), OVX+17 estradiol (E(2)) or OVX+Dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21 or 30 days after surgery and processed for immunohistochemistry to measure CD4(+), CD8(+) T cells, B220(+) B cells, nuclear DNA degradation and cleaved caspase-3 activity. Quantification of the staining was done by light microscopy and Image Pro Plus software. The results of our study show that lymphocytic infiltration preceded lacrimal gland apoptosis after ovariectomy. Moreover, removal of ovarian sex hormones accelerated these effects in the genetically predisposed animal and these effects were more severe and persistent compared to control animals. In addition, sex hormone replacement at physiological levels prevented these symptoms. The mechanisms by which decreased levels of sex hormones caused lymphocytic infiltration and apoptosis and the interaction of lack of sex hormones with the genetic elements remain to be elucidated. https://doi.org/10.1016/j.exer.2011.12.016 https://www.ncbi.nlm.nih.gov/pubmed/3296912 http://www.ncbi.nlm.nih.gov/pubmed/22227485 Cited in this article [1]

[14]

Cha S,Brayer J,Gao J,et al.A dual role for interferon-gamma in the pathogenesis of Sjögren’s syndrome-like autoimmune exocrinopathy in the nonobese diabetic mouse[J]. Scand J Immunol,2004,60(6):552-565.Abstract Sjogren's syndrome-like autoimmune exocrinopathy (AEC) in the nonobese diabetic (NOD) mouse progresses from a preimmune phase to an immune phase, resulting in dry mouth and/or dry eyes. In the present study, the impact of the prototypical T-helper type 1 cytokine, interferon-gamma (IFN-gamma), on the onset of AEC was investigated using both the IFN-gamma and the IFN-gamma receptor gene knockout mice, NOD.IFN-gamma(-/-) and NOD.IFN-gammaR(-/-), respectively. Neither the NOD.IFN-gamma(-/-) nor the NOD.IFN-gammaR(-/-) mice exhibited increased acinar cell apoptosis and abnormal salivary protein expression, typically observed in parental NOD mice prior to disease. Without these preimmune phase abnormalities, NOD.IFN-gamma(-/-) and NOD.IFN-gammaR(-/-) mice showed no subsequent autoimmune responses against the salivary glands at 20 weeks. Interestingly, real-time polymerase chain reaction and electrophoretic gel mobility shift assays suggested that IFN-gamma and STAT1, as well as the transcriptional activity of STAT1 in NOD glands, were increased at birth. Unlike the neonatal submandibular glands of NOD or NOD-scid mice that show abnormal glandular morphogenesis at birth, the submandibular glands of the newly constructed congenic strain, NOD-scid.IFN-gamma(-/-), were found to be normal. Taken together, IFN-gamma appears to play a critical role not only during the later immune phase of AEC, but also the early preimmune phase, independent of effector functions of immune cells. How exactly IFN-gamma functions during this period remains speculative. https://doi.org/10.1111/j.0300-9475.2004.01508.x https://www.ncbi.nlm.nih.gov/pubmed/15584966 http://www.ncbi.nlm.nih.gov/pubmed/15584966 Cited in this article [1]

[15]	Robinson CP,Brayer J,Yamachika S,et al.Transfer of human serum IgG to nonobese diabetic Igmu null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjögren’s syndrome[J]. Proc Natl Acad Sci USA,1998,95(13):7538-7543. Cited in this article [1]

[16]	Brayer JB,Cha S,Nagashima H,et al.IL-4-dependent effector phase in autoimmune exocrinopathy as defined by the NOD. IL-4-gene knockout mouse model of Sjögren’s syndrome[J]. Scand J Immunol,2001,54(1-2):133-140. Cited in this article [1]

[17]

Hayashi Y,Kojima A,Hata M,et al.A new mutation involving the sublingual gland in NFS/N mice. Partially arrested mucous cell differentiation[J]. Am J Pathol,1988,132(2):187-191.A new mutation in mice affecting the mucous cell differentiation of the sublingual glands is described. The normal mouse sublingual glands are mucus-secreting and virtually all the acinar cells differentiate to mucus-rich cells by the day of birth. In contrast, all endpieces of newborn mutant mice consisted of acini of immature cuboidal cells. However, normal mucous cells, staining intensively with mucin-specific stains such as Alcian blue at pH 2.5 or mucicarmine, appeared in the mutant mice from an early age singly or in groups in a small number of acini, and their number apparently increased with age to occupy over 30% of the total acinar cells. Ultrastructurally, irregular secretion granules of varying electron-density, distinct from ordinary sublingual mucin granules, were frequently observed in the cytoplasm of the immature acinar cells in the mutant phenotype. The genetic analysis showed that a single autosomal recessive gene determined the observed abnormality. This is the first salivary gland mutation and will provide a critical model for the study of salivary mucous cell differentiation. https://doi.org/10.1016/S0015-7368(88)72868-6 https://www.ncbi.nlm.nih.gov/pubmed/3400771 http://www.ncbi.nlm.nih.gov/pubmed/3400771 Cited in this article [1]

[18]	Haneji N,Hamano H,Yanagi K,et al.A new animal model for primary Sjögren’s syndrome in NFS/sld mutant mice[J]. J Immunol,1994,153(6):2769-2777. Cited in this article [1]

[19]

Hayashi Y,Haneji N,Hamano H,et al.Effector mechanism of experimental autoimmune sialadenitis in the mouse model for primary Sjögren’s syndrome[J]. Cell Immunol,1996,171(2):217-225.We have recently established a new animal model for primary Sj枚gren's syndrome in NFS/sld mutant mice thymectomized 3 days after birth (3dTX) bearing an autosomal recessive gene with sublingual gland differentiation arrest. In this study, we analyze developing mechanisms of experimental autoimmune sialadenitis (EAS) in the mouse model, focusing on local expressions of cytokine and cell adhesion molecule genes by reverse transcriptase-polymeric chain reaction (RT-PCR) and immunohistochemistry, kinetic analysis of splenic lymphocytes expressing activation markers, and I-Aq class-II molecules by flow cytometry (FACS). We found up-regulation of local cytokine genes (IL-1 beta, TNF-alpha, IL-2, IFN-gamma, IL-6, IL-10, IL-12p40) and cell adhesion molecule genes (ICAM-1, LFA-1, CD44, Mel-14) in the salivary glands from mice with EAS by RT-PCR, which were supported by immunohistochemistry. FACS analysis demonstrated that a significant proportion of splenic CD4+ T cells express activation markers (CD44, LFA-1, Mel-14low, CD45RB(low)) at a high level and an increase in expression of B220+ B cells bearing I-Aq class-II molecules. These data suggest that spontaneous EAS in 3dTX NFS/sld mutant mice may be triggered by an in situ activation of autoreactive CD4+ T cells comprising unique cytokine profile (high levels of IL-2, IFN-gamma, IL-10, and IL-12p40 mRNA) in the salivary glands. https://doi.org/10.1006/cimm.1996.0196 https://www.ncbi.nlm.nih.gov/pubmed/8806790 http://europepmc.org/abstract/MED/8806790 Cited in this article [1]

[20]

Ishimaru N,Yoneda T,Saegusa K,et al.Severe destructive autoimmune lesions with aging in murine Sjögren’s syndrome through Fas-mediated apoptosis[J]. Am J Pathol,2000,156(5):1557-1564.When we evaluated the age-associated changes in autoimmune exocrinopathy in a NFS/ sld murine model for primary Sjgren's syndrome (SS), severe destructive autoimmune lesions developed in the salivary and lacrimal glands in the aged mice, compared with those observed in the younger model. We detected a decreased secretion of saliva and tear flow in the aged group. A significant increase of TUNEL + -apoptotic epithelial duct cells in the salivary glands was detected in the aged SS animal model. A higher proportion of mouse salivary gland cells bearing Fas was found in the aged group, whereas no significant changes were seen on tissue-infiltrating CD4 + T cells bearing FasL in the salivary glands from young and aged mice. We detected an increased cleavage product of organ-specific autoantigen, 120-kd -fodrin, in the aged salivary gland tissues on immunoblotting, and an increase in serum autoantibody production against 120-kd -fodrin by enzyme-linked immunosorbent assay. An increase in the proliferative response of splenic T cells against organ-specific autoantigen was observed, whereas nonspecific concanavalin A responsiveness was decreased in the aged mice. In addition, a decrease in Fas expression was found on splenic CD4 + T cells in the aged mice, and anti-Fas mAb-stimulated apoptosis was down-regulated on CD4 + T cells. These results indicate that age-associated dysregulation of CD4 + T cells may play a crucial role on acceleration of organ-specific autoimmune lesions in a murine model for primary SS through Fas-mediated apoptosis. https://doi.org/10.1016/S0002-9440(10)65027-4 https://www.ncbi.nlm.nih.gov/pubmed/10793067 http://www.ncbi.nlm.nih.gov/pubmed/10793067 Cited in this article [1]

[21]	Zandbelt MM,Vogelzangs J,Van De Putte LB,et al. Antialpha-fodrin antibodies do not add much to the diagnosis of Sjögren’s syndrome[J]. Arthritis Res Ther,2004,6(1):33-38. Cited in this article [1]

[22]	Saegusa J,Kubota H.Sialadenitis in IQI/Jic mice:a new animal model of Sjögren’s syndrome[J]. J Vet Med Sci,1997,59(10):897-903. Cited in this article [2]

[23]	Takada K,Takiguchi M,Konno A,et al.Autoimmunity against a tissue kallikrein in IQI/Jic mice:a model for Sjögren’s syndrome[J]. J Biol Chem,2005,280(5):3982-3988. Cited in this article [1]

[24]	Kaczor-Urbanowicz KE,Martin Carreras-Presas C,Aro K,et al. Saliva diagnostics-current views and directions [J]. Exp Biol Med (Maywood), 2016.[2016-12-08]. http://jou- rnals.sagepub.com/doi/pdf/10.1177/1535370216681550. Cited in this article [1]

[25]

Seo Y,Fukushima H,Maruyama T,et al.Accumulation of p100,a precursor of NF-kappaB2,enhances osteoblastic differentiation in vitro and bone formation in vivo in aly/aly mice[J]. Mol Endocrinol,2012,26(3):414-422.We previously reported that alymphoplasia (aly/aly) mice, which have a natural loss-of-function mutation in the Nik gene, which encodes a kinase essential for the processing of p100 to p52 in the alternative nuclear factor-κB (NF-κB) pathway, show mild osteopetrosis with an increase in several parameters of bone formation: bone formation rate, mineral apposition rate, and osteoblast number. We therefore investigated the molecular mechanisms triggered by the alternative NF-κB pathway in the regulation of osteoblast differentiation using primary osteoblasts (POB) prepared from aly/aly mice. Alkaline phosphatase (ALP) activity and mineralization induced by the presence of β-glycerophosphate and ascorbic acid were enhanced in POB from aly/aly compared with wild-type (WT) mice. Furthermore, osteoblastic differentiation induced by bone morphogenetic protein 2 (BMP2), as shown by ALP activity, mRNA expression of osteocalcin, Id1, Osterix and Runx2, and Sma- and Mad-related protein (Smad)1/5/8 phosphorylation, was also enhanced in POB from aly/aly mice. The ectopic bone formation in vivo that was induced by BMP2 was enhanced in aly/aly mice compared with controls. Transfection of a mutant form of p100, p100ΔGRR, which cannot be processed to p52, stimulated ALP activity and Smad phosphorylation. In contrast to p100ΔGRR, overexpression of p52 inhibited these events. Both BMP2-induced ALP activity and Smad phosphorylation were reduced in POB from p100-deficient mice, which carry a homozygous deletion of the COOH-terminal ankyrin repeats of p100 but still express functional p52 protein. p52 and p100ΔGRR interacted with a BMP receptor, ALK2, in overexpressed COS7 cells and changed the ALK2 protein levels in opposite directions: p52 reduced ALK2 and p100 increased it. Thus, the alternative the NF-κB pathway via the processing of p52 from p100 negatively regulates osteoblastic differentiation and bone formation by modifying BMP activity. https://doi.org/10.1210/me.2011-1241 https://www.ncbi.nlm.nih.gov/pubmed/22282470 http://www.ncbi.nlm.nih.gov/pubmed/22282470 Cited in this article [1]

[26]

Wang HX,Yi SQ,Li J,et al.Effects of splenectomy on spontaneously chronic pancreatitis in aly/aly mice[J]. Clin Dev Immunol,2010,2010:614890. doi:10.1155/2010/614890.Background and Aim. Mice with alymphoplasia (aly/aly) mutation characterized by a lack of lymph nodes, Peyer's patches, and well-defined lymphoid follicles in the spleen were found. In this study, we used splenectomized aly/aly mice to elucidate the effects of secondary lymphoid organs in the development of aly/aly autoimmune pancreatitis. Methods. Forty-eight 10-week-old aly/aly mice were divided into two groups for splenectomy and sham operation. Histological and immunohistochemical analyses of the pancreas were performed at the ages of 20, 30, and 40 weeks old after operation, respectively. Results. Our results showed that mononuclear cell infiltration was restricted to the interlobular connective tissues at the age of 20 weeks, and not increase obviously at the age of 30 and 40 weeks in splenectomized aly/aly mice. Furthermore, an apparent decrease in the expressions of CD4+ T, CD8+ T, and B cells was detected in the pancreatic tissues compared with sham aly/aly mice, however, no significant difference in macrophage expression between mice with and without a splenectomy. Conclusions. Inflammation infiltration and development of the pancreatitis in aly/aly mice were suppressed effectively after splenectomy, which was, at least partly, correlated to inhibition of the infiltration of T and B cells in pancreatic tissues but not to macrophages. https://doi.org/10.1155/2010/614890 https://www.ncbi.nlm.nih.gov/pubmed/20369067 http://pubmedcentralcanada.ca/pmcc/articles/PMC2847759/

[27]

Kobayashi S,Ueda A,Ueda M,et al.Pathology of spontaneous dermatitis in CBy.ALY-aly mice[J]. Exp Anim,2008,57(2):159-163.CBy.ALY-aly/aly (C-aly) mice develop progressive dermatitis in areas of the face and dorsal neck from around three months of age. Staphylococcus aureus was detected in the skin lesions of C-aly mice. However, even when the mice were raised under S. aureus free conditions, a similar, though less severe, dermatitis was still observed. The mice showed a marked increase in the number of eosinophils in the peripheral blood and skin lesions, with no changes in plasma IgE levels. These findings suggest that the dermatitis of these mice may be an atypical allergic condition with little or no involvement of IgE. C-aly mice may be a useful animal model of chronic dermatitis or pruritus without elevated IgE levels. https://doi.org/10.1538/expanim.57.159 https://www.ncbi.nlm.nih.gov/pubmed/18421181 http://europepmc.org/abstract/MED/18421181 Cited in this article [1]

[28]

Tsubata R,Tsubata T,Hiai H,et al.Autoimmune disease of exocrine organs in immunodeficient alymphoplasia mice:a spontaneous model for Sjögren’s syndrome[J]. Eur J Immunol,1996,26(11):2742-2748.Mice homozygous for an autosomal recessive mutation aly (alymphoplasia) lack both lymph nodes and Peyer's patches, and show defects in both humoral and cellular immunity. Histopathological analysis revealed chronic inflammatory changes in exocrine organs such as the salivary gland, lacrimal gland, and pancreas of the homozygotes (aly/aly), but not the heterozygotes (aly/+). In these exocrine organs, mononuclear cells consisting mainly of CD4+ T cells infiltrate periductal areas, and, in some cases, the cell infiltration extended to lobules. The inflammatory changes in exocrine organs were transferred by a T cell-enriched fraction of spleen cells from homozygous animals. These results suggest that autoimmune mechanisms mediated by self-reactive T cells may be involved in the inflammatory lesions of various exocrine organs in the homozygous mice, although these mice show immunodeficiency. Inflammatory changes were also observed in the lung of the homozygotes. Since Sj枚gren's syndrome is characterized by diffuse lymphocyte infiltration in the periductal areas of the lacrimal and salivary glands and is occasionally associated with pulmonary disease, aly/aly mice may serve as a unique spontaneous model of Sjgren's syndrome. https://doi.org/10.1002/eji.1830261129 https://www.ncbi.nlm.nih.gov/pubmed/8921964 http://europepmc.org/abstract/MED/8921964 Cited in this article [1]

[29]	Pan L,Sato S,Frederick JP,et al.Impaired immune responses and B-cell proliferation in mice lacking the Id3 gene[J]. Mol Cell Biol,1999,19(9):5969-5980. Cited in this article [1]

[30]	Quong MW,Romanow WJ,Murre C.E protein function in lymphocyte development[J]. Annu Rev Immunol,2002,20:301-322. Cited in this article [1]

[31]

Rahimi Darabad R,Suzuki T,Richards SM,et al.Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice[J]. Exp Eye Res,2014,127:153-160.Abstract Researchers have proposed that estrogen deficiency will lead to a Sjgren's syndrome (SjS)-like lacrimal gland inflammation, aqueous tear deficiency and dry eye. The purpose of this study was to determine whether this proposal is correct. Lacrimal glands were obtained from adult, age-matched wild type (WT) and aromatase knockout (ArKO) mice, in which estrogen synthesis is completely eliminated. Tissues were also obtained from autoimmune MRL/Mp-lpr/lpr (MRL/lpr) mice as inflammation controls. Tear volumes in WT and ArKO mice were measured and glands were processed for molecular biological and histological evaluation. Our results demonstrate that estrogen absence does not lead to a SjS-like inflammation in lacrimal tissue or to an aqueous-deficient dry eye. There was no upregulation of genes associated with inflammatory pathways in lacrimal glands of male or female ArKO mice. Such inflammatory activity was prominent in autoimmune MRL/lpr tissues. We also found no evidence of inflammation in lacrimal gland tissue sections of estrogen-deficient mice, and tear volumes of ArKO males were actually increased as compared to those WT controls. Interestingly, our study did show that estrogen absence influences the expression of thousands of lacrimal gland genes, and that this impact is sex- and genotype-specific. Our findings demonstrate that estrogen absence is not a risk factor for the development of SjS-like lacrimal gland inflammation or for aqueous-deficient dry eye in mice. Copyright © 2014 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.exer.2014.07.017 https://www.ncbi.nlm.nih.gov/pubmed/25084452 http://www.sciencedirect.com/science/article/pii/S001448351400205X Cited in this article [2]

[32]

Shim GJ,Warner M,Kim HJ,et al.Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjögren’s syndrome[J]. Proc Natl Acad Sci USA,2004,101(34):12628-12633.Sjgren's syndrome (SS) is an incurable, autoimmune exocrinopathy that predominantly affects females and whose pathogenesis remains unknown. Like rheumatoid arthritis, its severity increases after menopause, and estrogen deficiency has been implicated. We have reported that estrogen receptor-alpha and -beta-knockout mice develop autoimmune nephritis and myeloid leukemia, respectively, but neither develops SS. One model of estrogen deficiency in rodents is the aromatase-knockout (ArKO) mouse. In these animals, there is elevated B lymphopoiesis in bone marrow. We now report that ArKO mice develop severe autoimmune exocrinopathy resembling SS. By 1 year of age, there is B cell hyperplasia in the bone marrow, spleen, and blood of ArKO mice and spontaneous autoimmune manifestations such as proteinuria and severe leukocyte infiltration in the salivary glands and kidney. Also, as is typically found in human SS, there were proteolytic fragments of alpha-fodrin in the salivary glands and anti-alpha-fodrin antibodies in the serum of both female and male ArKO mice. When mice were raised on a phytoestrogen-free diet, there was a mild but significant incidence of infiltration of B lymphocytes in WT mice and severe destructive autoimmune lesions in ArKO mice. In age-matched WT mice fed a diet containing normal levels of phytoestrogen, there were no autoimmune lesions. These results reveal that estrogen deficiency results in a lymphoproliferative autoimmune disease resembling SS and suggest that estrogen might have clinical value in the prevention or treatment of this disease. https://doi.org/10.1073/pnas.0405099101 https://www.ncbi.nlm.nih.gov/pubmed/15314222 http://www.jstor.org/stable/3373034 Cited in this article [1]

[33]

Li Y,Liu C,Hou W,et al.Retrograde ductal administration of the adenovirus-mediated NDRG2 gene leads to improved sialaden hypofunction in estrogen-deficient rats[J]. Mol Ther,2014,22(5):908-918.One of the most common oral manifestations of menopause is xerostomia. Oral dryness can profoundly affect quality of life and interfere with basic daily functions, such as chewing, deglutition, and speaking. Although the feeling of oral dryness can be ameliorated after estrogen supplementation, the side effects of estrogen greatly restrict its application. We previously found that N-myc downstream-regulated gene 2 (NDRG2) is involved in estrogen-mediated ion and fluid transport in a cell-based model. In the present study, we used an ovariectomized rat model to mimic xerostomia in menopausal women and constructed two adenovirus vectors bearing NDRG2 to validate their therapeutic potential. Ovariectomized rats exhibited severe sialaden hypofunction, including decreased saliva secretion and ion reabsorption as well as increased water intake. Immunohistochemistry revealed that the expression of NDRG2 and Na + reabsorption-related Na + /K + -ATPase and epithelial sodium channels (EnaC) decreased in ovariectomized rat salivary glands. We further showed that the localized delivery of NDRG2 improved the dysfunction of Na + and Cl reabsorption. In addition, the saliva flow rate and water drinking recovered to normal. This study elucidates the mechanism of estrogen deficiency-mediated xerostomia or sialaden hypofunction and provides a promising strategy for therapeutic intervention. https://doi.org/10.1038/mt.2013.286 https://www.ncbi.nlm.nih.gov/pubmed/24343104 http://europepmc.org/abstract/med/24343104 Cited in this article [1]

[34]	Carvalho VD,Silveira VA,do Prado RF,et al. Effect of estrogen therapy,soy isoflavones,and the combination therapy on the submandibular gland of ovariectomized rats[J]. Pathol Res Pract,2011,207(5):300-305. Cited in this article [1]

[35]

Scofield RH,Asfa S,Obeso D,et al.Immunization with short peptides from the 60-kDa Ro antigen recapitulates the serological and pathological findings as well as the salivary gland dysfunction of Sjögren’s syndrome[J].J Immunol,2005,175(12):8409-8414.Sjgren's syndrome is a poorly understood autoimmune inflammatory illness that affects the salivary and lacrimal glands as well as other organ systems. We undertook the present study to determine whether mice immunized with short peptides from the 60-kDa Ro (or SSA) Ag, which is a common target of the autoimmunity of Sjgren's syndrome, develop an illness similar to Sjgren's syndrome. BALB/c mice were immunized with one of two short peptides from 60-kDa Ro that are know to induce epitope spreading. The animals were analyzed for the presence of anti-Ro and anti-La (or SSB) in the sera by immunoblot and ELISA. Salivary glands were collected and examined by histology after H&E staining. Salivary lymphocytes were purified and studied for cell surface makers by fluorescence-activated cell sorting. Timed stimulated salivary flow was measured. As reported previously, BALB/c mice immunized with 60-kDa Ro peptides developed an immune response directed against the entire Ro/La ribonucleoprotein particle that was similar to that found in humans with lupus or Sjgren's syndrome. Functional studies showed a statistical decrease in salivary flow in immunized mice compared with controls. Furthermore, there were lymphocytic infiltrates in the salivary glands of immunized animals that were not present in controls. The infiltrates consisted of both CD4- and CD8+ T lymphocytes as well as B lymphocytes. BALB/c mice immunized with 60-kDa Ro peptides develop anti-Ro, salivary gland lymphocyte infiltrates, and salivary dysfunction that is highly reminiscent of human Sjgren's syndrome. https://doi.org/10.4049/jimmunol.175.12.8409 https://www.ncbi.nlm.nih.gov/pubmed/16339583 http://europepmc.org/abstract/MED/16339583 Cited in this article [1]

[36]	Chiorini JA,Cihakova D,Ouellette CE,et al.Sjögren syndrome:advances in the pathogenesis from animal models[J]. J Autoimmun,2009,33(3-4):190-196. Cited in this article [1]

[37]	Kurien BT,Dsouza A,Igoe A,et al.Immunization with 60 kD Ro peptide produces different stages of preclinical autoimmunity in a Sjögren’s syndrome model among multiple strains of inbred mice[J]. Clin Exp Immunol,2013,173(1):67-75. Cited in this article [1]

[38]

Iizuka M,Wakamatsu E,Tsuboi H,et al.Pathogenic role of immune response to M3 muscarinic acetylcholine receptor in Sjögren’s syndrome-like sialoadenitis[J]. J Autoimmun,2010,35(4):383-389.Abstract The aim of this study was to clarify the role of the immune response to muscarinic type 3 receptor (M3R) in the pathogenesis of Sj02gren's syndrome (SS). M3R(-/-) mice were immunized with murine M3R peptides and their splenocytes were inoculated into Rag1(-/-) (M3R(-/-)→Rag1(-/-)) mice. M3R(-/-)→Rag1(-/-) mice had high serum levels of anti-M3R antibodies and low saliva volume. Histological examination showed marked infiltration of mononuclear cells in the salivary glands and immunohistochemistry demonstrated that the majority of these cells were CD4(+) T cells with a few B cells and several IFN-γ- and IL-17-producing cells. Apoptotic cells were present in the salivary glands of M3R(-/-)→Rag1(-/-) mice. Moreover, transfer of only CD3(+) T cells from M3R(-/-) immunized with M3R peptides into Rag1(-/-) mice resulted in cell infiltration and destruction of epithelial cells in the salivary glands, suggesting that M3R reactive CD3(+) T cells play a pathogenic role in the development of autoimmune sialoadenitis. Our findings support the notion that the immune response to M3R plays a crucial role in the pathogenesis of SS-like autoimmune sialoadenitis. Copyright 08 2010 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.jaut.2010.08.004 https://www.ncbi.nlm.nih.gov/pubmed/20864316 http://europepmc.org/abstract/MED/20864316 Cited in this article [1]

[39]

Inagaki Y,Jinno-Yoshida Y,Hamasaki Y,et al.A novel autoantibody reactive with carbonic anhydrase in sera from patients with systemic lupus erythematosus and Sjögren’s syndrome[J]. J Dermatol Sci,1991,2(3):147-154.Carbonic anhydrase (CA) is an extremely basic zinc metalloenzyme with a wide phyletic distribution, and the enzyme is important for the regulation of acid-base status. A novel autoantibody reactive with carbonic anhydrase was demonstrated. Several different classes of CA are known in mammals. Using the immuno blotting method and immun-dot analysis, we found this autoantibody to be reactive with CA in the sera from patients with Sjgren's syndrome (20.8%), including a patient with Sjgren's syndrome and renal tubular acidosis, and in patients with systemic lupus erythematosus (31.6%). The autoantibody varied in the extent of its cross-reactivity among human CA I (or B), human CA II (or C), bovine CA I, bovine CA II, rabbit CA, and dog CA. The titers continued to float and tended to parallel disease activity. Positive reactivity of autoantibody was observed on eccrine sweat glands and the distal tubules of the kidney by the indirect immunofluorescent method. https://doi.org/10.1016/0923-1811(91)90060-B https://www.ncbi.nlm.nih.gov/pubmed/1908698 http://www.ncbi.nlm.nih.gov/pubmed/1908698 Cited in this article [2]

[40]

Yang L,Ju J,Zhang W,et al.Effects of muscarinic acetylcholine 3 receptor (208-227) peptide immunization on autoimmune response in nonobese diabetic mice[J]. Clin Dev Immunol,2013,2013:485213 doi:10.1155/2013/485213.The second extracellular loop (LFWQYFVGKRTVPPGECFIQFLSEPTITFGTAI, aa 205–237) of muscarinic acetylcholine 3 receptor (M3R) has been reported to be an epitope for autoantibodies generated during certain autoimmune disorders, including Sj02gren’s syndrome (SS). Autoantibodies against M3R228–237 have been shown to interfere with the function of M3R. However, few studies have been performed on the M3R205–227 peptide of the second extracellular loop. In the current study, we sought to investigate the effect of M3R208–227 peptide immunization on autoimmune response in NOD/LtJ mice. We synthesized the M3R208–227 peptide and immunized NOD/LtJ mice to investigate whether peptide-specific antibodies could be generated and whether immunization would lead to changes in autoimmune response in NOD/LtJ mice. Our results demonstrate that the secretions of Th-1, Th-2, and Th-17 cytokines are downregulated and lymphocytic infiltration is improved in the salivary glands and lacrimal glands following immunization with M3R208–227 peptide in NOD/LtJ mice, suggesting that peptide immunotherapy using the M3R208–227 peptide may represent a potential therapeutic alternative. https://doi.org/10.1155/2013/485213 https://www.ncbi.nlm.nih.gov/pubmed/243829733208227 http://pubmedcentralcanada.ca/pmcc/articles/PMC3872023/ Cited in this article [1]

[41]

邹新乐,李想,徐凯彪,等.毒蕈碱受体3抗原表位多肽诱导干燥综合征动物模型的研究[J]. 现代免疫学,2009,29(1):25-28.利用毒蕈碱受体3(M3R)抗原表位多肽N49免疫BALB/c小鼠,以生理盐水注射小鼠作为对照组,检测各组小鼠血清抗N49多肽抗体和颌下腺淋巴细胞浸润情况。结果显示,多肽免疫组小鼠血清抗N49多肽抗体阳性率达100%(13/13),抗体滴度普遍从免疫后第21天开始显著上升,其中有5只(5/13)小鼠出现颌下腺淋巴细胞浸润;对照组小鼠血清抗N49多肽抗体均为阴性,仅有1只(1/14)出现轻度颌下腺淋巴细胞浸润。进一步以M3R分子不同抗原表位多肽N251和N412为包被抗原,检测以上实验小鼠血清中的抗体情况,显示N49多肽免疫组小鼠血清中抗N251和N412多肽抗体阳性率分别为100%(13/13)和85%(11/13),且两者抗体滴度变化趋势与抗N49多肽抗体一致,而对照组小鼠血清中抗N251和N412多肽抗体均为阴性。表明N49多肽较成功地建立了BALB/c小鼠的干燥综合征(SS)模型,诱导出了典型的自身抗体、颌下腺淋巴细胞浸润和自身抗原M3R分子内表位扩展等特征,为进一步研究M3R等自身抗原在SS发生中的作用机制奠定了基础。 http://www.cqvip.com/Main/Detail.aspx?id=1000621903 Cited in this article [1]

[42]	Dite P,Novotny I,Trna J,et al.Autoimmune pancreatitis[J]. Best Pract Res Clin Gastroenterol,2008,22(1):131-143. Cited in this article [1]

[43]

Caccavo D,Afeltra A,Rigon A,et al.Antibodies to carbonic anhydrase in patients with connective tissue diseases:relationship with lung involvement[J]. Int J Immunopathol Pharmacol,2008,21(3):659-667.Abstract The aim of this study is to evaluate the presence of antibodies to carbonic anhydrase I and/or II (ACAI and ACAII) in patients affected by connective tissue diseases (CTD) and to investigate their association with lung involvement evaluated by High resolution CT scan (HRCT). Ninety-six patients affected by CTD were studied, i.e. 33 rheumatoid arthritis (RA), 8 psoriatic arthritis (PA), 8 ankylosing spondilitis (AS), 23 Systemic Lupus Erythematosus (SLE), 10 Sjogren Syndrome (SS), and 14 Systemic Sclerosis (SSc). ACA were detected by ELISA. The lung involvement was evaluated by means of a previously described HRCT score. According to a receiver operator characteristic curve, patients were divided into those with HRCT score > or = 10 and those with HRCT score or = 10 was predictive of interstitial lung disease. ACAI and/or ACAII were detected in 30/96 patients (31.2%) (P or = 10 and both their CRP and ACAI levels were significantly higher when compared with patients showing a HRCT score less than 10 (P or = 10 than in those with HRCT score less than 10 (P = 0.014 and P = 0.007, respectively). Due to the lower levels of complement fractions detected in patients with HRCT score > or = 10, a possible immune-complex-mediated pathogenic mechanism of lung involvement could be suggested. https://doi.org/10.1016/j.intimp.2008.03.014 https://www.ncbi.nlm.nih.gov/pubmed/18831934 http://europepmc.org/abstract/MED/18831934 Cited in this article [1]

[44]

Nishimori I,Bratanova T,Toshkov I,et al.Induction of experimental autoimmune sialoadenitis by immunization of PL/J mice with carbonic anhydrase Ⅱ[J]. J Immunol,1995,154(9):4865-4873.Experimental autoimmune sialoadenitis was induced in PL/J (H-2u) mice by intradermal immunization with human carbonic anhydrase II (CAII) and adjuvant containing monophosphoryl lipid A and trehalose diorynomycolate. Mice immunized with CAII showed a significant increase in the number and size of foci with lymphocytic infiltration in the salivary gland compared with mice immunized with adjuvant alone and untreated mice. In mice immunized with CAII, lymphocytic foci were observed around intercalated and intralobular ducts in the salivary glands, resulting in atrophy and replacement of acinar units. The epithelial cells of salivary ducts adjacent to the lymphocytic foci showed both degenerative and regenerative changes. Similar lymphocytic infiltrations were observed in the pancreas and kidney of a few mice immunized with CAII. Among several mouse strains with different H-2 haplotypes (p, q, r, s, and u), strains bearing H-2s and H-2u were susceptible to CAII-induced sialoadenitis. These results indicate that sialoadenitis induced by the immunization of CAII in mice may serve as a disease model of Sj枚gren's syndrome and that CAII or its derived peptides in association with the MHC may be one Ag recognized by an autoimmune response in this syndrome. https://doi.org/10.1084/jem.181.5.1929 https://www.ncbi.nlm.nih.gov/pubmed/7722336 http://www.ncbi.nlm.nih.gov/pubmed/7722336 Cited in this article [1]

[45]

Nishimori I,Miyaji E,Morimoto K,et al.Diminished cellular immune response to carbonic anhydrase Ⅱ in patients with Sjögren’s syndrome and idiopathic chronic pancreatitis[J]. Jop,2004,5(4):186-192.Abstract CONTEXT: A serum antibody to carbonic anhydrase II has been reported in patients with Sj02gren's syndrome and idiopathic chronic pancreatitis. OBJECTIVE: To evaluate cellular immune response to carbonic anhydrase II in patients with Sj02gren's syndrome and idiopathic chronic pancreatitis. PATIENTS: Idiopathic chronic pancreatitis (n=23), Sj02gren's syndrome (n=12), alcoholic chronic pancreatitis (n=3) and normal controls (n=13). MAIN OUTCOME MEASURES: Proliferation assay of peripheral blood mononuclear cells. RESULTS: Notable increased proliferation of the mononuclear cells upon stimulation with carbonic anhydrase II was observed in 2 patients with idiopathic chronic pancreatitis (9%) and 2 patients with Sj02gren's syndrome (17%) but not in patients with alcoholic chronic pancreatitis nor in normal controls. Among the four study groups, there was no significant difference in the prevalence rate of the positive proliferative responses (P=0.444). CONCLUSION: Carbonic anhydrase II may not be a major target antigen for the immunological process in the pathogenesis of Sj02gren's syndrome and idiopathic chronic pancreatitis. Serum antibody to carbonic anhydrase II may be detected in these patients as a consequence of the immune reaction against other antigens which mimic carbonic anhydrase II. https://www.ncbi.nlm.nih.gov/pubmed/15254347 http://www.ncbi.nlm.nih.gov/pubmed/15254347 Cited in this article [1]