Murine cytomegalovirus induces a Sj�gren's syndrome-like disease in C57Bl/6-lpr/lpr mice

Fleck, Martin; Kern, Earl R.; Zhou, Tong; Läng, B; Mountz, John D.

doi:10.1002/1529-0131(199812)41:12<2175::aid-art12>3.0.co;2-i

Cited by 79 publications

(77 citation statements)

References 44 publications

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“…This type of inflammation can be distinguished from chronic inflammatory lesions with large foci (aggregates Ͼ50 mononuclear cells) including T and B cells. B6-lpr, but not B6 mice, develop mild focal inflammation at 100 dpi (1-2 foci per lobe of SMG), despite the absence of detectable virus (6). To examine whether the autoimmune prone strain NZM2328 also develops chronic inflammation in the salivary gland upon MCMV infection and whether it was specific to this organ, we examined exocrine glands (submandibular, parotid, sublingual, and lacrimal gland) and kidneys to assess the type and severity of inflammation histologically.…”

Section: Acute and Chronic Inflammatory Lesions In Nzm2328 After MCMVmentioning

confidence: 97%

“…B6-lpr mice have been reported to develop mild chronic sialadenitis following acute infection without the presence of infectious virus (6). In this study, we sought to determine the ability of MCMV to induce SS-like disease in an immunocompetent autoimmune-prone strain, NZM2328.…”

Section: S Jögren's Syndrome (Ss)mentioning

confidence: 99%

“…Delayed MCMV clearance in the salivary gland of B6-lpr mice compared with B6 has been reported (6). We sought to determine the kinetics of viral clearance in the autoimmune-prone strain NZM2328.…”

Section: Kinetics Of MCMV Clearance In the Salivary And Lacrimal Glandsmentioning

confidence: 99%

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Severe Focal Sialadenitis and Dacryoadenitis in NZM2328 Mice Induced by MCMV: A Novel Model for Human Sjögren’s Syndrome

Ohyama¹,

Carroll²,

Deshmukh³

et al. 2006

The Journal of Immunology

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The genetic and environmental factors that control the development of Sjögren’s syndrome, an autoimmune disease mainly involving the salivary and lacrimal glands, are poorly understood. Viruses which infect the glands may act as a trigger for disease. The ability of sialotropic murine CMV (MCMV) to induce acute and chronic glandular disease was characterized in an autoimmune-prone mouse strain, NZM2328. MCMV levels were detectable in the salivary and lacrimal glands 14–28 days after i.p. infection and correlated with acute inflammation in the submandibular gland. After latency, virus was undetectable in the glands by PCR. At this stage, NZM2328 female mice developed severe chronic periductal inflammation in both submandibular and lacrimal glands in contrast to the much milder infiltrates found in female B6-lpr and male NZM2328. The focal infiltrates consisted of CD4+ and B220+ cells as opposed to diffuse CD4+, CD8+, and B220+ cells during acute infection. Salivary gland functional studies revealed a gender-specific progressive loss of secretory function between days 90 and 125 postinfection. Latent MCMV infection did not significantly affect the low incidence of autoantibodies to Ro/SSA and La/SSB Ags in NZM2328 mice. However, reactivities to other salivary and lacrimal gland proteins were readily detected. MCMV infection did not significantly alter the spontaneous onset of kidney disease in NZM2328. Thus, chronic inflammation induced by MCMV with decreased secretory function in NZM2328 mice resembles the disease manifestations of human Sjögren’s syndrome.

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Section: Acute and Chronic Inflammatory Lesions In Nzm2328 After MCMVmentioning

confidence: 97%

Section: S Jögren's Syndrome (Ss)mentioning

confidence: 99%

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Severe Focal Sialadenitis and Dacryoadenitis in NZM2328 Mice Induced by MCMV: A Novel Model for Human Sjögren’s Syndrome

Ohyama¹,

Carroll²,

Deshmukh³

et al. 2006

The Journal of Immunology

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“…Of particular interest, Fleck and colleagues reported infection of C57BL/6-lpr/lpr mice with murine cytomegalovirus with resultant acute and chronic sialoadenitis [71]. This inflammation persisted after clearance of the virus.…”

Section: Mouse Models and Gene Transfermentioning

confidence: 99%

“…Thus, this is the only previously reported mouse model of SS with convincingly high levels of anti-Ro and anti-La, although whether the anti-Ro is anti-60 kD Ro or anti-52 kD Ro, or both, is not clear. Pathology of other organs is not given, but the presence of anti-dsDNA, which is usually considered specific to lupus, implies that this is also a model of secondary SS [71].…”

Section: Mouse Models and Gene Transfermentioning

confidence: 99%

Horizons in Sjögren’s Syndrome Genetics

Williams

Cobb

Namjou

et al. 2007

Clinic Rev Allerg Immunol

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Sjögren's syndrome (SS) is a complex polygenic autoimmune disorder. A few major genetic effects have been identified. Historically, HLA and non-HLA genetic associations have been reported. Recently, the HLA region continued to reveal association findings. A new susceptibility region has been suggested by a study of a D6S349 microsatellite marker. Among non-HLA studies, recent association of immunoglobulin κ chain allotype KM1 with anti-La autoantibodies in primary Sjögren's syndrome confirms findings in a study from two decades ago. Meanwhile, mouse models have been employed to study the genetic contribution to salivary lymphadenitis or © Humana Press Inc. 2007 Correspondence to: John B. Harley, john-harley@omrf.ouhsc.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript dry eyes and mouth. Gene transfer exploration in mouse models shows promise. The authors review the HLA and non-HLA association studies and the mouse model work that has been reported. Newly developed genomic capacity will provide, in the future, a much closer approximation of the true picture of the genetic architecture of Sjögren's syndrome.

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Treatment of chronic sialadenitis in a murine model of Sj�gren's syndrome by localfasL gene transfer

Fleck¹,

Zhang²,

Kern³

et al. 2001

Arthritis & Rheumatism

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Objective Infection of Fas (Fas/CD95)–mutant C57BL/6 (B6)‐lpr/lpr mice with murine cytomegalovirus (MCMV) leads to a chronic sialadenitis similar to that of Sjögren's syndrome (SS). The aim of this study was to evaluate whether chronic sialadenitis would also occur in Fas ligand (FasL/CD95L)–mutant B6‐gld/gld mice upon infection with MCMV and whether the expression of FasL by local gene transfer using recombinant adenoviral vectors would be an effective therapeutic strategy. Methods B6‐gld/gld mice were infected intraperitoneally with MCMV, and salivary glands were analyzed histologically at different time points. For treatment of sialadenitis, recombinant adenoviral vectors expressing the fasL gene (AdLoxpFasL + AxCANCre) or the lacZ gene (AdCMVLacZ) were locally injected into the salivary glands of MCMV‐infected B6‐gld/gld mice and uninfected B6‐+/+ and B6‐gld/gld mice. Results Following MCMV infection, B6‐gld/gld mice developed an acute and chronic sialadenitis characterized by multiple foci of infiltrating T cells. After local injection of adenoviral vectors, high levels of lacZ or fasL gene expression could be detected in acinar and ductal cells. Treatment of acute and chronic sialadenitis in B6‐gld/gld mice with local fasL gene transfer resulted in a significant reduction in the number of inflammatory foci and tissue destruction in salivary glands compared with mice treated with AdCMVLacZ. Despite high levels of FasL expression after injection of recombinant vectors, <5% of ductal and acinar cells were TUNEL positive, demonstrating that, in this model of SS, acinar and ductal cells were not highly sensitive to FasL‐mediated apoptosis. Conclusion Chronic sialadenitis similar to that of SS developed in B6‐gld/gld mice after MCMV infection. FasL expression was reconstituted by local gene transfer, resulting in significant reduction of infiltrating mononuclear cells, which indicates that local gene transfer of fasL might be a novel treatment for chronic sialadenitis.

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Murine cytomegalovirus induces a Sj�gren's syndrome-like disease in C57Bl/6-lpr/lpr mice

Cited by 79 publications

References 44 publications

Severe Focal Sialadenitis and Dacryoadenitis in NZM2328 Mice Induced by MCMV: A Novel Model for Human Sjögren’s Syndrome

Severe Focal Sialadenitis and Dacryoadenitis in NZM2328 Mice Induced by MCMV: A Novel Model for Human Sjögren’s Syndrome

Horizons in Sjögren’s Syndrome Genetics

Treatment of chronic sialadenitis in a murine model of Sj�gren's syndrome by localfasL gene transfer

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