Sjögren's Syndrome‐Like Disease of C57BL/6.NOD‐<i>Aec1 Aec2</i> Mice: Gender Differences in Keratoconjunctivitis Sicca Defined by a Cross‐Over in the Chromosome 3 <i>Aec1</i> Locus

Nguyen, Cuong Q.; Singson, Eric; Kim, J.-Y.; Cornelius, Janet G.; Attia, R.; Doyle, Maı̀re E.; Bulosan, Marievic; Cha, Seunghee; Peck, Ammon B.

doi:10.1111/j.1365-3083.2006.01828.x

Cited by 39 publications

(37 citation statements)

References 56 publications

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“…A preliminary experiment was performed using samples from two NOD males and two NOD females to quantify peptide cleavage at various incubation time points (0 min, 5 min, 30 min, 2 h, 6 h, 16 h; data not shown). Although not reported in previous studies (34,45,46), we observed a sex bias for peptide cleavage such that male saliva cleaved peptide more quickly than female saliva, presumably owing to male saliva containing a higher concentration of PSP protease (Fig. 4B, 4C).…”

Section: Severity Of Sialadenitis But Not Insulitis Is Reduced In Ncontrasting

confidence: 69%

“…Chr1 and Chr3, in particular, have been shownto harbor overlappingloci (Idd5/Aec1and Idd3/Aec2) that can affect pathogenesis for both diseases (19,20,45). Sialadenitis, however, is not a direct result of diabetes onset because NOD mice that are congenic for a different MHC locus are protected from diabetes, but still develop sialadenitis and salivary gland dysfunction (44).…”

Section: Discussionmentioning

confidence: 99%

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An NZW-Derived Interval on Chromosome 7 Moderates Sialadenitis, But Not Insulitis in Congenic Nonobese Diabetic Mice

Burt

Watkins

Tan

et al. 2009

The Journal of Immunology

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Autoimmune lymphocytic infiltration of the salivary glands, termed sialadenitis, is a pathologic feature of Sjögren’s syndrome (SjS) that is also prominent in nonobese diabetic (NOD) mice. Genetic factors regulate sialadenitis, and a previous (NOD × NZW)F2 study detected linkage to murine chromosome (Chr) 7. The locus, subsequently annotated as Ssial3, maps to the distal end of Chr7 and overlaps a region associated with type 1 diabetes susceptibility in NOD mice. To examine whether Ssial3 could contribute to both diseases, or was specific for SjS, we generated a congenic mouse strain that harbored an NZW-derived Chr7 interval on the NOD genetic background. This congenic strain exhibited reduced sialadenitis compared with NOD mice and confirmed Ssial3. This reduction, however, did not ameliorate saliva abnormalities associated with SjS-like disease in NOD mice, nor were congenic mice protected against insulitis (lymphocytic infiltration of the pancreatic islets) or diabetes onset. Thus, the Ssial3 locus appears to have a tissue-specific effect for which the NZW allele is unable to prevent other autoimmune traits in the NOD mouse. Anomalous increases for antinuclear Ab production and frequency of marginal-zone B cells were also identified in congenic mice, indicating that the NZW-derived Chr7 interval has a complex effect on the NOD immune system.

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Section: Severity Of Sialadenitis But Not Insulitis Is Reduced In Ncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

An NZW-Derived Interval on Chromosome 7 Moderates Sialadenitis, But Not Insulitis in Congenic Nonobese Diabetic Mice

Burt

Watkins

Tan

et al. 2009

The Journal of Immunology

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“…This increase in lacrimal gland activity persisted until the end of the study at 16 wk postcannulation. autoantibodies and proinflammatory cytokines, such as IFN-gamma (IFN-γ) (21)(22)(23). Changes in the local and systemic immune system in the treated C57BL/6.NOD-Aec1/Aec2 mice were investigated by collection of salivary glands, lacrimal glands, and serum at the termination of the study.…”

Section: Aqp1 Gene Therapy Restores Salivary and Lacrimal Gland Fluidmentioning

confidence: 99%

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Lai

Yin

Cabrera-Pérez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Currently, no effective treatments exist for Sjögren’s syndrome, and there is a limited understanding of the physiological mechanisms associated with xerostomia and hyposalivation. The present work revealed that aquaporin 5 expression, a water channel critical for salivary gland fluid secretion, is regulated by bone morphogenetic protein 6. Increased expression of this cytokine is strongly associated with the most common symptom of primary Sjögren’s syndrome, the loss of salivary gland function. This finding led us to develop a therapy in the treatment of Sjögren’s syndrome by increasing the water permeability of the gland to restore saliva flow. Our study demonstrates that the targeted increase of gland permeability not only resulted in the restoration of secretory gland function but also resolved the hallmark salivary gland inflammation and systemic inflammation associated with disease. Secretory function also increased in the lacrimal gland, suggesting this local therapy could treat the systemic symptoms associated with primary Sjögren’s syndrome.

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“…The F1 mice were intercrossed and backcrossed to parental strains to generate the B6.Aec1Aec2Ifnar1 -/-mouse. All progeny were genotyped for the Aec1 and Aec2 loci using a panel of microsatellite markers as described previously (Nguyen et al, 2006). The Ifnar1 deficiency was monitored by a genespecific polymerase chain-reaction (PCR) and flow cytometry.…”

Section: Animalsmentioning

confidence: 99%

Type I Interferon Receptor Deficiency Prevents Murine Sjögren’s Syndrome

et al. 2013

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In Sjögren's Syndrome (SS), inherent glandular defects, autoimmunity, and mononuclear cell infiltration within the salivary glands cause reduced salivation leading to xerostomia. Excessive production of type I interferons (IFN), triggered by environmental and genetic factors, is considered pathogenic in this disorder. However, whether type I IFN production is causative or an outcome of the disease process is not known. To address this question, we introduced a deficiency of interferon alpha receptor 1 (Ifnar1) into B6.Aec1Aec2 mice, which are known to have the genetic loci necessary for developing a SS-like disorder. This new mouse strain, B6.Aec1Aec2Ifnar1 -/-, lacking type I IFN-mediated signaling, was characterized for pilocarpine-induced salivation, the presence of serum autoantibodies, sialoadenitis, and dacryoadenitis. Compared with the B6.Aec1Aec2Ifnar1 +/+ (wild-type) mice, the B6.Aec1Aec2Ifnar1 -/-(knockout) mice had significantly lower mononuclear cell infiltration in the salivary and lacrimal glands. The knockout mice were completely protected from salivary gland dysfunction. Surprisingly, they had a robust autoantibody response comparable with that of the wild-type mice. These findings demonstrate that, in the absence of type I IFN-mediated signaling, systemic autoantibody responses can be dissociated from glandular pathology. Our study suggests that, in genetically susceptible individuals, the type I IFN pathway can instigate certain features of SS.

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Sjögren's Syndrome‐Like Disease of C57BL/6.NOD‐Aec1 Aec2 Mice: Gender Differences in Keratoconjunctivitis Sicca Defined by a Cross‐Over in the Chromosome 3 Aec1 Locus

Cited by 39 publications

References 56 publications

An NZW-Derived Interval on Chromosome 7 Moderates Sialadenitis, But Not Insulitis in Congenic Nonobese Diabetic Mice

An NZW-Derived Interval on Chromosome 7 Moderates Sialadenitis, But Not Insulitis in Congenic Nonobese Diabetic Mice

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Type I Interferon Receptor Deficiency Prevents Murine Sjögren’s Syndrome

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