Genetically Programmed Development of Salivary Gland Abnormalities in the NOD (Nonobese Diabetic)-scidMouse in the Absence of Detectable Lymphocytic Infiltration: A Potential Trigger for Sialoadenitis of NOD Mice

Robinson, Carol; Yamamoto, Hideo; Peck, Ammon B.; Humphreys‐Beher, Michael G.

doi:10.1006/clin.1996.0050

Cited by 104 publications

(129 citation statements)

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“…Each membrane was incubated in a blocking buffer consisting of 3% nonfat dry milk and 3% bovine serum albumin (BSA) in Tris-buffered saline. The membranes were incubated with rabbit antirat PSP antibody (1 : 10 000 dilution) that is known to cross-react with mouse PSP [23,24]. The membranes were washed, then developed using alkaline phosphatase-conjugated goat antirabbit immunoglobulin (Ig) and substrate, as described in detail elsewhere [25].…”

Section: Methodsmentioning

confidence: 99%

“…With the onset of secretory dysfunction, there is a concomitant increase in salivary proteins that is not directly proportional to the reduced fluid volumes. Along with these increases in salivary protein concentrations, there are measurable decreases in amylase and epidermal growth factor activities [13,23], as well as the aberrant appearance of PSP in the submandibular glands [23]. In addition, the increased proteolytic activity can be detected in saliva, one moiety possessing the capacity to cleave PSP at a unique NLNL sequence located 20 amino acid residues from the N-terminal start site [24].…”

Section: Lack Of Immune-mediated Loss Of Secretory Function In the Nomentioning

confidence: 99%

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IL‐4‐Dependent Effector Phase in Autoimmune Exocrinopathy as Defined by the NOD.IL‐4‐Gene Knockout Mouse Model of Sjögren's Syndrome

et al. 2001

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NOD mice manifest many features of autoimmune exocrinopathy (Sjögren's syndrome), a disease generally characterized by a chronic, progressive immunological attack against the exocrine tissues of the salivary and lacrimal glands. Previous studies using the NOD congenic partner strain, NOD.Igμnull, defined an important role for B lymphocytes in the development of xerostomia, implicating autoantibodies reactive with the acetylcholine muscarinic receptor (M3R) as the possible effector mechanism. In the present study, we have examined the impact of the cytokine, interleukin (IL)‐4, on autoimmune exocrinopathy by using the IL‐4 gene knockout (KO) NOD mouse strain, NOD.IL‐4−/−. Despite manifesting the physiological aberrations and marked leukocytic infiltration of the salivary glands characteristic of autoimmune xerostomia in NOD mice, the NOD.IL‐4−/− mice do not develop xerostomia. However, NOD.IL‐4−/− mice that received adoptively transferred T lymphocytes derived from NOD.Igμ−/− mice progress to xerostomia, thereby reversing the defect. While progression or lack of progression to xerostomia correlated with the ability of the NOD.IL‐4−/− mice to express detectable anti‐M3R autoantibodies, the precise mechanism of how IL‐4 influences the development of autoimmune xerostomia remains speculative.

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Section: Methodsmentioning

confidence: 99%

Section: Lack Of Immune-mediated Loss Of Secretory Function In the Nomentioning

confidence: 99%

IL‐4‐Dependent Effector Phase in Autoimmune Exocrinopathy as Defined by the NOD.IL‐4‐Gene Knockout Mouse Model of Sjögren's Syndrome

et al. 2001

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“…Some work implicates lymphocytic infiltration and exposure to autoantibodies (including pathogenic autoantibodies to M3MR) directly in the loss of secretory function (Nguyen et al, 2000;van Blokland and Versnel, 2002). Other studies suggest that early changes in lacrimal gland function, specifically in the secretory pathway, may precede infiltration; for instance, NOD-scid mice exhibit differences in protein composition in saliva compared to controls (Robinson et al, 1996). The latter work suggests that there may be fundamental changes in the NOD mouse acinar secretory pathways that may predispose these mice to autoimmune disease.…”

Section: Introductionmentioning

confidence: 98%

Male NOD mouse external lacrimal glands exhibit profound changes in the exocytotic pathway early in postnatal development

Costa

Veigh

et al. 2006

Experimental Eye Research

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The lacrimal glands of male NOD mice exhibit many of the features of the human lacrimal gland in patients afflicted with the autoimmune disease, Sjögren's syndrome, including loss of secretory functions and lymphocytic infiltration into the lacrimal gland. To elucidate the early changes in the secretory pathway associated with development of Sjögren's syndrome, we investigated the organization of the exocytotic pathway in lacrimal glands of age-matched male BALB/c and NOD mice. Cryosections from lacrimal glands from 1 and 4 month male BALB/c and NOD mice were processed for confocal fluorescence and electron microscopic evaluation of different participants in exocytosis. No changes in apical actin filaments were noted in glands from NOD mice, but these glands exhibited thickening of basolateral actin relative to that seen in the BALB/c mice. Rab3D immunofluorescence associated with mature secretory vesicles was distributed abundantly in a continuous vesicular network concentrated beneath the apical plasma membrane in glands from 1 and 4 month BALB/c mice. In glands from 1 month NOD mice, rab3D immunofluorescence exhibited marked discontinuity and irregularity in the vesicular labeling pattern. While this change was also detected in glands from 4 month NOD mice, many of these glands exhibited an additional extension of rab3D labeling through the cell to the basolateral membrane. Electron microscopic analysis confirmed the formation of irregularly-shaped, unusually large secretory vesicles in lacrimal glands from NOD mice. Quantitation of multiple secretory vesicles from electron micrographs revealed a significant (p ≤5) increase in the percentage of secretory vesicles incorporated into multivesicular aggregates in lacrimal glands from 1 and 4 month NOD mice compared to BALB/c mice. The M3 muscarinic receptor, a key signaling effector of exocytosis, was redistributed away from its normally basolateral locale in glands from BALB/c mice, with concomitant enrichment in intracellular aggregates in glands from NOD mice. These findings show that lacrimal glands in NOD mice as young as 1 month contain aberrant secretory vesicles with altered effector composition that undergo premature cytoplasmic fusion, and that changes in the distribution of the M3 muscarinic receptor occur within the same time frame.

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“…In NOD mice (but not in MRL/lpr mice) the development of focal lymphocytic infiltrates in the salivary glands (sialoadenitis) is accompanied by a corresponding loss of the secretory function and changes in the protein composition of the saliva (Humphreys-Beher, 1996;Humphreys-Beher et al, 1994). These changes in protein composition have also been observed in NOD-SCID (severe combined immunodeficiency) mice (Robinson et al, 1996). The NOD-SCID mouse is devoid of functional T lymphocytes and B lymphocytes because of a homozygosity in the SCID mutation (Shultz et al, 1995).…”

mentioning

confidence: 98%

Two Different Types of Sialoadenitis in the NOD- and MRL/lpr Mouse Models for Sjögren's Syndrome: A Differential Role for Dendritic Cells in the Initiation of Sialoadenitis?

Blokland

Helden-Meeuwsen

Wierenga‐Wolf

et al. 2000

Laboratory Investigation

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SUMMARY: Sjö gren's syndrome is an autoimmune disease that primarily affects the salivary and lacrimal glands. In these glands, focal lymphocytic infiltrates develop. Little is known about the initiation of this autoimmune disease. Antigen-presenting cells (APC) such as dendritic cells (DC) can play a role in the initiation of autoimmunity. To date, no data on the presence of DC in Sjö gren's syndrome are available. Several mouse strains, the nonobese diabetic (NOD) and the MRL/lpr mouse, can be used as models for Sjö gren's syndrome. We compared the development of sialoadenitis in the submandibular glands (SMG) of NOD and MRL/lpr mice with particular focus on the presence of APC. DC, macrophages, T cells, and B cells in the SMG were studied by means of immunohistochemistry, after which positively stained cells were quantified. NOD-severe combined immunodeficiency (SCID) mice were used to study the presence of APC in the SMG in the absence of lymphocytes. Before lymphocytic infiltration, increased numbers of DC were detected in the SMG of NOD mice compared with those numbers in control mice and MRL/lpr mice, which suggests that DC play a role in the initiation of sialoadenitis in NOD mice. In the SMG of NOD mice, lymphocytic infiltrates organized in time. In MRL/lpr mice, however, lymphocytic infiltrates were already organized at the time of appearance. This organization was lost over time. In conclusion, two types of sialoadenitis are described in two mouse models for Sjö gren's syndrome. Differences exist with regard to early events that may lead to the development of sialoadenitis and to the composition and organization of inflammatory infiltrates. It is possible that different types of sialoadenitis also exist in humans and that the pathogenetic process in both the early and late phases of the autoimmune reaction differs among patients. (Lab Invest 2000, 80:575-585).

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Genetically Programmed Development of Salivary Gland Abnormalities in the NOD (Nonobese Diabetic)-scidMouse in the Absence of Detectable Lymphocytic Infiltration: A Potential Trigger for Sialoadenitis of NOD Mice

Cited by 104 publications

References 0 publications

IL‐4‐Dependent Effector Phase in Autoimmune Exocrinopathy as Defined by the NOD.IL‐4‐Gene Knockout Mouse Model of Sjögren's Syndrome

IL‐4‐Dependent Effector Phase in Autoimmune Exocrinopathy as Defined by the NOD.IL‐4‐Gene Knockout Mouse Model of Sjögren's Syndrome

Male NOD mouse external lacrimal glands exhibit profound changes in the exocytotic pathway early in postnatal development

Two Different Types of Sialoadenitis in the NOD- and MRL/lpr Mouse Models for Sjögren's Syndrome: A Differential Role for Dendritic Cells in the Initiation of Sialoadenitis?

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