Development of Sjögren’s Syndrome in Nonobese Diabetic-Derived Autoimmune-Prone C57BL/6.NOD-<i>Aec1Aec2</i> Mice Is Dependent on Complement Component-3

Nguyen, Cuong Q.; Kim, Hyuna; Cornelius, Janet G.; Peck, Ammon B.

doi:10.4049/jimmunol.179.4.2318

Cited by 46 publications

(38 citation statements)

References 45 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: 70%

“…Alternatively, ANAs do not appear to have a direct role in SjS-like disease in NOD mice (43); however, our observed increase in ANA production suggests that the B cell compartment of NOD.NZW-Chr7 female mice may be adversely affected by the congenic interval. A potential reservoir of autoreactive B cells is the MZB population (59), which has been implicated in mouse models of SjS-like disease (46,53). MZBs are also increased in NOD mice compared with non-autoimmune-prone mouse strains (60,61).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, an increase in MZBs has been correlated with SjS-like disease in C57BL/6 congenic mice, harboring NOD-derived intervals for Idd3 and Idd5, and in C57BL/6 BAFF transgenic mice (46,53). Although sialadenitis was reduced, we hypothesized that an increased level of MZBs may be correlated with saliva abnormalities (e.g., flow rate, PSP proteolytic activity) observed in congenic mice.…”

Section: Nodnzw-chr7 Mice Exhibit An Increase In the Frequency Of Spmentioning

confidence: 96%

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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: 70%

Section: Discussionmentioning

confidence: 99%

Section: Nodnzw-chr7 Mice Exhibit An Increase In the Frequency Of Spmentioning

confidence: 96%

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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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“…The expansion of MZ B cells in NOD mice has been associated with various autoimmune pathologies (12)(13)(14)(15)(16). However, the cause of their expansion in this strain was not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…This includes studies that show the following: 1) the MZ B cell subset undergoes a large secondary expansion prior to the onset of disease, which is associated with their aberrant migration into the pancreas and its draining lymph nodes (LN) (12); 2) transgenic B cell clones specific for the primary T1D autoantigen insulin are preferentially selected into the MZ subset (14); 3) MZ B cells in NOD mice have the capacity to present insulin to autoreactive CD4 + T cells as effectively as the FO subset (12); and 4) preferential depletion of this subset using an anti-CD21/35 mAb significantly decreased the incidence of cyclophosphamide-induced T1D in NOD mice (15). In addition, accumulation of MZ B cells has also been associated with pathology causing Sjögren's syndrome in nonautoimmune-prone C57BL/6 (B6) mice containing the Aec1 and Aec2 disease susceptibility loci from NOD mice (16).…”

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confidence: 99%

Intrinsic Molecular Factors Cause Aberrant Expansion of the Splenic Marginal Zone B Cell Population in Nonobese Diabetic Mice

Stolp

Mariño

Batten

et al. 2013

The Journal of Immunology

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Marginal zone (MZ) B cells are an innate-like population that oscillates between MZ and follicular areas of the splenic white pulp. Differentiation of B cells into the MZ subset is governed by BCR signal strength and specificity, NF-κB activation through the B cell–activating factor belonging to the TNF family (BAFF) receptor, Notch2 signaling, and migration signals mediated by chemokine, integrin, and sphingosine-1-phosphate receptors. An imbalance in splenic B cell development resulting in expansion of the MZ subset has been associated with autoimmune pathogenesis in various murine models. One example is the NOD inbred mouse strain, in which MZ B cell expansion has been linked to development of type 1 diabetes and Sjögren’s syndrome. However, the cause of MZ B cell expansion in this strain remains poorly understood. We have determined that increased MZ B cell development in NOD mice is independent of T cell autoimmunity, BCR specificity, BCR signal strength, and increased exposure to BAFF. Rather, mixed bone marrow chimeras showed that the factor(s) responsible for expansion of the NOD MZ subset is B cell intrinsic. Analysis of microarray expression data indicated that NOD MZ and precursor transitional 2-MZ subsets were particularly dysregulated for genes controlling cellular trafficking, including Apoe, Ccbp2, Cxcr7, Lgals1, Pla2g7, Rgs13, S1pr3, Spn, Bid, Cd55, Prf1, and Tlr3. Furthermore, these B cell subsets exhibited an increased steady state dwell time within splenic MZ areas. Our data therefore reveal that precursors of mature B cells in NOD mice exhibit an altered migration set point, allowing increased occupation of the MZ, a niche favoring MZ B cell differentiation.

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Interleukin‐7 Enhances the Th1 Response to Promote the Development of Sjögren's Syndrome–like Autoimmune Exocrinopathy in Mice

Jin¹,

Kawai²,

Cha

et al. 2013

Arthritis & Rheumatism

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Objective Although elevated IL-7 levels were reported in patients with primary Sjӧgren’s syndrome (pSjS), the role of IL-7 in this disease remains unclear. Here we characterized the previously unexplored role of IL-7 in the development and onset of pSjS using C57BL/6.NOD-Aec1Aec2 (B6.NOD-Aec) mouse model that recapitulates human pSjS. Methods For gain-of-function studies, recombinant IL-7 or control PBS was injected intraperitoneally (i.p.) into 12-week old B6.NOD-Aec mice for 8 weeks. For loss-of-function studies, neutralizing anti-IL-7 receptor antibody or its isotype control IgG was administered i.p. into 16-week old B6.NOD-Aec mice. Salivary flow measurement, histological and flow cytometric analysis of salivary glands, and serum antinuclear antibody assay were performed to assess various disease parameters. Results Administration of exogenous IL-7 accelerated, whereas blockade of IL-7 receptor signaling almost completely abolished the development of pSjS, based on salivary gland inflammation and apoptosis, autoantibody production and secretory dysfunction. IL-7 positively regulated IFN-γ-producing Th1 and CD8 T cells in the salivary glands without affecting IL-17. Moreover, IL-7 enhanced the expression of CXCR3 ligands in a T cell- and IFN-γ-dependent fashion. Accordingly, IFN-γ induced a human salivary gland epithelial cell line to produce CXCR3 ligands. IL-7 also increased the level of TNF-α, another Th1-associated cytokine that can facilitate tissue destruction and inflammation. Conclusion IL-7 plays a pivotal pathogenic role in SjS, which is underpinned by an enhanced Th1 response and IFN-γ-CXCR3 ligand-mediated lymphocyte infiltration of target organs. These results suggest that targeting IL-7 pathway may be a potential future strategy to prevent and treat SjS.

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Development of Sjögren’s Syndrome in Nonobese Diabetic-Derived Autoimmune-Prone C57BL/6.NOD-Aec1Aec2 Mice Is Dependent on Complement Component-3

Cited by 46 publications

References 45 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

Intrinsic Molecular Factors Cause Aberrant Expansion of the Splenic Marginal Zone B Cell Population in Nonobese Diabetic Mice

Interleukin‐7 Enhances the Th1 Response to Promote the Development of Sjögren's Syndrome–like Autoimmune Exocrinopathy in Mice

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