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. 2008

Arthritis & Rheumatism

259

228

Objective. Recently, the Th1/Th2 paradigm has been expanded by the discovery of Th17 cells, a subset of CD4؉ memory T cells characterized by their unique ability to secrete interleukin-17 (IL-17) family cytokines. Importantly, Th17 cells appear to be intimately involved in autoimmunity. We undertook the present study to investigate whether the Th17/IL-23 system is up-regulated in Sjögren's syndrome (SS).Methods. Sera, saliva, and salivary glands from C57BL/6.NOD-Aec1Aec2 mice (a model for primary SS), as well as sera, saliva, and salivary gland biopsy specimens obtained from patients with primary SS, were evaluated for IL-17 and IL-23 expression by immunohistochemistry, real-time polymerase chain reaction, and the Luminex system.Results. Immunohistochemical stainings of submandibular glands from C57BL/6.NOD-Aec1Aec2 mice and of salivary gland biopsy specimens from SS patients revealed strong positive staining for both IL-17 and IL-23 within lymphocytic foci and diffuse staining on epithelial tissues. Temporal expression of IL-17 and IL-23 in submandibular glands of C57BL/6.NODAec1Aec2 mice correlated with expression of retinoic acid-related orphan receptor ␥t, the Th17 cell master control gene. While IL-17 could not be detected in saliva from 4-20-week-old C57BL/6.NOD-Aec1Aec2 mice, this cytokine was present in the blood of mice up to age 16 weeks. This contrasted with sera and saliva from SS patients, in which IL-17 and IL-6 were present at varying levels.Conclusion. These results suggest that the Th17/ IL-23 system is up-regulated in C57BL/6.NOD-Aec1Aec2 mice and SS patients at the time of disease. A correlation between up-regulated IL-17/IL-23 expression and specific clinical manifestations of SS has yet to be identified.

Section: Discussionsupporting

confidence: 58%

Salivary gland tissue expression of interleukin‐23 and interleukin‐17 in Sjögren's syndrome: Findings in humans and mice

et al. 2008

Arthritis & Rheumatism

259

228

“…In phase 3, secretory dysfunction of the salivary and lacrimal glands occurs, most likely the result of production of Abs reactive with the muscarinic acetylcholine receptors (6,29), marked by significant loss of secreted proteins. An aberration within any one of these three phases, e.g., disruption of either the IFN-␥ (20) or IL4 gene (19,22), interrupts subsequent onset of clinical SjS-like disease.…”

Section: Pathophysiological Characteristics Of Sjsmentioning

confidence: 99%

“…Ϫ/Ϫ mice indicated that IgG1 isotype-specific anti-M3R autoantibodies were the more important autoantibody, acting as potential effectors of secretory dysfunction observed in submandibular and lacrimal glands (19,22). To determine the presence of anti-M3R Abs, aliquots of sera pooled from appropriate groups were incubated with mouse M3R-transfected Flp-In CHO cells, tagged using FITCconjugated anti-isotype-specific secondary Abs, and subsequently analyzed by flow cytometry (26).…”

Section: Aec1aec2c3mentioning

confidence: 99%

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

The Journal of Immunology

Kim

Cornelius

et al. 2007

The role of complement in the etiology of Sjögren’s syndrome (SjS), a human autoimmune disease manifested primarily by salivary and lacrimal gland dysfunction resulting in dry mouth/dry eye syndrome, remains ill-defined. In the present study, we examined the role of complement component-3 (C3) using a newly constructed C3-gene knockout mouse, C57BL/6.NOD-Aec1Aec2.C3−/−. Inactivation of C3 in the parental C57BL/6.NOD-Aec1Aec2 strain, a model of primary SjS, resulted in a diminished or total absence of both preclinical and clinical manifestations during development and onset of disease, including reduced acinar cell apoptosis, reduced levels of caspase-3, lack of leukocyte infiltration of submandibular glands, reduced synthesis of disease-associated autoantibodies, maintenance of normal glandular architecture, and retention of normal saliva secretion. In addition, C57BL/6-NOD.Aec1Aec2.C3−/− mice did not exhibit increased numbers of marginal zone B cells, a feature of SjS-prone C57BL/6-NOD.Aec1Aec2 mice. Interestingly, C57BL/6-NOD.Aec1Aec2.C3−/− mice retained some early pathological manifestations, including activation of serine kinases with proteolytic activity for parotid secretory protein. This improvement in the clinical manifestations of SjS-like disease in C57BL/6.NOD-Aec1Aec2.C3−/− mice, apparently a direct consequence of C3 deficiency, supports a much more important role for complement in the adaptive autoimmune response than previously recognized, possibly implicating an essential role for innate immunity.

“…Interestingly, both NOD.IL4 Ϫ/Ϫ and NOD.B10-H2 b .IL4 Ϫ/Ϫ mice failed to produce M3R autoantibodies of the IgG1 isotype (19,20). IL-4 is a pleiotropic cytokine involved in cell proliferation, activation, and differentiation (21).…”

mentioning

confidence: 99%

IL-4-STAT6 Signal Transduction-Dependent Induction of the Clinical Phase of Sjögren’s Syndrome-Like Disease of the Nonobese Diabetic Mouse

The Journal of Immunology

Gao

Kim

et al. 2007

NOD.B10-H2b and NOD/LtJ mice manifest, respectively, many features of primary and secondary Sjögren’s syndrome (SjS), an autoimmune disease affecting primarily the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes). B lymphocytes play a central role in the onset of SjS with clinical manifestations dependent on the appearance of autoantibodies reactive to multiple components of acinar cells. Previous studies with NOD.IL4−/− and NOD.B10-H2b.IL4−/− mice suggest that the Th2 cytokine, IL-4, plays a vital role in the development and onset of SjS-like disease in the NOD mouse model. To investigate the molecular mechanisms by which IL-4 controls SjS development, a Stat6 gene knockout mouse, NOD.B10-H2b.C-Stat6−/−, was constructed and its disease profile was defined and compared with that of NOD.B10-H2b.C-Stat6+/+ mice. As the NOD.B10-H2b.C-Stat6−/− mice aged from 4 to 24 wk, they exhibited leukocyte infiltration of the exocrine glands, produced anti-nuclear autoantibodies, and showed loss and gain of saliva-associated proteolytic enzymes, similar to NOD.B10-H2b.C-Stat6+/+ mice. In contrast, NOD.B10-H2b.C-Stat6−/− mice failed to develop glandular dysfunction, maintaining normal saliva flow rates. NOD.B10-H2b.C-Stat6−/− mice were found to lack IgG1 isotype-specific anti-muscarinic acetylcholine type-3 receptor autoantibodies. Furthermore, the IgG fractions from NOD.B10-H2b.C-Stat6−/− sera were unable to induce glandular dysfunction when injected into naive recipient C57BL/6 mice. NOD.B10-H2b.C-Stat6−/− mice, like NOD.B10-H2b.IL4−/− mice, are unable to synthesize IgG1 Abs, an observation that correlates with an inability to develop end-stage clinical SjS-like disease. These data imply a requirement for the IL-4/STAT6-pathway for onset of the clinical phase of SjS-like disease in the NOD mouse model.