IL-12 overexpression in mice as a model for Sjögren lung disease

Abstract

Interleukin-12 (IL-12), a Th1 proinflammatory cytokine, is reported to be increased in Sjögren syndrome. To evaluate the effects of local Th1/Th2 deregulation, we generated a transgenic mouse model that overexpresses IL-12 in the lungs. IL-12 transgenic mice developed bronchial and alveolar abnormalities strikingly similar to those found in the lungs of Sjögren patients. Pathologically, lung abnormalities began at approximately 4 mo of age and were characterized by lymphocytic infiltrates around the bronchi, intraluminal periodic acid Schiff-positive debris, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages. Functionally, these abnormalities translated into decreased mucociliary clearance (P<0.05 vs. wild-type littermates) and increased oxidative stress (P<0.01). The pathological and functional abnormalities were accompanied by significant changes in lung natural killer (NK) cells. The number of NK cells was fourfold higher in IL-12 transgenic than wild-type lungs (20% of all lymphoid cells vs. 5%) during the first month of life. NK cells then decreased within a narrow window of time (from 30 to 50 days of age), reaching a nadir of approximately 2% on day 50, and remained at these low levels thereafter. This new mouse model highlights the role of IL-12 in the initiation of Sjögren syndrome.

Spontaneous Autoimmune Dacryoadenitis in Aged CD25KO Mice

“…8 Additionally, a recent study characterizing a transgenic mouse model of SS overexpressing IL-12, the chief stimulator of the Th-1 axis and subsequent IFN-␥ production, detected focal lymphocytic infiltration of the salivary glands, LG, and the lungs, mimicking a SS phenotype. 48 Levels of IL-12, its receptor, IL-RB1, and the Th-1 lineage specific transcription factor, T-bet, were all significantly increased in our animal model of SS when compared with C57BL/6 mice. Another Th-1-related cytokine, IL-2, was found to be significantly higher in CD25KO than C57BL/6 mice.…”

Pulmonary Manifestations of Sjögren’s Syndrome

“…This inflammatory infiltrate causes bronchial hyperreactivity (18) manifested by dry cough, recurrent “bronchitis” and dyspnea (3). The overexpression of IL-12 in the lungs of mice resulted in bronchial and alveolar abnormalities strikingly similar to those found in the lungs of SS patients with lymphocytic infiltrates around the bronchi, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages leading to decreased mucociliary clearance and increased oxidative stress (20). The role played by IL-12 and other cytokines in the evolution of SS lung disease remains to be elucidated.…”

“…PFTs classically show restrictive disease and the diffusing capacity (DL CO ) appears to be the most sensitive test (19). The clinical course and prognosis for most patients with isolated follicular bronchiolitis is relatively good, and progressive lung disease is uncommon (20). …”

Pulmonary Extramedullary Hematopoiesis

“…Given the purported role of cytokines in the development of EMH and overexpression of interleukin-12 in models of Sjo¨gren-induced lung disease, our patient's P-EMH may in fact be related to the underlying Sjo¨gren syndrome. 1,20,21 She demonstrated clinical improvement in oxygen requirement, dyspnea, and ESR after increasing the dose of azathioprine aimed at treating the Sjo¨gren syndrome. This potential relationship between Sjo¨gren syndrome and P-EMH is certainly intriguing though not proven.…”