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

¹Department of Pediatrics and ²Department of Pathology, The Johns Hopkins School of Medicine; and ³Department of Molecular Microbiology and Immunology, The Johns Hopkins School of Public Health, Baltimore, Maryland

Submitted 11 April 2006 ; accepted in final form 19 May 2006

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 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 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.

autoimmunity; transgenic mice; inflammation; natural killer cells

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