To the Editor:

We thank Drs. Airoldi, Di Carlo, and Pistoia for their interesting comments. We described a model of SS that was established by increasing IL-12 signaling, whereas Dr. Airoldi and colleagues established a similar phenotype by abolishing IL-12 signaling (1). How can these observations be reconciled? First, apparent paradoxical effects are not uncommon in cytokine biology, especially in complex disorders like autoimmune diseases. For example, increased interferon-γ (IFNγ) signaling has been shown to induce type 1 diabetes mellitus (2), but at the same time increased IFNγ signaling could also suppress diabetes (3). It appears likely that both cellular and humoral immune responses contribute to disease pathogenesis, and these responses can yield completely different phenotypic outcomes when the same cytokine is increased or decreased. Second, it is important to note that the 2 animal models of SS are not identical. For example, the Il-12rb2–KO mice used by Airoldi et al (1) do not develop anti-SSA/Ro or anti-SSB/La antibodies, a key component of human SS that was also manifested in our IL-12–transgenic mice. The pathogenic role of these 2 autoantibodies remains to be established, but it is known that immunization of mice with a Ro peptide recapitulates many signs and symptoms of SS (4), associated with increased IL-12 expression in the salivary glands (Yin H, et al: unpublished observations). Finally, we completely agree with the conclusion that SS may comprise different pathogenetic entities leading to shared clinical manifestations.

Jelle L. Vosters MD* **, Melissa A. Landek-Salgado BA†, Hiroaki Kimura PhD†, Paul P. Tak MD, PhD‡, Patrizio Caturegli MD, MPH§, Hongen Yin MD, PhD¶, William D. Swaim PhD¶, John A. Chiorini PhD¶, * National Institutes of Health, Bethesda, MD, † Johns Hopkins School of Medicine, Baltimore, MD, ‡ University of Amsterdam, Amsterdam, The Netherlands, § Johns Hopkins School of Medicine and Johns Hopkins School of Public Health, Baltimore, MD, ¶ National Institutes of Health, Bethesda, MD, ** University of Amsterdam, Amsterdam, The Netherlands.