A novel dendritic cell (DC)-

Objective. The major human Fc receptor, Fc␥RIIa, is the most widespread activating FcR. Our aim was to determine the role of Fc␥RIIa in a transgenic mouse model of immune complex-mediated autoimmunity and to characterize the development of spontaneous autoimmune disease. Methods. Arthritis was induced in normal and

The healthy lung maintains a steady state of immune readiness to rapidly respond to injury from invaders. Integrins are important for setting the parameters of this resting state, particularly the epithelial-restricted αVβ6 integrin, which is upregulated during injury. Once expressed, αVβ6 moderates acute lung injury (ALI) through as yet undefined molecular mechanisms. We show that the upregulation of β6 during influenza infection is involved in disease pathogenesis. β6-deficient mice (β6 KO) have increased survival during influenza infection likely due to the limited viral spread into the alveolar spaces leading to reduced ALI. Although the β6 KO have morphologically normal lungs, they harbor constitutively activated lung CD11b+ alveolar macrophages (AM) and elevated type I IFN signaling activity, which we traced to the loss of β6-activated transforming growth factor-β (TGF-β). Administration of exogenous TGF-β to β6 KO mice leads to reduced numbers of CD11b+ AMs, decreased type I IFN signaling activity and loss of the protective phenotype during influenza infection. Protection extended to other respiratory pathogens such as Sendai virus and bacterial pneumonia. Our studies demonstrate that the loss of one epithelial protein, αVβ6 integrin, can alter the lung microenvironment during both homeostasis and respiratory infection leading to reduced lung injury and improved survival.

Many adhesion molecule pathways have been invoked as mediating leukocyte recruitment during immune complex-induced inflammation. However the individual roles of these molecules have not been identified via direct visualization of an affected microvasculature. Therefore, to identify the specific adhesion molecules responsible for leukocyte rolling and adhesion in immune complex-dependent inflammation we used intravital microscopy to examine postcapillary venules in the mouse cremaster muscle. Wild-type mice underwent an intrascrotal reverse-passive Arthus model of immune complex-dependent inflammation and subsequently, leukocyte-endothelial cell interactions and P- and E-selectin expression were assessed in cremasteric postcapillary venules. At 4 hours, the reverse-passive Arthus response induced a significant reduction in leukocyte rolling velocity and significant increases in adhesion and emigration. P-selectin expression was increased above constitutive levels whereas E-selectin showed a transient induction of expression peaking between 2.5 to 4 hours and declining thereafter. While E-selectin was expressed, rolling could only be eliminated by combined blockade of P- and E-selectin. However, by 8 hours, all rolling was P-selectin-dependent. In contrast, inhibition of vascular cell adhesion molecule-1 had a minimal effect on leukocyte rolling, but significantly reduced both adhesion and emigration. These observations demonstrate that immune complex-mediated leukocyte recruitment in the cremaster muscle involves overlapping roles for the endothelial selectins and vascular cell adhesion molecule-1.