Pathogenic natural antibodies recognizing annexin IV are required to develop intestinal ischemia-reperfusion injury.

Intestinal ischemia-reperfusion (IR) injury is initiated when natural IgM Abs recognize neo-epitopes that are revealed on ischemic cells. The target molecules and mechanisms whereby these neo-epitopes become accessible to recognition are not well understood. Proposing that isolated intestinal epithelial cells (IEC) may carry IR-related neo-epitopes, we used in vitro IEC binding assays to screen hybridomas created from B cells of unmanipulated wild-type C57BL/6 mice. We identified a novel IgM mAb (mAb B4) that reacted with the surface of IEC by flow cytometric analysis and was alone capable of causing complement activation, neutrophil recruitment and intestinal injury in otherwise IR-resistant Rag1(-/-) mice. mAb B4 was found to specifically recognize mouse annexin IV. Preinjection of recombinant annexin IV blocked IR injury in wild-type C57BL/6 mice, demonstrating the requirement for recognition of this protein to develop IR injury in the context of a complex natural Ab repertoire. Humans were also found to exhibit IgM natural Abs that recognize annexin IV. These data in toto identify annexin IV as a key ischemia-related target Ag that is recognized by natural Abs in a pathologic process required in vivo to develop intestinal IR injury.

Effect of topical ciprofloxacin/dexamethasone or dexamethasone alone on acute Streptococcus pneumoniae rhinosinusitis in mice.

OBJECTIVE: To test whether intranasal ciprofloxacin/dexamethasone or dexamethasone alone affects the course of acute bacterial rhinosinusitis in mice. STUDY DESIGN: We performed a randomized, double-blind, parallel, placebo-controlled study in mice. SUBJECTS AND METHODS: Three groups of 10 C57Bl/6 mice were infected with Streptococcus pneumoniae, and then 1 day later randomized to treatment with placebo, ciprofloxacin plus dexamethasone, or dexamethasone. The mice were killed 3 or 10 days after treatment was begun. RESULTS: The placebo-treated mice became infected and developed an inflammatory cell infiltration in their sinuses. None of the treatments significantly affected the course of the illness. CONCLUSION: The lack of topical, intranasal efficacy of ciprofloxacin and dexamethasone could be attributed to subpotent dosage, rapid nasal clearance, or inability of the drops to reach the site of infection. Treatment with dexamethasone neither improved nor worsened the bacterial infection.

Distinct and separable roles of the complement system in factor H-deficient bone marrow chimeric mice with immune complex disease.

Plasma complement factor H (Cfh) is a potent complement regulator, whereas Cfh on the surface of rodent platelets is responsible for immune complex processing. For dissection between the two, bone marrow chimeras between Cfh-deficient (Cfh(-/-)) and wild-type C57BL/6 mice were created. Platelet Cfh protein was tracked with the Cfh status of the bone marrow donor, indicating that platelet Cfh is of intrinsic origin. In an active model of immune complex disease, Cfh(-/-) mice that were reconstituted with wild-type bone marrow had levels of platelet-associated immune complexes comparable to those of wild-type mice and were protected against the excessive glomerular deposition of immune complexes seen in Cfh(-/-) mice, yet these mice still developed glomerular inflammation. In contrast, wild-type mice with Cfh(-/-) bone marrow had reduced platelet-associated immune complexes and extensive glomerular deposition of complement-activating immune complexes, but they did not develop glomerular pathology. The large quantities of glomerular C3 in wild-type mice with Cfh(-/-) bone marrow were in the form of iC3b and C3dg, whereas active C3b remained in Cfh(-/-) recipients of wild-type bone marrow. These data show that plasma Cfh limits complement activation in the circulation and other accessible sites such as the glomerulus, whereas platelet Cfh is responsible for immune complex processing.