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Anti-KC Autoantibody:KC Complexes Cause Severe Lung Inflammation in Mice via IgG Receptors

¹ Department of Biochemistry, University of Texas Health Center, Tyler, Texas; ² Cardiovascular Research Group, Division of Clinical Sciences (North), Sheffield University, United Kingdom; ³ Section of Pulmonary and Critical Care Medicine, Harborview Medical Center, and ⁴ Medical Research Service, Seattle VA Medical Center, Seattle, Washington

Correspondence and requests for reprints should be addressed to Anna K. Kurdowska, Ph.D., Department of Biochemistry, University of Texas Health Center, 11937 US Highway 271, Tyler, TX 75708-3154. E-mail: anna.kurdowska{at}uthct.edu.

We have shown previously that high concentrations of IL-8 associated with anti-IL-8 autoantibodies (anti–IL-8:IL-8 complexes) are present in lung fluids from patients with the acute respiratory distress syndrome (ARDS), and correlate both with the development and outcome of ARDS. We also detected deposition of these complexes in lung tissues from patients with ARDS but not in control tissues. Moreover, we determined that IgG receptors (FcRs) mediate activity of anti–IL-8:IL-8 complexes. In the current study, we generated anti-KC (KC = chemokine (CXC motif) ligand 1 (CXCL1)) autoantibody:KC immune complexes (KC–functional IL-8) in lungs of mice to develop a mouse model of autoimmune complex–induced lung inflammation. Both wild-type (WT) and -chain–deficient mice that lack receptors for immune complexes (FcRs) were studied. First, the mice were immunized with KC to induce anti-KC autoantibodies. Then, KC was administered intratracheally to generate anti-KC:KC complexes in the lung. Presence of anti-KC:KC complexes was associated with development of severe pulmonary inflammation that was, however, dramatically suppressed in -chain–deficient mice. Second, because sepsis is considered the major risk factor for development of ARDS, we evaluated LPS-treated WT as well as -chain–deficient mice for the presence of anti-KC:KC complexes and pulmonary inflammatory responses. We detected complexes between anti-KC autoantibodies and KC in lung lavages and tissues of mice treated with LPS. Moreover, -chain–deficient mice that lack receptors for immune complexes were protected from LPS-induced pulmonary inflammation. Our results suggest that immune complexes containing autoantibodies contribute to development of lung inflammation in LPS-treated mice.

Key Words: chemokine • autoantibody • immune complex • endotoxin • lung

CLINICAL RELEVANCE Our model of anti-KC:KC-induced lung inflammation can be used for testing new therapies. The observation that these complexes contribute to development of lung inflammation in LPS-treated mice is novel, and may aid in understanding the pathology of acute lung injury.

 

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