Regulation of the alternative pathway of complement modulates injury and immunity in a chronic model of dextran sulphate sodium-induced colitis.

Abstract

The role of complement in inflammatory bowel disease (IBD) has been studied primarily using acute models, and it is unclear how complement affects processes in more relevant chronic models of IBD in which modulation of adaptive immunity and development of fibrosis have pathogenic roles. Using mice deficient in C1q/mannose-binding lectin (MBL) or C3, we demonstrated an important role for these opsonins and/or the classical pathway C3 convertase in providing protection against mucosal injury and infection in a model of chronic dextran sulphate sodium (DSS)-induced colitis. In contrast, deficiency of the alternative pathway (fB(-/-) mice) had significantly less impact on injury profiles. Consequently, the effect of a targeted inhibitor of the alternative pathway was investigated in a therapeutic protocol. Following the establishment of colitis, mice were treated with CR2-fH during subsequent periods of DSS treatment and acute injury (modelling relapse). CR2-fH significantly reduced complement activation, inflammation and injury in the colon, and additionally reduced fibrosis. Alternative pathway inhibition also altered the immune response in the chronic state in terms of reducing numbers of B cells, macrophages and mature dendritic cells in the lamina propria. This study indicates an important role for the alternative pathway of complement in the pathogenesis and the shaping of an immune response in chronic DSS-induced colitis, and supports further investigation into the use of targeted alternative pathway inhibition for the treatment of IBD.

• Authors: M Elvington, J Schepp-Berglind, S Tomlinson
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 179 Issue 3 Pg. 500-8 (Mar 2015) ISSN: 1365-2249 [Electronic] England
• PMID: 25293413 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 British Society for Immunology.

Chemical References

• CR2-fH protein
• Complement C3
• Complement Inactivating Agents
• Mannose-Binding Lectin
• Receptors, Complement 3d
• Recombinant Fusion Proteins
• Complement Factor H
• Dextran Sulfate

Topics

• Animals
• Chronic Disease
• Colitis (chemically induced, drug therapy, immunology)
• Complement C3 (genetics)
• Complement Factor H (genetics)
• Complement Inactivating Agents (administration & dosage)
• Complement Pathway, Alternative (drug effects, genetics)
• Dextran Sulfate (administration & dosage)
• Disease Models, Animal
• Female
• Humans
• Immunity, Mucosal (drug effects, genetics)
• Intestines (drug effects, immunology)
• Mannose-Binding Lectin (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Targeted Therapy
• Receptors, Complement 3d (genetics)
• Recombinant Fusion Proteins (administration & dosage, genetics)