Protection of human nasal respiratory epithelium from complement-mediated lysis by cell-membrane regulators of complement activation.

Abstract

Complement in the respiratory tract protects the host from invading micoorganisms and other inhaled insults, but may damage normal tissue. Recently we reported that human respiratory epithelium from the nose to the alveoli expresses three cell-membrane regulators of complement activation: membrane cofactor protein (MCP, CD46), decay accelerating factor (DAF; CD55), and CD59. In this study we investigated whether two of these complement-regulatory proteins, DAF and CD59, protect human nasal epithelial cells from complement-mediated lysis. Treatment of nasal epithelial cells in suspension with 50% or 100% normal human serum (NHS) lysed small percentages of cells (8% and 16%, respectively). Addition of complement activators, rabbit serum antinasal epithelial cells (anti-NEC), or lipopolysaccharide (LPS) increased cell lysis in the presence of 50% NHS in a dose-dependent manner up to 50% and 35% lysis, respectively. Human serum deficient in C3 or C7 did not lyse nasal epithelial cells even in the presence of anti-NEC. To assay the contribution of DAF and CD59 to cell protection against lysis, nasal epithelial cells in suspension were treated with appropriate blocking antibodies. Both anti-DAF and anti-CD59 markedly increased the susceptibility of human nasal epithelial cells to lysis by complement. At 50% NHS, anti-DAF and anti-CD59 antibodies increased epithelial cell lysis from 8% to 24% and 67%, respectively. A similar pattern of response to complement was demonstrated by monolayers of substrate-anchored cultured cells. These results indicate that DAF and CD59 protect human nasal epithelial cells from complement-mediated lysis; however, intense activation of complement may overcome this protection, leading to cell death and tissue injury. We speculate that imbalance between complement regulation and complement activation in the human respiratory tract in disease may result in tissue injury and impaired tissue function.

Generation of complement C3 and expression of cell membrane complement inhibitory proteins by human bronchial epithelium cell line

“…These cell membrane CIP molecules are expressed in healthy subjects and their expression is increased in various lung diseases characterised by inflammation or malignant transformation12 and also in human lung cancer cell lines, both unstimulated and stimulated with proinflammatory cytokines 1314 We also found that these molecules are essential for protecting cultured human nasal respiratory epithelial cells from being lysed by human serum complement 15…”

Expression of Complement Factor H by Lung Cancer Cells

“…Additionally, lung tumors show minimal deposition of C3b and no activation of the lytic membrane attack complex. In vitro studies have confirmed that lung cancer cell lines are extremely resistant to complement-mediated lysis, and this resistance is much higher than that observed in normal cells such as human nasal epithelium primary cell cultures (5,39). Besides, lung cancer cell lines have the ability of limiting the activation of complement in their cell membrane and express high levels of cell membrane complement inhibitory proteins (5).…”

“…For these reasons, it was suggested that membrane-associated complement regulatory proteins may act as mediators of lung cancer resistance to complement activation (38). However, neutralizing antibodies against CD46 and CD59 are not effective in increasing the susceptibility to complementmediated lysis (5), whereas the same antibodies are very effective in facilitating complement-mediated lysis of noncancer nasal epithelial cells (39). This suggests the existence of alternative mechanisms that would explain the resistance to complement activation in lung cancer.…”

The Role of Complement in the Diagnosis and Management of Allergic Rhinitis and Allergic Asthma

“…C3aR, expressed in healthy epithelial cells, submucosal glands, and nerves, is additionally expressed in the endothelium of surrounding sinuses and muscle layers in severe, persistent AR [21]. The nasal and respiratory tract epithelia express complement regulatory molecules such as membrane cofactor protein (CD46), decay-accelerating factor (DAF, CD55), and CD59 [22,23], suggesting complement activation is tightly controlled in the nasal mucosa. However, it is not known if or how such cellular complement regulators are modulated during allergy.…”