Complement regulation and diseases caused by regulatory defects
THE CONTEXT
Complement regulators protect normal host tissues by limiting active complement fragments and removing deposited fragments. Failure of this protection can cause tissue injury.
Protection of host tissues
•
Regulators expressed on normal host cells prevent healthy tissues from being injured where complement is activated.
•
Large amounts of complement deposition can overwhelm these regulators, as in autoimmune diseases involving complement-fixing antibodies against the individual's own cells and tissues.
C1 inhibitor
•
C1 inhibitor blocks activation of C1, the first protein of the classical complement pathway.
DAF, CD59, and paroxysmal nocturnal hemoglobinuria
•
Decay accelerating factor (DAF) and CD59 are attached to plasma membranes through glycophosphatidylinositol (GPI*) anchors.
•
DAF prevents formation of C3 convertases, whereas CD59 inhibits formation of the membrane attack complex.
•
An acquired deficiency of the enzyme responsible for creating GPI anchors causes loss of these regulators, excessive complement activation, and red-cell lysis.
•
This process gives rise to paroxysmal nocturnal hemoglobinuria (PNH); red cells are sensitive to complement-mediated lysis.
Factor H
•
Factor H is a plasma protein that promotes inactivation of C3 convertase. Its deficiency results in excessive complement activation.
•
Factor H mutations are associated with hemolytic uremic syndrome and wet macular degeneration.
•
Wet macular degeneration is characterized by increased permeability of retinal vessels.