Pore formation by beta-2-microglobulin: a mechanism for the pathogenesis of dialysis associated amyloidosis

Beta-2 microglobulin (beta 2M, molecular weight 10,000) is a 99 residue imm une system protein which is part of the MHC Class I complex whose role is t o present antigens to T cells. beta 2M serum levels rise dramatically in re nal failure, and a syndrome called " dialysis associated amyloidosis " occu rs with time in a majority of hemodialysis patients who exhibit beta 2M amy loid deposits in joints, bone and other organs(1). beta 2M can also induce Ca++ efflux from calvariae, collagenase production, and bone resportion(2-1 ). We report here that beta 2M formed relatively nonselective, long-lived, voltage independent ion channels in planar phospholipid bilayer membranes a t physiologically relevant concentrations. The channels were inhibited by C ongo red and blocked by zinc suggesting that they exist in an aggregated be ta sheet stale as is common with other amyloid fibril forming peptides. Mul tiple single channel conductances were seen suggesting that various oligome rs of beta 2M may be capable of forming channel structures. We suggest that beta 2M channel formation may account for some of the pathophysiologic eff ects seen in dialysis associated amyloidosis. These findings lend further w eight to the "channel hypothesis" of amyloid pathogenesis.