Further studies of the biochemical basis of paroxysmal nocturnal hemoglobinuria (PNH) have been performed in collaboration with Dr. Hans Muller-Eberhard and the group at Scripps Clinic. Earlier work had shown that these erythrocytes are missing a complement regulatory protein, DAF, but that the precursors of PNH cells have this protein on their surface. Work this year has demonstrated that a second protein that regulates complement activation termed homologous restriction protein (HRP) is missing from PNH erythrocytes. Recently, this protein has been shown to prevent the insertion of the membrane attack complex formed by complement activation to the surface of cells. Thus the fact that this protein is missing explains the exquisite sensitivity of these cells to complement mediated lysis. In vivo and in vitro studies of deposition of complement components on erythrocytes have been performed using both guinea pig and human materials. In the guinea pig it has been shown that there are marked differences in the numbers of components deposited by IgM and IgG antibody with IgM producing far more complement deposition on a guinea pig erythrocyte surface. The fragment of complement, also present on the surface, has been shown to be C3bi rather than C3b. In the human system but not in the guinea pig system, C3b was converted to C3d. In both systems, the C3 was shed rather rapidly from the red cell; an unexpected finding. These studies are being performed to determine what happens when red cells are injected into the circulation of human beings. Bacteria will undergo much the same processing, however, they are very difficult to study because their surfaces are complex and activate multiple pathways of complement activation. The importance of these studies is emphasized by the findings with Dr. Quinn that the clearance of complement coated red cells in patients with AIDS are distinctly abnormal, with the patients unable to remove the usual number of the cells from the circulation by phagocytosis once the binding reaction has occurred on the surface of the phagocyte. Thus, in the long run, discovering the events that take place during these pathophysiologic processes will help us understand the nature of the frequent infections that occur in this patient group.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
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