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A WAR WITH THE MOLECULES: LOUIS PILLEMER AND THE HISTORY OF PROPERDIN* WILLIAM DAVIS RATNOFFt The history of the evolution of knowledge concerning properdin is as much the story of the personalities of the investigators as it is of scientific controversy. Properdin is a component of the complement system, a group of 1 1 plasma proteins, vital to immunologic host defense, designated C1-C9 (Cl being composed of 3 proteins) in the order of discovery. These proteins mediate inflammation through alteration of cell membranes, enhancement of phagocytosis by opsonization and Chemotaxis, increased capillary permeability, and lysis of foreign cells. In disease, complement may damage the host. Some animal and human genetic deficiencies of complement components cause clinically detectable derangements in immunity. Complement proteins, or components, participate sequentially. The classic pathway of activation begins upon contact of these proteins with aggregated immunoglobulins or antigen-antibody complexes. This causes the components to react in the order Cl, C4, C2, C3, then C5 through C9. These proteins circulate as inert precursors. When the first component becomes activated, it assumes enzymatic properties that lead to activation of the next component, and so on until the last component is activated. When activated, the terminal components, beginning with C3, acquire the observed immunologic properties and thus bring about biologically important phenomena. *Adapted from the 1974 Leonard J. Siff Prize baccalaureate thesis, the Department of the History of Science, Harvard University. This essay was submitted to the second Perspectives Writing Award Contest for Authors under 35. I am grateful to Mrs. Jean Burrell Pillemer, Dr. Lester Adelson, Dr. Michael Heidelberger, Dr. Hans Hirschmann, Dr. Simon Koletsky, Dr. Myron A. Leon, Dr. Irwin H. Lepow, Dr. Manfred M. Mayer, Dr. Alan R. Moritz, Dr. Hans J. Müller-Eberhard, Dr. George B. Naff, Dr. Robert A. Nelson, Jr., Dr. Jack Pensky, Dr. Herbert J. Rapp, Dr. Fred S. Rosen, Dr. Abram B. Stavitsky, Mr. Earl W. Todd, and the late Dr. Douglas D. Bond, who allowed me to interview them in person or by letter and provided advice and unpublished information. I greatly appreciate the helpful advice of Prof. Alwin M. Pappenheimer, Jr.; I am deeply indebted to Dr.Joan Cadden and Prof. John T. Edsall for guidance and encouragement, and to Mr. Todd for inspiration. !Department of Medicine, University Hospitals of Cleveland, Cleveland, Ohio 44106.© 1980 by The University of Chicago. 0031-5982/80/2304-0138$01.00 638 I William Davis Ratnoff · Louis Pillemer and the History ofProperdin The terminal components can be activated without immunoglobulin. This alternative (or properdin) pathway is initiated by contact with several lipopolysaccharides, including endotoxin. Alternative-pathway proteins activate C3 and the terminal components without participation of Cl, C4, or C2. The physiologic role of the properdin system is incompletely understood, but it may be important early during infection, before antibody can be produced, in gram-negative sepsis and endotoxic shock, and possibly in the immunologically naive animal, such as the fetus. Genetic deficiencies of the properdin system, comparable to those of the classic pathway, have been described. The biochemistry of steps immediately preceding C3 activation has been established, but the mechanism of initiation remains elusive. In contrast, initiation of the classic pathway and the mechanism of cell lysis are understood in molecular terms. How our current ideas about properdin developed is a story of discovery , initial acceptance and subsequent controversy, rejection, and oblivion, followed by rediscovery and reacceptance years later. Reviews and original scientific papers muted the existence of emotional controversy about properdin. Consequently, oral and written accounts, obtained in letters and interviews with investigators involved in the original work and controversy or in the rediscovery, were necessary to elucidate the story. Louis Pillemer Louis Pillemer, who discovered properdin, was born in Johannesburg in 1908 but was raised in the small Kentucky town of Catlettsburg, where other children made fun of him because of his stutter and obesity [1-3]. In adolescence, however, he became tall and strong and played football as a formidable tackle. Scouring the Kentucky hills, a scout discovered Pillemer and enticed him with a scholarship to play football for Ohio State University [I]; Pillemer failed academically after the first term [3]. A college in West Virginia...


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