The Complement System 
John P. Atkinson, M.D. — Investigator 
Dr. Atkinson is also Professor of Medicine and of Microbiology and Immunology at Washington University 
School of Medicine and Physician at Barnes Hospital, St. louts. He received his B.A. degree in zoology 
and his M.D. degree from the University of Kansas. His training in internal medicine was at Massachusetts 
General Hospital, Boston, and at the NIH. His postdoctoral research training was at the NIH and Wash- 
ington University. 
MANY poorly understood but relatively com- 
mon and serious human diseases involve 
aberrations of the immune system. 
The function of the immune system is to recog- 
nize microorganisms and eliminate them from 
the host. A major means of accomplishing this is 
through the synthesis of antibodies and comple- 
ment components that attach to the foreign sub- 
stance. These proteins circulate in blood and are 
either formed in response to the organism (anti- 
bodies) or present at all times (complement) . 
The work in this laboratory centers on the com- 
plement system. Complement consists of pro- 
teins that interact with each other in a reaction 
resembling a cascade or waterfall: one activates 
the next. The activated molecules that result 
from this destroy the invading microbe and pro- 
mote the inflammatory response. The comple- 
ment system is a powerful, swift, and highly ef- 
fective means to fight infection. As might be 
anticipated, an inherited deficiency of a comple- 
ment component predisposes an individual to 
infections. 
The production of antibodies is triggered by 
the invasion of the body by a foreign substance. 
The binding of antibodies to a target such as a 
bacterium initiates a series of reactions in which 
complement proteins swarm onto the surface of 
the microbe. Such components serve as a ligand 
for complement receptors on blood cells. A for- 
eign particle soon becomes adherent to and then 
ingested by these blood cells. During comple- 
ment activation, small fragments (peptides) that 
promote the inflammatory response are liberated 
from the complement proteins. These molecules 
dilate blood vessels and summon scavenger cells, 
called phagocytes, from the bloodstream. The 
phagocytic white blood cells, upon arrival at the 
site, find organisms that are already prepared for 
ingestion, because they are coated with antibody 
and complement. This phenomenon is known as 
opsonization (from the Greek word opsonein, to 
prepare for the table). As a result, the infection is 
sequestered and eliminated via phagocytosis. 
Sometimes, however, the immune system, in- 
stead of synthesizing antibodies to foreign mate- 
rials, seemingly makes a mistake and produces 
antibodies that react with its own cells. For exam- 
ple, in certain immune disorders, the individual 
makes antibodies to his or her own red blood 
cells. Antibody and complement then attach to 
the red blood cells and destroy them. Such condi- 
tions are known as autoimmune diseases, in this 
case autoimmune hemolytic anemia. 
In other pathologic conditions, the immune 
system does not efficiently eliminate the in- 
fectious particles, and excessive quantities of im- 
mune complexes form. Immune complexes con- 
sist of antibodies, complement proteins, and the 
foreign particle. These immune complexes are 
proinflammatory and cause tissue damage if de- 
posited in undesirable locations such as joints, 
skin, and kidney, leading to arthritis, dermatitis, 
and glomerulonephritis, respectively. 
Thus there are two general ways in which the 
humoral immune system can damage its own tis- 
sue. The first is to produce antibodies to self com- 
ponents. The second is to form excessive 
amounts of immune complexes. 
Our goal is to understand how immune com- 
plexes form and are processed. We are studying a 
biologic mechanism that evolved to remove im- 
mune complexes from the circulation. This pro- 
cess helps prevent the pathologic accumulation 
of these complexes in tissue. This system can be 
likened to an "inner space shuttle." The physio- 
logic vehicle for this journey is the red blood 
cell. The red blood cell participates in this reac- 
tion through a complement receptor protein on 
its surface. These receptor proteins latch onto 
complement-coated foreign particles, such as vi- 
ruses and bacteria. As the circulating red blood 
cell passes through the liver or spleen, its im- 
mune cargo is released and metabolized. The red 
blood cell then returns to the circulation ready to 
ferry another load. 
Our laboratory is studying the complement re- 
ceptor involved in this process. We are also exam- 
ining the complement proteins that swarm onto 
the foreign panicles. Furthermore, we are inves- 
tigating certain "housekeeping" proteins of the 
complement system. Because of the powerful de- 
structive capabilities of the complement system, 
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