The Complement System 
John P. Atkinson, M.D. — Investigator 
Dr. Atkinson is also Professor of Medicine and of Molecular Microbiology at Washington University School 
of Medicine and Physician at Barnes Hospital, St. Louis. He received his B.A. degree in zoology and M.D. 
degree from the University of Kansas. His training in internal medicine was at Massachusetts General 
Hospital, Boston, and at NIH. He conducted postdoctoral research at NIH and Washington University. 
MANY poorly understood but relatively com- 
mon and serious human diseases involve 
aberrations of the immune system. Such condi- 
tions range from mild forms of arthritis to life- 
threatening autoimmune illnesses such as sys- 
temic lupus erythematosus. 
The immune system provides a powerful ar- 
senal of proteins to attack and eliminate infecting 
microorganisms. A major means of accomplishing 
this task is through the special biologic partner- 
ship of antibodies and complement. Proteins 
from these two systems 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. Its name is derived from its func- 
tion of "assisting" antibody in immune reactions. 
However, we now know that the complement 
system also serves as an independent immune sys- 
tem capable of attacking foreign elements by it- 
self. This first-line defense appears to have oc- 
curred early in evolution, preceding antibody. 
The complement system consists of at least 30 
proteins that interact with each other in reactions 
resembling a cascade or waterfall. The activated 
molecules that result from this scheme destroy 
the invading microbe and promote the inflamma- 
tory response. The complement system is a pow- 
erful, swift, and highly effective means to fight 
infectious organisms. As might be anticipated, an 
inherited deficiency of a complement compo- 
nent predisposes an individual to infections. 
The production of antibodies is triggered when 
foreign substances invade the body. Although 
complement independently attacks the patho- 
gen, the binding of antibodies to a target such as a 
bacterium initiates and potentiates a series of re- 
actions in which complement proteins swarm 
onto the surface of the microbe. Such compo- 
nents serve as ligands for complement receptors 
on blood cells. A foreign particle so coated 
quickly becomes adherent to and is ingested by 
these blood cells. During complement activa- 
tion, 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 phago- 
cytic white blood cells, upon arrival at the site, 
find organisms that are already prepared for in- 
gestion; i.e., they are coated with antibody and 
complement. This phenomenon is known as op- 
sonization (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, individuals 
make antibodies to their own red blood cells. An- 
tibody and complement then attach to the red 
blood cells and destroy them. Such conditions are 
known as autoimmune diseases, in this case au- 
toimmune 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. This leads to arthritis, dermati- 
tis, 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- 
components. 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- 
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