Mechanisms of Immunological Self-Tolerance 
and Autoimmunity 
Christopher C. Goodnow, B.V.Sc, Ph.D. — Assistant Investigator 
Dr. Goodnow is also Assistant Professor of Microbiology and Immunology at Stanford University School of 
Medicine. He was educated in the United States and Australia and received B.S. and veterinary degrees 
from the University of Sydney. After training in molecular immunology with Mark Davis at Stanford 
University, he returned to the University of Sydney to complete doctoral and postdoctoral studies 
on immunological tolerance in the laboratory of Antony Basten. 
EACH individual B and T lymphocyte in the 
immune system expresses antigen receptors 
of one type on its surface, which confer on the 
cell an ability to recognize one of the millions of 
different antigens; and there are millions of dif- 
ferent lymphocytes in the immune system. Given 
the system's annihilative powers, it is remarkable 
that tissue components of our own bodies are 
spared during immunological attacks on invading 
foreign organisms. Normally the immune system 
can recognize one's tissue components as "self" 
and tolerate them. Self-tolerance is lost, however, 
in a variety of "autoimmune" diseases, such as 
systemic lupus erythematosus, type I diabetes 
mellitus, and rheumatoid arthritis, resulting in 
inexorable destruction of particular organs and 
tissues. The mechanisms that maintain self- 
tolerance in healthy individuals, and the factors 
that lead to its breakdown in autoimmune dis- 
ease, are the main focus of our laboratory. 
It has been theorized for many decades that 
self-tolerance might somehow result from the si- 
lencing or elimination of lymphocytes bearing 
antigen receptors that happen to recognize self 
antigens. To determine whether this idea was 
correct, however, has been difficult, since it is 
almost impossible to track the life of any one cell 
among millions. 
Advances in biotechnology, in particular the 
advent of transgenic mice, have opened doors to 
the development of ways to follow the life of par- 
ticular immune cells in vivo. Transgenic mice 
are genetically altered at the outset of embryonic 
development by microinjecting carefully de- 
signed cassettes (transgenes) into fertilized oo- 
cytes. With colleagues in the laboratory of Antony 
Basten at the University of Sydney, we produced 
transgenic mice in which most of the B lympho- 
cytes expressed identical, rather than widely dif- 
fering, antigen receptors. 
This was done by introducing transgenes that 
coded for a single antibody molecule (since anti- 
body molecules serve as antigen receptors on B 
lymphocytes) . The particular molecule was one 
that recognized and bound a foreign protein, hen 
egg-white lysozyme, and because the transgene 
was expressed in essentially all the B lympho- 
cytes, they all now recognized lysozyme in an 
identical fashion. 
The extraordinary abundance of lysozyme- 
binding B cells in the transgenic mice has made it 
possible to track the development and fate of 
these cells in the body. To determine the fate of B 
cells that might happen to recognize a self anti- 
gen rather than a foreign one, we prepared addi- 
tional transgenic mice in which transgene cas- 
settes led to the synthesis and production of 
lysozyme by the mouse itself. When the two types 
of mice are mated, a fraction of their offspring 
inherit both types of transgene and thus contain 
large numbers of lysozyme-binding B cells that 
encounter lysozyme expressed as if it were a nor- 
mal self constituent. 
The self-reactive B cells that develop in these 
mice undergo one of three distinct fates. First, if 
lysozyme is present at too low a concentration or 
it binds to the B cell's receptors with too low an 
affinity, no signal is registered by the cell. As a 
result, the B cells are neither activated nor ren- 
dered tolerant but remain fully capable of mount- 
ing an antibody response if they receive a 
stronger stimulus subsequently. Second, when 
higher concentrations of soluble lysozyme are 
bound with sufficient affinity, the B cells con- 
tinue to follow their normal maturation program 
but store some sort of negative signal, such that 
they are unable to mount an antibody response 
when stimulated to do so. Third, if lysozyme is 
encountered in a form where it is displayed on 
cell surfaces, and thus bound by the B cell with 
extremely high avidity, developing B cells in the 
bone marrow are triggered to abort their matura- 
tion program and die. 
These distinct cellular events help to explain 
the long-standing observation that self-tolerance 
is an actively acquired but incomplete process 
and suggest a number of possible avenues along 
which autoimmunity may ultimately develop. 
For example, our laboratory has found that toler- 
ant B cells that have stored a negative signal can 
nevertheless recover the ability to mount an effi- 
cient antibody response. Recovery of function 
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