Mechanisms of Immunological Self-Tolerance 
and Autoimmunity 
Christopher C. Goodnow, 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 Uni- 
versity, he returned to the University of Sydney to complete doctoral and postdoctoral studies on immu- 
nological 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-toler- 
ance in healthy individuals, and the factors that 
lead to its breakdown in autoimmune disease, 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 gene cassettes (transgenes) into fertilized 
oocytes. With colleagues in the laboratory of An- 
tony Basten at the University of Sydney, we pro- 
duced transgenic mice in which most of the B 
lymphocytes expressed identical, rather than 
widely differing, 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. In this particular case, 
where lysozyme is free in solution in the blood- 
stream, the B cells are indeed profoundly si- 
lenced, much as was predicted decades before. 
Precise alterations in the design of the intro- 
duced cassettes are allowing us to build upon this 
model and explore the details of the normal pro- 
cess of self-tolerance. In one striking example, 
where lysozyme has been restructured so that it 
remains bound to cell membranes of transgenic 
animals rather than free in the blood, we find that 
lysozyme-binding B cells are not only function- 
ally silenced but are in fact completely elimi- 
nated from the sites in lymphoid organs where 
immune responses are normally mounted. This 
finding points to important differences in the way 
the immune system tolerates different classes of 
self antigens in the body. We are planning to ex- 
tend this approach to other important classes of 
self antigen by constructing additional strains of 
transgenic mice. 
Another approach to understanding the process 
of self-tolerance in B lymphocytes makes use of 
the different forms of antibody, such as the immu- 
noglobulins IgM, IgD, and IgG, which are differ- 
entially used as antigen receptors by B lympho- 
cytes at distinct stages in their life span. By 
redesigning the antibody transgenes, we are 
currently comparing the behavior of B cells ex- 
pressing these different receptor isotypes either 
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