has begun to analyze the first lines of transgenic 
mice where lysozyme expression should be targeted 
to the thyroid gland. (This project has been sup- 
ported by a grant from the National Institutes of 
Health.) 
Dr. Goodnow is also Assistant Professor of Mi- 
crobiology and Immunology at Stanford Univer- 
sity School of Medicine. 
Articles 
Basten, A., Brink, R., Peake, P., Adams, E., Crosbie, 
J., Hartley, S., and Goodnow, C.C. 1991. Self 
tolerance in the B-cell repertoire. Immunol Rev 
122:5-19. 
Goodnow, C.C. 1992. Safe havens for self-reactive 
cells. Cwrr5/o/ 2:417-419. 
Goodnow, C.C. 1992. Transgenic mice and analy- 
sis of B-cell tolerance. Annu Rev Immunol 
10:489-518. 
Hartley, S.B., Crosbie, J., Brink, R., Kantor, A.B., 
Basten, A., and Goodnow, C.C. 1991. Elimina- 
tion from peripheral lymphoid tissues of self- 
reactive B lymphocytes recognizing membrane- 
bound antigens. Nature 353:765-769. 
Mason, D.Y., Jones, M., and Goodnow, C.C. 1992. 
Development and follicular localization of toler- 
ant B lymphocytes in lysozyme/anti-Iysozyme 
IgM/IgD transgenic mice. Int Immunol 4:163- 
175. 
MODELS OF COMPLEMENT RECEPTOR AND REGULATORY PROTEIN FUNCTION 
V. Michael Holers, M.D., Assistant Investigator 
Complement proteins and their activation frag- 
ments play a central role in host defense against for- 
eign antigens. Fragments of activated complement 
bound to targets mediate their attachment by spe- 
cific receptors to cells of the immune system. Sec- 
ondary effects on cells bound by these targets via 
complement receptors include changes in intracel- 
lular calcium, phosphorylation of specific sub- 
strates, cell adhesion, and the transcriptional activa- 
tion state of specific genes. 
Fragments of activated complement may also de- 
posit randomly on self membranes rather than on 
desired targets. To protect against this, intrinsic cell 
membrane proteins have evolved with a primary 
role of inactivating these self membrane-bound 
fragments. 
Complement receptors and membrane regulatory 
proteins that mediate both attachment of comple- 
ment-bound targets and the control of inappropriate 
deposition are pan of a large family called the regu- 
lators of complement activation (RCA). The genes 
encoding this protein family are found at a single 
locus on human chromosome lq32. The structure 
of the members of this family consists of a related 
60- to 70-amino acid repeat, designated a short 
consensus repeat, containing four conserved cys- 
teines and one conserved tryptophan. Analysis of the 
genomic structures of this family has suggested deri- 
vation from a common element. 
Currently both the structure-function relation- 
ships of these proteins and the phenotypic changes 
resulting from the attachment of complement- 
bound fragments to their receptors on cells of the 
immune system are being investigated. Dr. Holers 
has concentrated most of his efforts during the past 
three years on human complement receptor 2 
(CR2) , which is the receptor for a complement com- 
ponent C3 fragment designated C3d, in addition to 
being the receptor for the Epstein-Barr virus (EBV) . 
More recently Dr. Holers has begun to establish 
mouse models of RCA protein family activities in 
order to study their roles in specific immune re- 
sponses. 
Human CR2 
Human CR2 is an ~ 145-kDa B cell receptor con- 
sisting structurally of 15 or 16 short consensus re- 
peats followed by transmembrane and short intracy- 
toplasmic domains. Recently Dr. Holers has focused 
on two areas in regard to CR2. First, the structural 
determinants on the molecule that mediate binding 
to C3 and EBV are being probed by a combination of 
mutagenesis and peptide-based methods. Using 
these techniques, he has identified a number of 
peptide sequences in CR2 that are likely to be con- 
tact sites for C3 and EBV binding. (This project is 
supported by funds from the National Institutes of 
Health.) 
Dr. Holers is also studying the ability of CR2 to 
regulate cell-cell adhesion when bound by its li- 
gands. He is determining the structural characteris- 
tics of CR2 that influence its ability to mediate this 
type of adhesion. In addition, he is analyzing the 
signaling pathways involved. His studies suggest 
IMMUNOLOGY 333 
