Mark J. Shlomchik talks with
ScienceWatch.com and answers a few questions about
this month's New Hot Paper in the field of
Toll-like receptor 7 and TLR9
dictate autoantibody specificity and have opposing
inflammatory and regulatory roles in a murine model of
Authors: Christensen, SR, et al.
Year: SEP 2006
* Yale Univ, Sch Med, Immunol Sect, 333 Cedar St, New
Haven, CT 06510 USA.
* Yale Univ, Sch Med, Immunol Sect, New Haven, CT 06510
(addresses have been truncated)
Why do you think your paper is highly cited? Does
it describe a new discovery, methodology, or synthesis of
This paper by Christensen et al. is highly cited because it is the
first to comprehensively evaluate the roles of
Toll-like receptors (TLRs) in the regulation of
systemic autoimmunity in a well-characterized murine model. It has long
been known that DNA- and RNA-containing molecules are dominant
self-antigens in lupus. This is the basis of the classic anti-nuclear
antibody (ANA) reaction, a sine qua non of lupus.
However, the reason for the dominant targeting of these autoantigens was
not known. In vitro work had suggested that TLRs that recognize
nucleic acids, particularly TLR9 that recognizes DNA and TLR7 that
recognizes RNA, might be important. Conventionally these TLRs were thought
to recognize pathogen-associated forms of these nucleic acids, but we
postulated that in autoimmunity they might recognize “self”
forms of these molecules.
Would you summarize the significance of your paper
in layman’s terms?
future, we will want to determine
if TLR7 and TLR9 are the only
receptors involved in
We crossed “knockout” alleles of TLR7 and TLR9 onto the
lupus-prone genetic background strain MRL.Faslpr. These mice normally make
both anti-DNA and anti-RNA autoantibodies. When we made the mutant alleles
homozygous, we found that anti-DNA type autoantibodies were absent in the
TLR9-deficient mice while anti-RNA type autoantibodies were missing in the
TLR7-deficient mice. This directly established the roles of these two TLRs
in the generation of humoral autoimmunity.
It might have been predicted that the absence of either TLR would also
ameliorate disease, given the entrenched idea that lupus is an
autoantibody-mediated disease, and indeed the lack of TLR7 led to reduced
pathology and immune activation. However, it turned out that the absence of
TLR9 actually exacerbated disease. This unexpected finding indicated that
TLR9 played a regulatory role, though the mechanism remains unclear.
Given that TLR7 and TLR9 are expressed in similar tissues and are thought
to signal via the same pathway, this divergence is even more intriguing.
The findings also had important clinical and drug-development implications,
indicating that targeting TLR9 alone for inhibition would not be an ideal
strategy. Indeed, a number of companies are developing TLR inhibitors to
treat autoimmune diseases including lupus, some of which are already in the
In general terms, this research helped us to understand why anti-nuclear
antibodies are made in lupus. It demonstrated that a part of the immune
system that was thought to detect bacteria and virus could be hijacked
during autoimmunity to signal an inappropriate immune reaction to
one’s own DNA and RNA. At the same time, it guided efforts to develop
drugs that would inhibit these same signals and suggested that if the
correct receptor were inhibited by such drugs, that lupus could be treated
How did you become involved in this research, and
were there any particular problems encountered along the way?
Our lab has had a longstanding interest in understanding how autoreactive B
cells are activated in systemic autoimmune diseases like lupus and also how
autoreactive B cells promote disease. Our interest in TLRs was sparked by
work of our collaborator Dr. Ann Marshak-Rothstein at Boston University,
who made the conceptual breakthrough that TLRs could be important. This
work used in vitro assays of autoreactive B cells, focusing on
autoreactive B cells that our lab had studied intensively. Since our lab is
very adept at in vivo models and disease assessment, we decided to
take the next step of investigating “knockouts” of TLRs in
murine models of lupus.
Where do you see your research leading in the
In the future, we will want to determine if TLR7 and TLR9 are the only
receptors involved in lupus. In addition, there could be other so-called
“innate immune receptors” that could be involved in this or
other autoimmune diseases. A number of groups are now working on these
issues. We also want to determine how TLR9 functions as a negative
regulator of disease. Key to this will be to understand in which cell types
TLR9 and TLR7 function and what the consequences are of their signaling.
This will require more complex genetic approaches that we are now
Mark Shlomchik, M.D., Ph.D.
Professor of Laboratory Medicine and Immunobiology
Yale University School of Medicine
New Haven, CT, USA