|
Chris Karp talks with
ScienceWatch.com and answers a few questions about
this month's Fast Breaking Paper Paper in the field of
Immunology.
|
|
Article Title: Allergenicity resulting from functional
mimicry of a Toll-like receptor complex protein
Authors: Trompette, A;Divanovic, S;Visintin, A;Blanchard,
C;Hegde, RS;Madan, R;Thorne, PS;Wills-Karp, M;Gioannini,
TL;Weiss, JP;Karp, CL
Journal: NATURE, Volume: 457, Issue: 7229, Page: 585-U9, Year:
JAN 29 2009
* Childrens Hosp, Med Ctr, Div Mol Immunol, Cincinnati, OH
45229 USA.
* Childrens Hosp, Med Ctr, Div Mol Immunol, Cincinnati, OH
45229 USA.
(addresses have been truncated.)
|
|
Why do you think your paper is highly
cited?
I think that there are several possible interlinked reasons. Firstly, the
general underlying biological problem is one that has been fairly
intractable to investigation—what the molecular underpinnings of
allergenicity are; that is, why specific, otherwise apparently innocuous
proteins are recognized in a maladaptive way by the adaptive immune systems
of many people.
Secondly, the mechanism defined for the allergen studied in this paper, the
major dust mite allergen, is particularly satisfying—functional
mimicry by Der p 2 of a lipid-binding member of an innate immune signaling
complex protein.
|
"We and others are very interested in further defining
the molecular mechanisms underlying activation of the
innate immune system by allergens."
|
Thirdly, there may well be a generality to the findings. Other members of
this family of proteins are major allergens; more generally, as most
defined major allergens are thought to be lipid-binding proteins, there is
a strong suggestion that intrinsic adjuvant activity by such proteins and
their accompanying lipid cargo may have some generality as a mechanism
underlying the phenomenon of allergenicity.
Would you summarize the significance of your paper
in layman's terms?
There is an ongoing epidemic of allergic asthma, particularly in countries
throughout the Western world. Allergy, and allergic asthma, occurs when a
particular kind of immune response, harmful to the responding host, is made
against specific proteins (allergens). Allergic people tend to mount these
harmful immune responses against the identical, otherwise innocuous,
proteins.
Why these particular proteins tend to be targets of such immune responses
has largely been unclear. The studies reported in this paper suggest that
the major allergen from dust mites, Der p 2, drives activation of immune
responses because it is a functional mimic of a host protein whose role is
to facilitate activation of the immune system.
How did you become involved in this research, and
were there any problems along the way?
It was something of an "aha" moment. I was at a toll-like receptors (TLR)
meeting in Taormina, Sicily to present data on an endogenous inhibitor of
TLR signaling—RP105. During the conference, Nick Gay, a superb
structural biologist from Cambridge, gave a presentation in which, after
lamenting the current lack of any crystal structure for a TLR, or the TLR4
helper molecule MD-2, he modeled MD-2 based on a solved crystal
structure—Der p.
Well primed—both by the work of my wife (Marsha Wills-Karp) on asthma
pathogenesis as well as by my work on lipopolysaccharides (LPS) signaling
and my interest in the hygiene hypothesis—I put a very talented
person in the lab (Aurelien Trompette) to work on determining whether the
structural similarities between MD-2 and Der p 2 were matched by functional
similarities.
Where do you see your research leading in the
future?
We and others are quite interested in further defining the molecular
mechanisms underlying activation of the innate immune system by allergens.
The clear hope is that a better molecular understanding will lead to novel
preventive and therapeutic approaches to allergic asthma and other allergic
diseases.
Christopher Karp, M.D.
Gunnar Esiason/Cincinnati Bell Professor
Director, Division of Molecular Immunology
Cincinnati Children's Hospital Medical Center
And the University of Cincinnati College of Medicine
Cincinnati, OH, USA
Web |
Web
KEYWORDS: TLR4-MD-2 COMPLEX; CRYSTAL-STRUCTURE; ALLERGIC DISEASE; CELL
ACTIVATION; ENDOTOXIN; MD-2; ASTHMA; LIPOPOLYSACCHARIDE; RESPONSES;
EXPOSURE.
