Researchers at the University of California, San Diego School of Medicine, with collaborators in Korea and Scotland, have identified a
novel signaling pathway critical to the immune response of cells
associated with the initiation of allergic asthma.. With molecular target found comes possibility of new therapies for millions of Americans.
The discovery, they
say, could point the way to new therapies that suppress the inflammatory
allergic response, offering potential relief to millions of Americans
with the chronic lung condition and potentially other allergic diseases.The results are published in the January 19 online Early Edition of the Proceedings of the National Academy of Sciences.
Specifically, the scientists demonstrated that T helper 2 (Th2) type
inflammation in allergic asthma involves dendritic cells (DC), a type of
white blood cell, which trigger a reduction in the production of cyclic
AMP or cAMP, a key messenger molecule for signaling inside cells. In
mouse models, deletion of the gene that codes for a protein that
promotes the production of cAMP resulted in spontaneous bronchial
asthma, which shares many similarities with human asthma. Conversely,
increasing cAMP levels inhibited the cells’ inflammatory response that
results in asthma’s characteristic symptoms.
“These findings and the related mechanism are very different from the
current residing view of activation of specific T helper cell
responses,” said principal investigator Eyal Raz, MD, professor of
medicine.
“The role of cAMP formation and action in dendritic cells in the
induction of allergic response was really surprising,” added co-author
Paul Insel, MD, professor of pharmacology and medicine. “It suggested to
us that this signaling pathway is involved in other immune-related
functions.”
The immune response of humans, mice and other vertebrates consists of
two fundamental components. The first is the innate immune system,
which recognizes and responds to pathogens in an immediate, but
generalized, way and does not confer long-lasting immunity. The second
is the adaptive immune system in which highly specialized T and B cells
eliminate or prevent pathogen growth – and create immunological memory
in case of future encounters with the same pathogen.
Th2 immunity is one of two major aspects of adaptive immunity. Th1
responses target intracellular pathogens, such as viruses and bacteria
that have invaded host cells. The Th2 response is more effective against
extracellular pathogens (such as bacteria, parasites and toxins that
operate outside of cells) and also plays a major role in allergic
reactions and related diseases.
Allergic asthma is triggered by inhaled allergens, such as pet
dander, pollen, mold and dust mites. It is characterized by inflammation
and narrowing of the airways, resulting in wheezing, chest tightness,
shortness of breath, coughing and other symptoms. The common form of
allergic asthma is associated with an exaggerated Th2 immune response.
Allergic asthma affects people of all ages, most often appearing in
childhood. More than 25 million Americans suffer from the condition.
“This research will open a new field of exploration of DC-related
molecules as mediators that influence Th2 induction and Th2 ‘bias,’”
said Jihyung Lee, PhD, a post-doctoral fellow and first author of the
study. “We have already identified some of these molecules. Others are
under investigation and we hope to identify them in the near-future.”
Co-author Nicholas Webster, PhD, professor of medicine and a member
of the Veteran’s Affairs San Diego Healthcare System, said “such
molecules or ones that mimic or block them might be used as novel
therapeutics of allergic and asthmatic diseases.” Raz noted that the
genetic mouse model developed for the research shares multiple
similarities with human allergic asthma, “We are quite optimistic the
mice will reveal additional, novel insights into human allergy,” he
said.
Other co-authors include Xiangli Li, Sara S. Choi, David H. Broide,
Maripat Corr and Jongdae Lee, UCSD Department of Medicine; Tae Hoon Kim,
UCSD Department of Medicine and Korea University and Fiona Murray, UCSD
Department of Medicine and University of Aberdeen.
Funding for this research came, in part, from the National Institutes
of Health (grants HD12303, CA23100, DK063491, AI38425, AI70535,
AI72115, AI095623, AI0177989), VA grant I01BX000130 and the Crohn’s and
Colitis Foundation of America.